Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | ClinVar | gnomAD | ESM1b | AlphaMissense | REVEL | PSMutPred | FoldX | Rosetta | Foldetta | PremPS | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | DOI | ||||||||||||||||||||||||||||||||||||||
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| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Score | Prediction | IP RF | SP RF | Prediction | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | 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.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 | 0.884 | Likely Pathogenic | 0.1087 | 0.4777 | 3.69 | Destabilizing | 0.2 | 5.41 | Destabilizing | 4.55 | Destabilizing | 0.53 | Ambiguous | -7.66 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.56 | Benign | 0.00 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||
| 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 | 0.442 | Likely Benign | 0.2961 | 0.2209 | 3.10 | Destabilizing | 0.7 | 2.85 | Destabilizing | 2.98 | Destabilizing | 1.11 | Destabilizing | -5.37 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.92 | Pathogenic | 0.02 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.835C>T | R279W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279W is listed in ClinVar with an uncertain significance (ClinVar ID 1204186.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining pathogenic‑predicating tools—FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently predict a deleterious impact. Uncertain or inconclusive results come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R279W, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | Uncertain | 1 | -11.417 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 0.485 | Likely Benign | 0.1200 | 0.2519 | 2.00 | Destabilizing | 0.8 | 1.47 | Ambiguous | 1.74 | Ambiguous | 0.80 | Ambiguous | -6.29 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.88 | Pathogenic | 0.00 | Affected | 3.39 | 18 | 2 | -3 | 3.6 | 30.03 | 270.0 | 38.3 | 0.1 | 0.0 | 0.3 | 0.0 | Uncertain | The guanidinium group of Arg279, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), can form hydrogen bond with the backbone carbonyl groups of nearby loop residues (e.g., Ser296, Ser331, and As332) and form salt bridges with the carboxylate groups of Asp330 and Asp332. In the WT simulations, Arg279 sporadically forms a salt bridge even with the carboxylate group of Glu613, loosely connecting the C2 domain and GAP domain. Meanwhile, the indole ring of the Trp279 side chain is unable to hydrogen bond with the loop residues in the variant simulations. The lack of hydrogen bond or salt bridge formation with the loop residues could be significant, as Arg279 and the loops face the polar head group region of the membrane. Thus, although Trp279 could interact with the membrane surface as a “lipid anchor,” any changes to the wider loop dynamics could still adversely affect the formation of a stable SynGAP-membrane association. However, no definite conclusions on the effect of the residue swap on the SynGAP-membrane association can be drawn from solvent-only simulations. | |||||||||||||
| c.836G>A | R279Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279Q is reported in gnomAD (ID 6‑33437741‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect are SIFT and AlphaMissense‑Optimized; those that agree on a pathogenic effect are SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of reliable predictors (nine pathogenic vs two benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | 6-33437741-G-A | 6 | 3.72e-6 | -8.730 | Likely Pathogenic | 0.761 | Likely Pathogenic | Likely Benign | 0.554 | Likely Pathogenic | 0.2680 | 0.1792 | 1.37 | Ambiguous | 0.1 | 0.88 | Ambiguous | 1.13 | Ambiguous | 1.35 | Destabilizing | -2.61 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.94 | Pathogenic | 0.06 | Tolerated | 3.39 | 18 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||
| 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 | 0.626 | Likely Pathogenic | 0.2179 | 0.3281 | 1.42 | Ambiguous | 0.9 | 4.27 | Destabilizing | 2.85 | Destabilizing | 1.21 | Destabilizing | -5.01 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.836G>T | R279L 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R279L is reported in gnomAD (ID 6‑33437741‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | 6-33437741-G-T | 1 | 6.20e-7 | -12.390 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 0.576 | Likely Pathogenic | 0.1682 | 0.3266 | 0.01 | Likely Benign | 0.2 | 0.14 | Likely Benign | 0.08 | Likely Benign | 0.39 | Likely Benign | -5.37 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.91 | Pathogenic | 0.03 | Affected | 3.39 | 18 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||
| c.1300G>A | V434I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434I (ClinVar ID 212346.0, status Uncertain) is present in gnomAD (ID 6‑33438205‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions or stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | Uncertain | 1 | 6-33438205-G-A | 1 | 6.19e-7 | -6.999 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.192 | Likely Benign | 0.0675 | 0.3415 | -0.04 | Likely Benign | 0.0 | 0.22 | Likely Benign | 0.09 | Likely Benign | 0.31 | Likely Benign | -0.82 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.53 | Benign | 0.18 | Tolerated | 3.37 | 29 | 4 | 3 | 0.3 | 14.03 | 246.7 | -27.7 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Benign | The iso-propyl side chain of Val434, located at the end of an α helix (res. Met414-Glu436), packs against hydrophobic residues in an interhelix space (e.g., Met430, Ala707, Leu711). In the variant simulations, the sec-butyl group of Ile434 is able to form the same hydrophobic interactions. Accordingly, the residue swap does not negatively affect the protein structure based on the simulations. | |||||||||
| c.1300G>C | V434L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools, Rosetta and AlphaMissense‑Default, give uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta, a protein‑folding stability method, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that V434L is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -8.697 | Likely Pathogenic | 0.477 | Ambiguous | Likely Benign | 0.225 | Likely Benign | 0.0895 | 0.3813 | -0.05 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.49 | Likely Benign | 0.20 | Likely Benign | -2.30 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.64 | Benign | 0.27 | Tolerated | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||
| 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 | 0.417 | Likely Benign | 0.0596 | 0.3391 | 3.64 | Destabilizing | 0.1 | 3.27 | Destabilizing | 3.46 | Destabilizing | 0.27 | Likely Benign | -3.93 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.44 | Benign | 0.04 | Affected | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||
| 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 | 0.592 | Likely Pathogenic | 0.1307 | 0.0741 | 3.26 | Destabilizing | 0.0 | 3.33 | Destabilizing | 3.30 | Destabilizing | 1.78 | Destabilizing | -5.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.38 | Benign | 0.13 | Tolerated | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||
| 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 | 0.238 | Likely Benign | 0.2338 | 0.2292 | 1.72 | Ambiguous | 0.0 | 2.51 | Destabilizing | 2.12 | Destabilizing | 1.00 | Destabilizing | -2.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.58 | Benign | 0.75 | Tolerated | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||
| 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 | 0.564 | Likely Pathogenic | 0.1758 | 0.2408 | 3.08 | Destabilizing | 0.0 | 4.37 | Destabilizing | 3.73 | Destabilizing | 1.91 | Destabilizing | -5.16 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.39 | Benign | 0.07 | Tolerated | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.634T>A | S212T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S212T is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With most evidence pointing to deleterious effects and no conflicting ClinVar annotation, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -11.473 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 0.767 | Likely Pathogenic | 0.1077 | 0.6284 | 0.32 | Likely Benign | 0.2 | 2.03 | Destabilizing | 1.18 | Ambiguous | 0.58 | Ambiguous | -2.58 | Deleterious | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 5.79 | Benign | 0.01 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.634T>C | S212P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX and FATHMM, whereas the remaining tools—REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic. High‑accuracy methods give consistent pathogenic results: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. With the overwhelming majority of tools supporting pathogenicity and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -13.051 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.809 | Likely Pathogenic | 0.1859 | 0.5679 | 0.02 | Likely Benign | 0.9 | 6.30 | Destabilizing | 3.16 | Destabilizing | 0.90 | Ambiguous | -4.13 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 5.75 | Benign | 0.01 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||
| c.634T>G | S212A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212A has no ClinVar record and is not listed in gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, PROVEAN, and FATHMM, while pathogenic predictions arise from REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts benign stability. Overall, the majority of conventional tools lean toward pathogenicity, whereas the most reliable high‑accuracy methods are either benign or inconclusive. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -8.890 | Likely Pathogenic | 0.869 | Likely Pathogenic | Ambiguous | 0.752 | Likely Pathogenic | 0.4639 | 0.4509 | -0.13 | Likely Benign | 0.1 | 0.13 | Likely Benign | 0.00 | Likely Benign | 0.75 | Ambiguous | -2.48 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 5.83 | Benign | 0.01 | Affected | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||
| c.635C>A | S212Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212Y is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include FoldX, FATHMM, and premPS. In contrast, a majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, is inconclusive for this variant. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence from multiple in silico predictors indicates that S212Y is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -14.812 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.819 | Likely Pathogenic | 0.0555 | 0.6120 | 0.43 | Likely Benign | 0.5 | 2.32 | Destabilizing | 1.38 | Ambiguous | 0.22 | Likely Benign | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||
| c.635C>G | S212C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include FoldX, premPS, and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are inconclusive are Rosetta and Foldetta. The high‑accuracy consensus methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -11.656 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.840 | Likely Pathogenic | 0.0785 | 0.6270 | 0.16 | Likely Benign | 0.1 | 0.98 | Ambiguous | 0.57 | Ambiguous | 0.47 | Likely Benign | -4.29 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 5.73 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.635C>T | S212F 2D  AIThe SynGAP1 missense variant S212F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and premPS, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) predict a pathogenic outcome. The remaining tools, Foldetta and Rosetta, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall consensus of the majority of predictors and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -14.029 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.820 | Likely Pathogenic | 0.0503 | 0.6259 | 0.11 | Likely Benign | 1.6 | 0.88 | Ambiguous | 0.50 | Ambiguous | -0.02 | Likely Benign | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||
| c.637A>C | I213L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I213L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all classify the variant as benign, while AlphaMissense‑Default predicts it as pathogenic and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a benign effect. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the collective evidence, and this benign prediction 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. | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -7.673 | In-Between | 0.577 | Likely Pathogenic | Likely Benign | 0.489 | Likely Benign | 0.0771 | 0.2857 | 0.29 | Likely Benign | 0.4 | 0.20 | Likely Benign | 0.25 | Likely Benign | 0.45 | Likely Benign | -1.45 | Neutral | 0.447 | Benign | 0.177 | Benign | 5.89 | Benign | 0.18 | Tolerated | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.637A>G | I213V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I213V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta’s stability analysis is uncertain. Overall, the evidence strongly favors a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -6.133 | Likely Benign | 0.364 | Ambiguous | Likely Benign | 0.413 | Likely Benign | 0.1008 | 0.2959 | 0.67 | Ambiguous | 0.2 | 0.58 | Ambiguous | 0.63 | Ambiguous | 0.47 | Likely Benign | -0.69 | Neutral | 0.128 | Benign | 0.048 | Benign | 5.82 | Benign | 0.10 | Tolerated | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||
| 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 | 0.815 | Likely Pathogenic | 0.0473 | 0.2560 | 0.96 | Ambiguous | 0.7 | 2.66 | Destabilizing | 1.81 | Ambiguous | 0.73 | Ambiguous | -3.30 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.79 | Benign | 0.01 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.638T>A | I213N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I213N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; FoldX is uncertain and is treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -15.069 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.862 | Likely Pathogenic | 0.0750 | 0.0412 | 1.71 | Ambiguous | 0.8 | 2.81 | Destabilizing | 2.26 | Destabilizing | 1.85 | Destabilizing | -5.81 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.83 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.638T>C | I213T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I213T missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining evidence—SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently indicates pathogenicity. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence supports a pathogenic classification for I213T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -11.080 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.882 | Likely Pathogenic | 0.0905 | 0.0708 | 1.46 | Ambiguous | 0.8 | 1.32 | Ambiguous | 1.39 | Ambiguous | 1.49 | Destabilizing | -3.99 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.82 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.638T>G | I213S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I213S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -12.858 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.879 | Likely Pathogenic | 0.2290 | 0.0800 | 2.00 | Destabilizing | 1.1 | 2.95 | Destabilizing | 2.48 | Destabilizing | 1.53 | Destabilizing | -4.88 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.83 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||
| c.639C>G | I213M 2D  AIThe SynGAP1 missense variant I213M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are PROVEAN and FATHMM, while a larger group—REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) return uncertain or inconclusive results and are therefore treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -10.777 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.680 | Likely Pathogenic | 0.0611 | 0.2524 | 0.66 | Ambiguous | 0.5 | 1.58 | Ambiguous | 1.12 | Ambiguous | 0.85 | Ambiguous | -2.31 | Neutral | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.85 | Benign | 0.01 | Affected | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||
| c.1222A>C | T408P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T408P is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. FoldX, premPS, and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie and thus unavailable; Foldetta remains uncertain. Overall, the majority of available predictions (six pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | -10.384 | Likely Pathogenic | 0.230 | Likely Benign | Likely Benign | 0.323 | Likely Benign | 0.1985 | 0.5779 | 1.08 | Ambiguous | 0.3 | 2.27 | Destabilizing | 1.68 | Ambiguous | 0.73 | Ambiguous | -4.19 | Deleterious | 0.998 | Probably Damaging | 0.963 | Probably Damaging | 4.07 | Benign | 0.05 | Affected | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||
| c.1222A>G | T408A 2D  AISynGAP1 missense variant T408A is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, a protein‑folding stability method, also predicts benign. Overall, the balance of evidence favors a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | Uncertain | 1 | -8.304 | Likely Pathogenic | 0.114 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.3970 | 0.4674 | 0.37 | Likely Benign | 0.6 | -0.06 | Likely Benign | 0.16 | Likely Benign | 0.72 | Ambiguous | -3.07 | Deleterious | 0.540 | Possibly Damaging | 0.131 | Benign | 4.16 | Benign | 0.14 | Tolerated | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||
| c.1222A>T | T408S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T408S is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, FoldX, Rosetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates benign stability. Consequently, the variant is most likely benign, and this prediction does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | -6.277 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.044 | Likely Benign | 0.3256 | 0.4767 | 0.10 | Likely Benign | 0.0 | 0.39 | Likely Benign | 0.25 | Likely Benign | 0.18 | Likely Benign | -1.48 | Neutral | 0.182 | Benign | 0.127 | Benign | 4.24 | Benign | 0.21 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.1223C>A | T408K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T408K is not listed in ClinVar (ClinVar ID None) and has no reported allele in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, SIFT, FATHMM, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default; premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign effect. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | -11.841 | Likely Pathogenic | 0.756 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | 0.1205 | 0.3384 | -0.44 | Likely Benign | 0.2 | 0.14 | Likely Benign | -0.15 | Likely Benign | 0.88 | Ambiguous | -3.79 | Deleterious | 0.851 | Possibly Damaging | 0.163 | Benign | 4.17 | Benign | 0.15 | Tolerated | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||
| c.1223C>G | T408R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T408R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The premPS score is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. With six benign versus seven pathogenic calls overall, the evidence is mixed, but the presence of two independent high‑accuracy benign predictions and the lack of ClinVar or gnomAD support suggests the variant is most likely benign, and this does not contradict any existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | -12.075 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.138 | Likely Benign | 0.1029 | 0.3180 | -0.48 | Likely Benign | 0.1 | -0.24 | Likely Benign | -0.36 | Likely Benign | 0.79 | Ambiguous | -4.06 | Deleterious | 0.991 | Probably Damaging | 0.645 | Possibly Damaging | 4.12 | Benign | 0.15 | Tolerated | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||
| c.1223C>T | T408I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T408I missense variant is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438128‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Tools with uncertain or mixed outputs are AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points toward a benign effect, and this conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | 6-33438128-C-T | 1 | 6.19e-7 | -10.023 | Likely Pathogenic | 0.542 | Ambiguous | Likely Benign | 0.131 | Likely Benign | 0.0905 | 0.6700 | -0.16 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.42 | Likely Benign | 0.38 | Likely Benign | -4.53 | Deleterious | 0.976 | Probably Damaging | 0.607 | Possibly Damaging | 4.08 | Benign | 0.05 | Affected | 3.38 | 28 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||
| c.1321G>A | V441I 2D AIThe SynGAP1 missense variant V441I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while only ESM1b predicts it as pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign stability. No contradictory evidence is present. Based on the collective predictions, the variant is most likely benign, and this conclusion does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -8.773 | Likely Pathogenic | 0.122 | Likely Benign | Likely Benign | 0.135 | Likely Benign | 0.0694 | 0.3412 | -0.24 | Likely Benign | 0.3 | 0.11 | Likely Benign | -0.07 | Likely Benign | 0.25 | Likely Benign | -0.82 | Neutral | 0.287 | Benign | 0.038 | Benign | 3.41 | Benign | 0.16 | Tolerated | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||
| c.1321G>C | V441L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V441L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the preponderance of evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -9.546 | Likely Pathogenic | 0.395 | Ambiguous | Likely Benign | 0.135 | Likely Benign | 0.0961 | 0.3881 | -0.43 | Likely Benign | 0.0 | 0.59 | Ambiguous | 0.08 | Likely Benign | 0.45 | Likely Benign | -2.27 | Neutral | 0.165 | Benign | 0.028 | Benign | 3.43 | Benign | 0.11 | Tolerated | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||
| c.1321G>T | V441F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V441F missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools lean toward a benign interpretation, and the high‑accuracy predictions are split but favor benign. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -13.519 | Likely Pathogenic | 0.653 | Likely Pathogenic | Likely Benign | 0.355 | Likely Benign | 0.0670 | 0.3269 | -0.26 | Likely Benign | 0.0 | 0.32 | Likely Benign | 0.03 | Likely Benign | 0.54 | Ambiguous | -4.22 | Deleterious | 0.992 | Probably Damaging | 0.658 | Possibly Damaging | 3.37 | Benign | 0.08 | Tolerated | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||
| c.1322T>A | V441D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V441D is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and Foldetta, whereas a majority of tools (SGM Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. FoldX and Rosetta are inconclusive, and AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show that the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while Foldetta predicts benign stability. Overall, the balance of evidence leans toward pathogenicity, 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 | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -15.392 | Likely Pathogenic | 0.934 | Likely Pathogenic | Ambiguous | 0.308 | Likely Benign | 0.1232 | 0.0698 | -0.57 | Ambiguous | 0.1 | 0.56 | Ambiguous | -0.01 | Likely Benign | 1.15 | Destabilizing | -6.07 | Deleterious | 1.000 | Probably Damaging | 0.959 | Probably Damaging | 3.38 | Benign | 0.10 | Tolerated | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||
| c.1322T>C | V441A 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V441A is listed in ClinVar as uncertain and is present in gnomAD (ID 6‑33438227‑T‑C). Consensus from most in silico predictors favors a benign effect: REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized all report benign. Pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and ESM1b, while premPS and AlphaMissense‑Default remain uncertain. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports benign. Overall, the preponderance of evidence points to a benign impact, aligning with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | Conflicting | 2 | 6-33438227-T-C | 3 | 1.86e-6 | -9.439 | Likely Pathogenic | 0.359 | Ambiguous | Likely Benign | 0.053 | Likely Benign | 0.2390 | 0.1800 | -0.14 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.10 | Likely Benign | 0.95 | Ambiguous | -2.92 | Deleterious | 0.513 | Possibly Damaging | 0.214 | Benign | 3.44 | Benign | 0.93 | Tolerated | 3.37 | 29 | 0 | 0 | -2.4 | -28.05 | 195.0 | 44.6 | 0.0 | 0.1 | 0.5 | 0.0 | X | X | Uncertain | The iso-propyl side chain of Val441, located on the outer surface of an α helix (res. Asn440-Thr458), does not interact with other residues in the WT simulations. In the variant simulations, the methyl side chain of Ala441 is similarly hydrophobic and does not form any interactions on the outer helix surface. Although the residue swap does not negatively affect the protein structure based on the simulations, it is noteworthy that the residue faces the RasGTPase interface. Thus, the effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||
| c.1322T>G | V441G 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V441G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions come from REVEL, FoldX, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; the remaining tools (Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized remains benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenic, and Foldetta is inconclusive. Taken together, the majority of evidence points to a benign effect, but the SGM Consensus and several individual pathogenic predictors introduce uncertainty. Therefore, the variant is most likely benign based on the overall prediction landscape, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -12.380 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.273 | Likely Benign | 0.1664 | 0.1715 | 0.18 | Likely Benign | 0.0 | 1.25 | Ambiguous | 0.72 | Ambiguous | 0.95 | Ambiguous | -5.88 | Deleterious | 0.841 | Possibly Damaging | 0.997 | Probably Damaging | 3.41 | Benign | 0.24 | Tolerated | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.2008C>A | L670M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L670M occurs in the GAP domain. ClinVar contains no entry for this variant, but it is present in gnomAD (ID 6‑33441267‑C‑A). Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, Foldetta, and the SGM‑Consensus score (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; Rosetta gives an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | 6-33441267-C-A | 2 | 1.24e-6 | -9.438 | Likely Pathogenic | 0.125 | Likely Benign | Likely Benign | 0.038 | Likely Benign | 0.0826 | 0.3849 | -0.11 | Likely Benign | 0.0 | 0.70 | Ambiguous | 0.30 | Likely Benign | 0.06 | Likely Benign | -0.16 | Neutral | 0.970 | Probably Damaging | 0.777 | Possibly Damaging | 3.40 | Benign | 0.25 | Tolerated | 3.39 | 27 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||
| c.2008C>G | L670V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L670V 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score all indicate benign. Only ESM1b predicts pathogenicity, while FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta remains uncertain. Taken together, the overwhelming majority of evidence supports a benign interpretation, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | -9.829 | Likely Pathogenic | 0.113 | Likely Benign | Likely Benign | 0.025 | Likely Benign | 0.1558 | 0.4108 | 1.45 | Ambiguous | 0.1 | 1.05 | Ambiguous | 1.25 | Ambiguous | 0.15 | Likely Benign | -0.60 | Neutral | 0.127 | Benign | 0.023 | Benign | 3.67 | Benign | 0.74 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.2009T>A | L670Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670Q is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that are inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as Likely Benign, while Foldetta remains uncertain. Overall, the majority of available evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | -8.217 | Likely Pathogenic | 0.306 | Likely Benign | Likely Benign | 0.152 | Likely Benign | 0.1088 | 0.1303 | 1.02 | Ambiguous | 0.1 | 1.21 | Ambiguous | 1.12 | Ambiguous | 0.96 | Ambiguous | -1.12 | Neutral | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 3.40 | Benign | 0.36 | Tolerated | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.2009T>C | L670P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. Stability‑based methods are inconclusive: FoldX, Rosetta, and the combined Foldetta output are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar assertion; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | -4.916 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.211 | Likely Benign | 0.3590 | 0.1474 | 0.56 | Ambiguous | 0.3 | 1.83 | Ambiguous | 1.20 | Ambiguous | -0.25 | Likely Benign | 2.42 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.41 | Benign | 0.26 | Tolerated | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.2009T>G | L670R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign effect. There is no ClinVar annotation to contradict this assessment, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | -9.801 | Likely Pathogenic | 0.552 | Ambiguous | Likely Benign | 0.193 | Likely Benign | 0.1327 | 0.1145 | 0.64 | Ambiguous | 0.1 | 1.42 | Ambiguous | 1.03 | Ambiguous | 0.67 | Ambiguous | -1.74 | Neutral | 0.993 | Probably Damaging | 0.755 | Possibly Damaging | 3.43 | Benign | 0.41 | Tolerated | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||
| 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 | 0.589 | Likely Pathogenic | 0.1902 | 0.0212 | 4.26 | Destabilizing | 0.2 | 4.18 | Destabilizing | 4.22 | Destabilizing | 1.82 | Destabilizing | -8.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.95 | Pathogenic | 0.06 | Tolerated | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| 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 | 0.588 | Likely Pathogenic | 0.2021 | 0.0212 | 3.01 | Destabilizing | 0.3 | 2.58 | Destabilizing | 2.80 | Destabilizing | 1.95 | Destabilizing | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.94 | Pathogenic | 0.01 | Affected | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||
| c.838T>G | Y280D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -16.885 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.580 | Likely Pathogenic | 0.3593 | 0.0212 | 5.91 | Destabilizing | 0.2 | 5.89 | Destabilizing | 5.90 | Destabilizing | 2.00 | Destabilizing | -9.19 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.94 | Pathogenic | 0.02 | Affected | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.839A>C | Y280S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the substitution as pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -13.491 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.635 | Likely Pathogenic | 0.3993 | 0.1227 | 4.63 | Destabilizing | 0.3 | 4.80 | Destabilizing | 4.72 | Destabilizing | 2.03 | Destabilizing | -8.27 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.00 | Pathogenic | 0.05 | Affected | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| c.839A>G | Y280C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic or likely pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect on protein stability. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -10.645 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.629 | Likely Pathogenic | 0.2877 | 0.1296 | 3.85 | Destabilizing | 0.2 | 4.45 | Destabilizing | 4.15 | Destabilizing | 1.68 | Destabilizing | -8.24 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.96 | Pathogenic | 0.01 | Affected | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||
| c.839A>T | Y280F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—premPS, ESM1b, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive and therefore unavailable. Overall, the majority of available predictions favor a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -7.844 | In-Between | 0.414 | Ambiguous | Likely Benign | 0.544 | Likely Pathogenic | 0.2263 | 0.2398 | 0.49 | Likely Benign | 0.2 | 0.03 | Likely Benign | 0.26 | Likely Benign | 0.87 | Ambiguous | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.98 | Pathogenic | 0.02 | Affected | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||
| c.1369A>C | S457R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenic, whereas Foldetta’s stability analysis is uncertain. Overall, the majority of evidence points toward a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.468 | Likely Benign | 0.0781 | 0.3426 | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1369A>G | S457G 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S457G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S457G. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -9.154 | Likely Pathogenic | 0.811 | Likely Pathogenic | Ambiguous | 0.382 | Likely Benign | 0.2735 | 0.4074 | 0.86 | Ambiguous | 0.0 | 0.87 | Ambiguous | 0.87 | Ambiguous | 0.65 | Ambiguous | -3.82 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 3.35 | Benign | 0.13 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||
| c.1369A>T | S457C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S457C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, Foldetta, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give mixed results: AlphaMissense‑Optimized is inconclusive and therefore not used as evidence; the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign effect. Overall, the majority of individual predictors lean toward pathogenicity, while the high‑accuracy Foldetta result suggests benign stability. Given the predominance of pathogenic calls and the lack of ClinVar evidence, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -8.152 | Likely Pathogenic | 0.815 | Likely Pathogenic | Ambiguous | 0.497 | Likely Benign | 0.0865 | 0.6284 | -0.12 | Likely Benign | 0.0 | -0.79 | Ambiguous | -0.46 | Likely Benign | 0.56 | Ambiguous | -4.81 | Deleterious | 0.999 | Probably Damaging | 0.987 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.1370G>A | S457N 2D  AIThe SynGAP1 missense variant S457N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus methods give a mixed picture: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the majority of individual predictors lean toward pathogenicity, but the high‑accuracy Foldetta result suggests a benign impact. Thus, the variant is most likely pathogenic based on the preponderance of predictions, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | Uncertain | 1 | -10.221 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.241 | Likely Benign | 0.1015 | 0.4980 | 0.19 | Likely Benign | 0.0 | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.67 | Ambiguous | -2.76 | Deleterious | 0.940 | Possibly Damaging | 0.843 | Possibly Damaging | 3.28 | Benign | 0.06 | Tolerated | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||
| c.1370G>C | S457T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457T has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX and Rosetta provide uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicting likely pathogenic, and Foldetta predicting benign. Overall, the majority of high‑confidence tools lean toward a benign effect, and there is no conflict with the ClinVar status, which is currently unreported. Thus, the variant is most likely benign based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -8.772 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.273 | Likely Benign | 0.1154 | 0.6487 | 0.82 | Ambiguous | 0.1 | -0.57 | Ambiguous | 0.13 | Likely Benign | 0.38 | Likely Benign | -2.83 | Deleterious | 0.866 | Possibly Damaging | 0.780 | Possibly Damaging | 3.34 | Benign | 0.09 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.1370G>T | S457I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457I lies within the GAP domain. ClinVar has no entry for this change, and it is absent from gnomAD. Prediction tools that report a benign effect include FoldX and FATHMM, whereas the majority of other in silico predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized—classify it as pathogenic. Uncertain results come from Rosetta, Foldetta and premPS. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN) is Likely Pathogenic, and Foldetta remains inconclusive. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -13.170 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.557 | Likely Pathogenic | 0.0779 | 0.6095 | -0.26 | Likely Benign | 0.3 | -0.96 | Ambiguous | -0.61 | Ambiguous | 0.65 | Ambiguous | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.34 | Benign | 0.02 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||
| c.1371T>A | S457R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, SGM‑Consensus confirms a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence from multiple independent predictors indicates that S457R is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.343 | Likely Benign | 0.0781 | 0.3426 | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1371T>G | S457R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, SGM‑Consensus confirms a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence from multiple independent predictors indicates that S457R is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.343 | Likely Benign | 0.0781 | 0.3426 | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1483G>A | E495K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools with inconclusive results (Rosetta and premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also as pathogenic, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) indicates a benign effect. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect for E495K, which is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Uncertain | 1 | -11.478 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.869 | Likely Pathogenic | 0.1974 | 0.5039 | 0.15 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.41 | Likely Benign | 0.70 | Ambiguous | -3.91 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||
| c.1483G>C | E495Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E495Q missense variant is not listed in ClinVar and has no reported allele in gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, and Foldetta, all of which score the substitution as benign. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta predicts benign stability. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -11.050 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | 0.748 | Likely Pathogenic | 0.1093 | 0.4973 | -0.27 | Likely Benign | 0.1 | 0.11 | Likely Benign | -0.08 | Likely Benign | 0.89 | Ambiguous | -2.92 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.42 | Pathogenic | 0.01 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1484A>C | E495A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E495A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include FoldX, while the remaining evaluated algorithms (REVEL, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. No contradictory evidence is present from ClinVar or population databases. Overall, the preponderance of predictions supports a pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -9.229 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.834 | Likely Pathogenic | 0.2711 | 0.4259 | 0.42 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.64 | Ambiguous | 0.69 | Ambiguous | -5.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.38 | Pathogenic | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1484A>G | E495G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E495G missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438516‑A‑G). Among the available in‑silico predictors, the following tools uniformly indicate a pathogenic effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which itself is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a benign outcome; predictions that are uncertain (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Pathogenic,” and Foldetta as “Uncertain.” Overall, the preponderance of pathogenic predictions strongly suggests that the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Uncertain | 1 | 6-33438516-A-G | 1 | 6.20e-7 | -9.400 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 0.867 | Likely Pathogenic | 0.2177 | 0.4784 | 1.21 | Ambiguous | 0.0 | 2.06 | Destabilizing | 1.64 | Ambiguous | 0.78 | Ambiguous | -6.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.46 | Pathogenic | 0.02 | Affected | 3.37 | 35 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||
| c.1484A>T | E495V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495V is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence (10 pathogenic‑predicted tools versus 4 benign) indicates that E495V is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -12.031 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.887 | Likely Pathogenic | 0.0646 | 0.5457 | 0.43 | Likely Benign | 0.2 | -0.32 | Likely Benign | 0.06 | Likely Benign | 0.47 | Likely Benign | -6.83 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1485A>C | E495D 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant E495D is listed in ClinVar with an uncertain significance (ClinVar ID 2000233.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from SIFT and ESM1b, and pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN classifies the variant as likely pathogenic. AlphaMissense‑Optimized also predicts pathogenicity, whereas Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of deleterious impact. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Conflicting | 2 | -3.574 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.566 | Likely Pathogenic | 0.1778 | 0.3064 | 1.39 | Ambiguous | 0.1 | 1.03 | Ambiguous | 1.21 | Ambiguous | 0.98 | Ambiguous | -2.52 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 3 | 2 | 0.0 | -14.03 | 220.6 | 38.8 | 0.0 | 0.0 | 0.1 | 0.1 | X | X | Uncertain | Glu495 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighboring Lys492 and with Arg596 on an opposing α-helix (res. Glu582-Met603) in the WT simulations. In the variant simulations, the acidic carboxylate side chain of Asp495 can also form salt bridges with both Lys492 and Arg596. However, the shorter side chain of aspartate tends to favor forming a salt bridge with the nearby Arg499 on the same α-helix instead. Asp495 might not maintain the salt bridge with Arg596 on the opposing α-helix as efficiently as Glu495 in the WT, potentially weakening the tertiary structure. Regardless, the potential negative effect is likely to be minor, with no deleterious effects observed on the protein structure during the simulations. However, due to its location at the GAP-Ras interface, the effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1485A>T | E495D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495D is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from SIFT and ESM1b, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta provides no definitive stability change. Overall, the variant is most likely pathogenic based on the consensus of predictive algorithms, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -3.574 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.566 | Likely Pathogenic | 0.1778 | 0.3064 | 1.39 | Ambiguous | 0.1 | 1.03 | Ambiguous | 1.21 | Ambiguous | 0.98 | Ambiguous | -2.52 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 3 | 2 | 0.0 | -14.03 | 220.6 | 38.8 | 0.0 | 0.0 | 0.1 | 0.1 | X | X | Uncertain | Glu495 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighboring Lys492 and with Arg596 on an opposing α-helix (res. Glu582-Met603) in the WT simulations. In the variant simulations, the acidic carboxylate side chain of Asp495 can also form salt bridges with both Lys492 and Arg596. However, the shorter side chain of aspartate tends to favor forming a salt bridge with the nearby Arg499 on the same α-helix instead. Asp495 might not maintain the salt bridge with Arg596 on the opposing α-helix as efficiently as Glu495 in the WT, potentially weakening the tertiary structure. Regardless, the potential negative effect is likely to be minor, with no deleterious effects observed on the protein structure during the simulations. However, due to its location at the GAP-Ras interface, the effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||
| c.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 | 0.246 | Likely Benign | 0.1615 | 0.6238 | 1.37 | Ambiguous | 0.1 | 2.56 | Destabilizing | 1.97 | Ambiguous | 0.76 | Ambiguous | -6.12 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.57 | Pathogenic | 0.07 | Tolerated | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||
| c.1045C>G | P349A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM, with the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability or pathogenicity scores are available. Overall, the majority of evidence points to a pathogenic effect, and this assessment 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. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -8.663 | Likely Pathogenic | 0.202 | Likely Benign | Likely Benign | 0.257 | Likely Benign | 0.3789 | 0.5505 | 1.37 | Ambiguous | 0.0 | 1.68 | Ambiguous | 1.53 | Ambiguous | 0.76 | Ambiguous | -6.01 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||
| c.1045C>T | P349S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 P349S missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are FoldX, ESM1b, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools, including the high‑accuracy methods, predict a pathogenic effect. Thus, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | Uncertain | 1 | -7.654 | In-Between | 0.217 | Likely Benign | Likely Benign | 0.277 | Likely Benign | 0.3771 | 0.5756 | 1.92 | Ambiguous | 0.1 | 2.28 | Destabilizing | 2.10 | Destabilizing | 0.87 | Ambiguous | -6.13 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.66 | Pathogenic | 0.06 | Tolerated | 3.37 | 25 | 1 | -1 | 0.8 | -10.04 | 194.9 | -18.1 | -0.1 | 0.0 | 0.2 | 0.1 | X | X | Potentially Pathogenic | The cyclic pyrrolidine side chain of Pro349, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), allows the strand to end and make a tight turn before a short α helical section within a loop connecting to another β strand (res. Thr359-Pro364). In the variant simulations, the hydroxyl group of Ser349 forms a hydrogen bond with the backbone amide group of Ala351 in the short helical section. Conversely, the backbone amide group of Ser349 (absent in proline) does not form any intra-protein hydrogen bonds. However, the β strand end connects to the α helical section in a more stable and consistent manner compared to the WT. Although the residue swap does not cause major adverse effects on the protein structure in the simulations, it is possible that the tight turn at the β strand end could not be created during folding without the presence of proline. | ||||||||||||
| c.1046C>A | P349Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 P349Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Default, Foldetta) give uncertain or inconclusive results. High‑accuracy assessments further clarify the variant’s likely effect: AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -10.545 | Likely Pathogenic | 0.508 | Ambiguous | Likely Benign | 0.345 | Likely Benign | 0.1480 | 0.4766 | 0.98 | Ambiguous | 0.1 | 1.87 | Ambiguous | 1.43 | Ambiguous | 0.91 | Ambiguous | -6.40 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.54 | Pathogenic | 0.06 | Tolerated | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||
| c.1046C>G | P349R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349R is 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 majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Rosetta. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for P349R. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -14.001 | Likely Pathogenic | 0.791 | Likely Pathogenic | Ambiguous | 0.335 | Likely Benign | 0.1395 | 0.3009 | 0.99 | Ambiguous | 0.1 | 2.15 | Destabilizing | 1.57 | Ambiguous | 0.93 | Ambiguous | -7.22 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.55 | Pathogenic | 0.01 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||
| c.1046C>T | P349L 2D  AIThe SynGAP1 missense variant P349L is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized, whereas the majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy methods give conflicting results: AlphaMissense‑Optimized reports a benign outcome, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Other stability‑based predictors (FoldX, Rosetta, premPS) are also inconclusive. Overall, the preponderance of evidence from the consensus of multiple in‑silico tools points to a pathogenic effect for P349L. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -11.734 | Likely Pathogenic | 0.650 | Likely Pathogenic | Likely Benign | 0.326 | Likely Benign | 0.2222 | 0.6867 | 0.70 | Ambiguous | 0.6 | 1.17 | Ambiguous | 0.94 | Ambiguous | 0.57 | Ambiguous | -8.04 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| c.1600T>A | S534T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Thus, the overall evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -4.925 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.200 | Likely Benign | 0.1238 | 0.5064 | 0.10 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.28 | Likely Benign | 0.19 | Likely Benign | -2.42 | Neutral | 0.676 | Possibly Damaging | 0.933 | Probably Damaging | 3.32 | Benign | 0.07 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.1600T>C | S534P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534P is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438843‑T‑C). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy assessments are consistent with a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the aggregate predictions, the variant is most likely benign, which does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | Uncertain | 1 | 6-33438843-T-C | 3 | 1.86e-6 | -5.056 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.203 | Likely Benign | 0.2071 | 0.4650 | -0.40 | Likely Benign | 0.2 | 0.35 | Likely Benign | -0.03 | Likely Benign | 0.47 | Likely Benign | -3.81 | Deleterious | 0.993 | Probably Damaging | 0.993 | Probably Damaging | 3.32 | Benign | 0.05 | Affected | 3.37 | 35 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||
| c.1600T>G | S534A 2D 3DClick to see structure in 3D Viewer AISynGAP1 S534A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. No evidence suggests a deleterious effect. Therefore, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -4.691 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.163 | Likely Benign | 0.5042 | 0.3131 | Weaken | 0.01 | Likely Benign | 0.0 | -0.01 | Likely Benign | 0.00 | Likely Benign | 0.11 | Likely Benign | -1.70 | Neutral | 0.880 | Possibly Damaging | 0.994 | Probably Damaging | 3.36 | Benign | 0.42 | Tolerated | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||
| c.1601C>A | S534Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534Y has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, FATHMM, premPS, AlphaMissense‑Optimized, and Foldetta, while those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of tools (seven versus six) lean toward a pathogenic effect, and the high‑accuracy consensus is split, leaving the variant’s impact uncertain. Based on the aggregate predictions, the variant is most likely pathogenic, which does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -11.540 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | 0.314 | Likely Benign | 0.0629 | 0.5073 | -0.01 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.33 | Likely Benign | 0.46 | Likely Benign | -5.02 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||
| c.1601C>G | S534C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is uncertain, so both are treated as unavailable. No other high‑accuracy predictions are available. Overall, the evidence is evenly split between benign and pathogenic predictions, leaving the variant’s clinical significance inconclusive. There is no ClinVar status to contradict this balanced prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -8.077 | Likely Pathogenic | 0.247 | Likely Benign | Likely Benign | 0.308 | Likely Benign | 0.0984 | 0.4861 | 0.18 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.54 | Ambiguous | 0.56 | Ambiguous | -4.05 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||
| c.1601C>T | S534F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Tools with uncertain results are AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this is consistent with the lack of ClinVar evidence; thus the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -10.948 | Likely Pathogenic | 0.492 | Ambiguous | Likely Benign | 0.313 | Likely Benign | 0.0621 | 0.5379 | -0.03 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.43 | Likely Benign | 0.43 | Likely Benign | -5.09 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||
| c.1042G>A | V348M 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant V348M is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that report a clear outcome fall into two groups: benign calls come from REVEL, Foldetta, PROVEAN, and AlphaMissense‑Optimized; pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Default, ESM1b) give uncertain results, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority. High‑accuracy methods specifically show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus is not available. With four benign and four pathogenic predictions, the evidence is evenly split, providing no definitive direction. Therefore, the variant is not clearly benign or pathogenic based on current predictions, and this lack of consensus does not contradict its ClinVar uncertain status. 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 | Uncertain | 1 | -7.076 | In-Between | 0.546 | Ambiguous | Likely Benign | 0.191 | Likely Benign | 0.0903 | 0.4748 | -1.19 | Ambiguous | 0.1 | 0.72 | Ambiguous | -0.24 | Likely Benign | 0.76 | Ambiguous | -1.62 | Neutral | 0.966 | Probably Damaging | 0.564 | Possibly Damaging | 1.58 | Pathogenic | 0.03 | Affected | 3.37 | 25 | 2 | 1 | -2.3 | 32.06 | 253.8 | -47.4 | -0.3 | 0.1 | 0.2 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val348, located in an anti-parallel β sheet strand (res. Gly341-Pro349), packs against multiple hydrophobic C2 domain residues (e.g., Leu353, Leu323, Leu402). In the variant simulations, the thioether side chain of Met348 can form similar interactions as valine due to its comparable hydrophobic profile. In fact, the thioether group of methionine can even stack favorably with the phenol ring of Tyr363 in the anti-parallel β sheet strand (res. Ala399-Ile411). Overall, the residue swap does not appear to cause negative effects on the protein structure based on the simulations. | |||||||||||||
| c.1042G>C | V348L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No other high‑confidence tools provide conflicting evidence. Based on the preponderance of predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -4.842 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.1088 | 0.4953 | -0.58 | Ambiguous | 0.0 | 0.04 | Likely Benign | -0.27 | Likely Benign | 0.24 | Likely Benign | -0.75 | Neutral | 0.264 | Benign | 0.030 | Benign | 1.89 | Pathogenic | 0.62 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1042G>T | V348L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No other high‑confidence tools provide conflicting evidence. Based on the preponderance of predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -4.842 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.1088 | 0.4953 | -0.58 | Ambiguous | 0.0 | 0.04 | Likely Benign | -0.27 | Likely Benign | 0.24 | Likely Benign | -0.75 | Neutral | 0.264 | Benign | 0.030 | Benign | 1.89 | Pathogenic | 0.62 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1043T>A | V348E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348E 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) indicate pathogenicity. 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, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No prediction or stability result is 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 the ClinVar status, which currently has no entry for V348E. 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 | -11.135 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.470 | Likely Benign | 0.1089 | 0.1922 | 2.41 | Destabilizing | 0.1 | 2.20 | Destabilizing | 2.31 | Destabilizing | 2.14 | Destabilizing | -5.26 | Deleterious | 0.989 | Probably Damaging | 0.637 | Possibly Damaging | 1.56 | Pathogenic | 0.01 | Affected | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||
| 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 | 0.175 | Likely Benign | 0.3223 | 0.2437 | 2.46 | Destabilizing | 0.1 | 3.13 | Destabilizing | 2.80 | Destabilizing | 2.23 | Destabilizing | -3.42 | Deleterious | 0.622 | Possibly Damaging | 0.152 | Benign | 1.59 | Pathogenic | 0.14 | Tolerated | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||
| 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 | 0.419 | Likely Benign | 0.2229 | 0.2082 | 3.97 | Destabilizing | 0.2 | 5.70 | Destabilizing | 4.84 | Destabilizing | 2.23 | Destabilizing | -6.18 | Deleterious | 0.637 | Possibly Damaging | 0.989 | Probably Damaging | 1.56 | Pathogenic | 0.00 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1324A>C | K442Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K442Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -10.410 | Likely Pathogenic | 0.562 | Ambiguous | Likely Benign | 0.268 | Likely Benign | 0.3353 | 0.1014 | 0.05 | Likely Benign | 0.1 | 0.03 | Likely Benign | 0.04 | Likely Benign | 0.25 | Likely Benign | -3.10 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 3.39 | Benign | 0.18 | Tolerated | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||
| c.1324A>G | K442E 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K442E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split consensus: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized remains uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No single evidence decisively outweighs the others. Therefore, the variant’s pathogenicity remains uncertain; the predictions do not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -12.813 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 0.324 | Likely Benign | 0.2943 | 0.0789 | -0.05 | Likely Benign | 0.1 | -0.21 | Likely Benign | -0.13 | Likely Benign | 0.24 | Likely Benign | -3.34 | Deleterious | 0.997 | Probably Damaging | 0.966 | Probably Damaging | 3.47 | Benign | 0.16 | Tolerated | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1325A>C | K442T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K442T missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a benign stability change; AlphaMissense‑Optimized remains inconclusive. Overall, the predictions are evenly split, with no single consensus. Thus, the variant is most likely benign based on the majority of evidence, and this assessment does not contradict any ClinVar record (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -11.273 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.330 | Likely Benign | 0.1510 | 0.2859 | 0.30 | Likely Benign | 0.2 | 0.21 | Likely Benign | 0.26 | Likely Benign | 0.22 | Likely Benign | -5.01 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.43 | Benign | 0.07 | Tolerated | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.1325A>G | K442R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K442R is catalogued in gnomAD (ID 6‑33438230‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tools predicting a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies the variant as benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | 6-33438230-A-G | 1 | 6.20e-7 | -5.761 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.098 | Likely Benign | 0.3885 | 0.0778 | 0.13 | Likely Benign | 0.1 | 0.29 | Likely Benign | 0.21 | Likely Benign | 0.51 | Ambiguous | -1.42 | Neutral | 0.972 | Probably Damaging | 0.875 | Possibly Damaging | 3.46 | Benign | 0.35 | Tolerated | 3.37 | 29 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||
| c.1325A>T | K442I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K442I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy assessments are: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions, including the two high‑accuracy pathogenic calls, indicate a pathogenic impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -14.921 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.350 | Likely Benign | 0.0943 | 0.3073 | 0.16 | Likely Benign | 0.1 | -0.16 | Likely Benign | 0.00 | Likely Benign | 0.30 | Likely Benign | -6.91 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.02 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||
| c.1326A>C | K442N 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K442N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and the folding‑stability method Foldetta (which integrates FoldX‑MD and Rosetta outputs). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward pathogenicity, but the presence of several strong benign predictions and a benign folding‑stability result introduces uncertainty. Based on the current computational evidence, the variant is most likely pathogenic, and this 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 | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -11.039 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.161 | Likely Benign | 0.2686 | 0.1314 | 0.37 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.45 | Likely Benign | 0.31 | Likely Benign | -4.05 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.46 | Benign | 0.10 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1326A>T | K442N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K442N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and the folding‑stability method Foldetta (which integrates FoldX‑MD and Rosetta outputs). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward pathogenicity, but the presence of several strong benign predictions and a benign folding‑stability result introduces uncertainty. Based on the current computational evidence, the variant is most likely pathogenic, and this 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 | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -11.039 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.161 | Likely Benign | 0.2686 | 0.1314 | 0.37 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.45 | Likely Benign | 0.31 | Likely Benign | -4.05 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.46 | Benign | 0.10 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1366C>A | Q456K 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q456K is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; premPS and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of tools (six pathogenic vs five benign) and the SGM‑Consensus result point toward a pathogenic interpretation, while Foldetta suggests stability‑preserving benignity. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -13.768 | Likely Pathogenic | 0.806 | Likely Pathogenic | Ambiguous | 0.391 | Likely Benign | 0.1321 | 0.2547 | 0.21 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.22 | Likely Benign | 0.78 | Ambiguous | -3.75 | Deleterious | 0.969 | Probably Damaging | 0.875 | Possibly Damaging | 3.36 | Benign | 0.13 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||
| c.1366C>G | Q456E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remaining uncertain. Overall, the predictions are split, but the high‑accuracy consensus leans toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -12.982 | Likely Pathogenic | 0.503 | Ambiguous | Likely Benign | 0.233 | Likely Benign | 0.1191 | 0.1276 | 0.71 | Ambiguous | 0.1 | 0.87 | Ambiguous | 0.79 | Ambiguous | 0.65 | Ambiguous | -2.76 | Deleterious | 0.998 | Probably Damaging | 0.964 | Probably Damaging | 3.41 | Benign | 0.15 | Tolerated | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||
| c.1367A>C | Q456P 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q456P is listed in ClinVar with an uncertain significance (ClinVar ID 2697090.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. High‑accuracy methods specifically report pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, which contradicts the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | Uncertain | 1 | -15.250 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.469 | Likely Benign | 0.2256 | 0.3631 | 3.68 | Destabilizing | 0.2 | 8.43 | Destabilizing | 6.06 | Destabilizing | 0.82 | Ambiguous | -5.66 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.34 | Benign | 0.07 | Tolerated | 3.37 | 34 | -1 | 0 | 1.9 | -31.01 | |||||||||||||||||||||
| c.1367A>G | Q456R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta (a folding‑stability method combining FoldX‑MD and Rosetta outputs) predicts benign. No evidence from the data contradicts ClinVar status, which is currently unclassified. Based on the available predictions, the variant is most likely benign, though the evidence is conflicting and does not conflict with the lack of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -11.326 | Likely Pathogenic | 0.801 | Likely Pathogenic | Ambiguous | 0.295 | Likely Benign | 0.1241 | 0.1124 | 0.21 | Likely Benign | 0.1 | 0.12 | Likely Benign | 0.17 | Likely Benign | 0.33 | Likely Benign | -3.69 | Deleterious | 0.980 | Probably Damaging | 0.943 | Probably Damaging | 3.37 | Benign | 0.20 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||
| c.1367A>T | Q456L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation, with no evidence of contradiction with the ClinVar status. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -10.272 | Likely Pathogenic | 0.492 | Ambiguous | Likely Benign | 0.347 | Likely Benign | 0.0554 | 0.4317 | -0.88 | Ambiguous | 0.1 | -0.30 | Likely Benign | -0.59 | Ambiguous | 0.28 | Likely Benign | -6.65 | Deleterious | 0.987 | Probably Damaging | 0.914 | Probably Damaging | 3.49 | Benign | 0.36 | Tolerated | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||
| c.1368G>C | Q456H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the lack of ClinVar annotation. Thus, based on the available computational evidence, the variant is most likely benign, though a high‑accuracy consensus suggests a possible pathogenic effect that warrants further investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -7.993 | In-Between | 0.598 | Likely Pathogenic | Likely Benign | 0.214 | Likely Benign | 0.0987 | 0.2358 | 0.74 | Ambiguous | 0.1 | 0.39 | Likely Benign | 0.57 | Ambiguous | 0.32 | Likely Benign | -4.07 | Deleterious | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 3.37 | Benign | 0.19 | Tolerated | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||
| c.1368G>T | Q456H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the lack of ClinVar annotation. Thus, based on the available computational evidence, the variant is most likely benign, though a high‑accuracy consensus suggests a possible pathogenic effect that warrants further investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -7.993 | In-Between | 0.598 | Likely Pathogenic | Likely Benign | 0.214 | Likely Benign | 0.0987 | 0.2358 | 0.74 | Ambiguous | 0.1 | 0.39 | Likely Benign | 0.57 | Ambiguous | 0.32 | Likely Benign | -4.07 | Deleterious | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 3.37 | Benign | 0.19 | Tolerated | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||
| 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 | 0.912 | Likely Pathogenic | 0.3415 | 0.3154 | 4.05 | Destabilizing | 0.1 | 3.41 | Destabilizing | 3.73 | Destabilizing | 1.33 | Destabilizing | -6.26 | Deleterious | 0.982 | Probably Damaging | 0.533 | Possibly Damaging | 5.62 | Benign | 0.02 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.716G>A | R239K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R239K missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM, while the majority of other in silico predictors (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default) indicate a pathogenic impact. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Because uncertain or unavailable results are not taken as evidence for or against pathogenicity, the overall evidence still leans toward a deleterious effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -12.492 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.719 | Likely Pathogenic | 0.5222 | 0.4000 | Weaken | 1.93 | Ambiguous | 0.2 | 1.62 | Ambiguous | 1.78 | Ambiguous | 1.41 | Destabilizing | -2.52 | Deleterious | 0.882 | Possibly Damaging | 0.428 | Benign | 5.78 | Benign | 0.03 | Affected | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||
| c.716G>C | R239T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239T is recorded in gnomAD (ID 6‑33435567‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX reports an uncertain effect and is therefore not considered. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Consequently, the variant is most likely pathogenic according to the available computational evidence, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | 6-33435567-G-C | 1 | 6.19e-7 | -14.792 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.869 | Likely Pathogenic | 0.1805 | 0.4414 | 1.96 | Ambiguous | 0.3 | 2.44 | Destabilizing | 2.20 | Destabilizing | 1.21 | Destabilizing | -5.35 | Deleterious | 0.259 | Benign | 0.064 | Benign | 5.66 | Benign | 0.01 | Affected | 3.40 | 14 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||
| c.716G>T | R239I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -19.414 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.890 | Likely Pathogenic | 0.1480 | 0.3985 | 4.32 | Destabilizing | 0.5 | 2.53 | Destabilizing | 3.43 | Destabilizing | 0.83 | Ambiguous | -7.16 | Deleterious | 0.985 | Probably Damaging | 0.724 | Possibly Damaging | 5.69 | Benign | 0.00 | Affected | -2 | -3 | 9.0 | -43.03 | |||||||||||||||||||||||||
| c.717A>C | R239S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R239S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -13.418 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.813 | Likely Pathogenic | 0.3160 | 0.3788 | 3.67 | Destabilizing | 0.1 | 2.94 | Destabilizing | 3.31 | Destabilizing | 1.26 | Destabilizing | -5.31 | Deleterious | 0.900 | Possibly Damaging | 0.376 | Benign | 5.64 | Benign | 0.02 | Affected | 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 | 0.813 | Likely Pathogenic | 0.3160 | 0.3788 | 3.67 | Destabilizing | 0.1 | 2.94 | Destabilizing | 3.31 | Destabilizing | 1.26 | Destabilizing | -5.31 | Deleterious | 0.900 | Possibly Damaging | 0.376 | Benign | 5.64 | Benign | 0.02 | Affected | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||
| c.937G>A | E313K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313K is listed in ClinVar as Benign (ClinVar ID 3695040.0) and is not reported in gnomAD. Prediction tools that report a benign effect are absent; all available predictors that provide a definitive call classify the variant as pathogenic. These include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus indicates Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. Based on the overwhelming pathogenic predictions, the variant is most likely pathogenic, which contradicts its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | Likely Benign | 1 | -12.902 | Likely Pathogenic | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.575 | Likely Pathogenic | 0.2540 | 0.7708 | 0.64 | Ambiguous | 0.6 | 1.40 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | -3.31 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||
| c.937G>C | E313Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 E313Q is listed in ClinVar with an Uncertain significance status and is not reported in gnomAD. Prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized indicates a benign effect, Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign stability, whereas the SGM‑Consensus remains pathogenic. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not contradict the ClinVar designation of Uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | Uncertain | 1 | -11.420 | Likely Pathogenic | 0.629 | Likely Pathogenic | Likely Benign | 0.505 | Likely Pathogenic | 0.1523 | 0.7396 | 0.19 | Likely Benign | 0.1 | 0.55 | Ambiguous | 0.37 | Likely Benign | 0.50 | Likely Benign | -2.42 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.88 | Pathogenic | 0.05 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||
| c.938A>C | E313A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313A is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized, whereas the remaining pathogenic‑or‑likely‑pathogenic predictors are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -14.591 | Likely Pathogenic | 0.747 | Likely Pathogenic | Likely Benign | 0.680 | Likely Pathogenic | 0.3416 | 0.6743 | 1.07 | Ambiguous | 0.3 | 0.97 | Ambiguous | 1.02 | Ambiguous | 0.62 | Ambiguous | -4.88 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.88 | Pathogenic | 0.02 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.938A>G | E313G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—all of which classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Taken together, the overwhelming consensus from both general and high‑accuracy predictors indicates that E313G is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -14.615 | Likely Pathogenic | 0.912 | Likely Pathogenic | Ambiguous | 0.750 | Likely Pathogenic | 0.2638 | 0.6680 | 2.00 | Destabilizing | 0.5 | 2.42 | Destabilizing | 2.21 | Destabilizing | 0.79 | Ambiguous | -5.50 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.83 | Pathogenic | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.938A>T | E313V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E313V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas a majority of tools (REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the preponderance of evidence points to a pathogenic effect for E313V. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -13.169 | Likely Pathogenic | 0.821 | Likely Pathogenic | Ambiguous | 0.655 | Likely Pathogenic | 0.1132 | 0.7900 | 0.34 | Likely Benign | 0.1 | -0.02 | Likely Benign | 0.16 | Likely Benign | 0.21 | Likely Benign | -5.73 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.93 | Pathogenic | 0.05 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.939G>C | E313D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and SIFT, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating a likely pathogenic effect, and Foldetta yielding an uncertain stability change. Overall, the balance of evidence points to a pathogenic interpretation; this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -8.309 | Likely Pathogenic | 0.636 | Likely Pathogenic | Likely Benign | 0.346 | Likely Benign | 0.1970 | 0.4640 | 0.87 | Ambiguous | 0.0 | 0.96 | Ambiguous | 0.92 | Ambiguous | 0.60 | Ambiguous | -1.66 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.88 | Pathogenic | 0.14 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.939G>T | E313D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and SIFT, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating a likely pathogenic outcome, and Foldetta yielding an uncertain stability change. Overall, the balance of evidence points to a pathogenic effect for E313D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -8.309 | Likely Pathogenic | 0.636 | Likely Pathogenic | Likely Benign | 0.346 | Likely Benign | 0.1970 | 0.4640 | 0.87 | Ambiguous | 0.0 | 0.96 | Ambiguous | 0.92 | Ambiguous | 0.60 | Ambiguous | -1.66 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.88 | Pathogenic | 0.14 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| 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 | 0.533 | Likely Pathogenic | 0.2255 | 0.0499 | 2.82 | Destabilizing | 0.6 | 3.37 | Destabilizing | 3.10 | Destabilizing | 2.16 | Destabilizing | -7.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.76 | Pathogenic | 0.01 | Affected | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| c.871T>C | Y291H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291H is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a likely pathogenic verdict; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -8.749 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.355 | Likely Benign | 0.2403 | 0.0499 | 2.13 | Destabilizing | 0.2 | 2.61 | Destabilizing | 2.37 | Destabilizing | 1.56 | Destabilizing | -4.04 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.77 | Pathogenic | 0.02 | Affected | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||
| c.871T>G | Y291D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -17.570 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.650 | Likely Pathogenic | 0.4300 | 0.0331 | 4.13 | Destabilizing | 0.6 | 3.86 | Destabilizing | 4.00 | Destabilizing | 1.91 | Destabilizing | -8.19 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.75 | Pathogenic | 0.01 | Affected | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.872A>C | Y291S 2D AIThe SynGAP1 missense variant Y291S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in silico predictors classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -11.928 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.588 | Likely Pathogenic | 0.4850 | 0.2079 | 3.47 | Destabilizing | 0.8 | 4.47 | Destabilizing | 3.97 | Destabilizing | 2.01 | Destabilizing | -7.31 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.83 | Pathogenic | 0.02 | Affected | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| c.872A>G | Y291C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | Uncertain | 1 | -8.997 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.505 | Likely Pathogenic | 0.3053 | 0.2527 | 2.90 | Destabilizing | 0.4 | 3.51 | Destabilizing | 3.21 | Destabilizing | 1.35 | Destabilizing | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.76 | Pathogenic | 0.01 | Affected | 3.38 | 23 | 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.872A>T | Y291F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all predict a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic effect, while premPS remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence supports a benign classification, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -4.095 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.148 | Likely Benign | 0.2362 | 0.3441 | -0.43 | Likely Benign | 0.1 | -0.10 | Likely Benign | -0.27 | Likely Benign | 0.71 | Ambiguous | -2.31 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.77 | Pathogenic | 0.27 | Tolerated | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||
| c.940T>A | F314I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a pathogenic effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict deleterious or pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. Tools with uncertain or inconclusive results include Rosetta, Foldetta, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, while Foldetta’s stability prediction is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this is consistent with the lack of ClinVar annotation (i.e., no benign classification). Therefore, the variant is most likely pathogenic, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -7.059 | In-Between | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.534 | Likely Pathogenic | 0.2052 | 0.2308 | 2.23 | Destabilizing | 0.4 | 1.08 | Ambiguous | 1.66 | Ambiguous | 1.31 | Destabilizing | -4.98 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.26 | Pathogenic | 0.01 | Affected | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||
| c.940T>C | F314L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -6.004 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.476 | Likely Benign | 0.2204 | 0.3089 | 0.87 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.85 | Ambiguous | 1.21 | Destabilizing | -4.85 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.30 | Pathogenic | 0.05 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.940T>G | F314V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). All available in silico predictors classify the variant as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta—each return a pathogenic prediction. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -8.907 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.594 | Likely Pathogenic | 0.2054 | 0.2075 | 3.31 | Destabilizing | 0.4 | 2.54 | Destabilizing | 2.93 | Destabilizing | 1.44 | Destabilizing | -5.90 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.26 | Pathogenic | 0.00 | Affected | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||
| c.941T>A | F314Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas a majority of tools (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive—AlphaMissense‑Optimized, FoldX, and Foldetta—are treated as unavailable. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, while Foldetta’s combined stability analysis is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -13.297 | Likely Pathogenic | 0.918 | Likely Pathogenic | Ambiguous | 0.374 | Likely Benign | 0.1427 | 0.2173 | 1.33 | Ambiguous | 0.1 | 0.29 | Likely Benign | 0.81 | Ambiguous | 1.28 | Destabilizing | -2.62 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 1.20 | Pathogenic | 0.02 | Affected | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||
| c.941T>C | F314S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314S (located in the C2 domain) is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Thus, the variant is most likely pathogenic based on predictions, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -14.371 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.735 | Likely Pathogenic | 0.4113 | 0.0600 | 4.51 | Destabilizing | 0.4 | 3.36 | Destabilizing | 3.94 | Destabilizing | 2.59 | Destabilizing | -6.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.15 | Pathogenic | 0.00 | Affected | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||
| c.941T>G | F314C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. All available evidence points to a damaging effect. Consequently, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -12.458 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.674 | Likely Pathogenic | 0.2401 | 0.1075 | 3.37 | Destabilizing | 0.3 | 2.64 | Destabilizing | 3.01 | Destabilizing | 2.49 | Destabilizing | -6.89 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.13 | Pathogenic | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||
| c.942T>A | F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -6.004 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.336 | Likely Benign | 0.2204 | 0.3089 | 0.87 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.85 | Ambiguous | 1.21 | Destabilizing | -4.85 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.30 | Pathogenic | 0.05 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.942T>G | F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -6.004 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.336 | Likely Benign | 0.2204 | 0.3089 | 0.87 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.85 | Ambiguous | 1.21 | Destabilizing | -4.85 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.30 | Pathogenic | 0.05 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.1309C>A | P437T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P437T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta yielding an uncertain stability change. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.011 | Likely Pathogenic | 0.484 | Ambiguous | Likely Benign | 0.305 | Likely Benign | 0.1659 | 0.5782 | 1.35 | Ambiguous | 0.0 | -3.46 | Stabilizing | -1.06 | Ambiguous | 0.54 | Ambiguous | -6.67 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||
| c.1309C>G | P437A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P437A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, Rosetta, FATHMM, AlphaMissense‑Optimized, and premPS. Those that predict pathogenicity are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Tools with uncertain or inconclusive results are AlphaMissense‑Default, FoldX, and Foldetta. High‑accuracy assessments give AlphaMissense‑Optimized a benign prediction. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (pathogenic), FATHMM (benign), and PROVEAN (pathogenic), yields a pathogenic consensus. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the balance of evidence leans toward a pathogenic effect for P437A, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -12.059 | Likely Pathogenic | 0.392 | Ambiguous | Likely Benign | 0.266 | Likely Benign | 0.3489 | 0.4775 | 1.23 | Ambiguous | 0.0 | -3.14 | Stabilizing | -0.96 | Ambiguous | 0.50 | Likely Benign | -6.53 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.51 | Benign | 0.03 | Affected | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||
| c.1309C>T | P437S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P437S is not reported in ClinVar (ClinVar ID: None) but is present in gnomAD (ID 6‑33438214‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, whereas PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome; the remaining methods (FoldX, Foldetta, premPS, AlphaMissense‑Default) are uncertain and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic interpretation. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | 6-33438214-C-T | 2 | 1.24e-6 | -11.964 | Likely Pathogenic | 0.518 | Ambiguous | Likely Benign | 0.226 | Likely Benign | 0.3548 | 0.4843 | 1.14 | Ambiguous | 0.0 | -3.31 | Stabilizing | -1.09 | Ambiguous | 0.60 | Ambiguous | -6.60 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.49 | Benign | 0.01 | Affected | 3.38 | 26 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||
| c.1310C>A | P437H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P437H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the balance of evidence favors a pathogenic classification for P437H, 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 | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.496 | Likely Pathogenic | 0.826 | Likely Pathogenic | Ambiguous | 0.343 | Likely Benign | 0.1819 | 0.4328 | 1.19 | Ambiguous | 0.0 | -3.28 | Stabilizing | -1.05 | Ambiguous | 0.31 | Likely Benign | -7.75 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.44 | Benign | 0.01 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||
| c.1310C>G | P437R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P437R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With the majority of tools indicating pathogenicity and the high‑accuracy consensus leaning toward pathogenic, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.094 | Likely Pathogenic | 0.879 | Likely Pathogenic | Ambiguous | 0.461 | Likely Benign | 0.1448 | 0.2846 | 0.34 | Likely Benign | 0.1 | -3.52 | Stabilizing | -1.59 | Ambiguous | 0.61 | Ambiguous | -7.72 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.51 | Benign | 0.03 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||
| c.1310C>T | P437L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P437L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta are uncertain. Taken together, the majority of evidence points toward a pathogenic impact for P437L, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.554 | Likely Pathogenic | 0.787 | Likely Pathogenic | Ambiguous | 0.324 | Likely Benign | 0.2228 | 0.6354 | 1.10 | Ambiguous | 0.0 | -3.52 | Stabilizing | -1.21 | Ambiguous | 0.35 | Likely Benign | -8.48 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.67 | Benign | 0.04 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| c.1423C>G | R475G 2D AIThe SynGAP1 missense variant R475G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenicity. Only Rosetta and AlphaMissense‑Optimized return uncertain results, and no tool predicts a benign outcome. High‑accuracy methods provide a consistent view: AlphaMissense‑Optimized is uncertain, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. Taken together, the overwhelming majority of evidence supports a pathogenic classification for R475G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | -14.466 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 0.697 | Likely Pathogenic | 0.2779 | 0.2310 | 2.39 | Destabilizing | 1.0 | 1.64 | Ambiguous | 2.02 | Destabilizing | 1.11 | Destabilizing | -6.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.1423C>T | R475W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475W is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438455‑C‑T). Prediction tools that agree on a benign effect include only Foldetta, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) uniformly predict a pathogenic impact; FoldX, Rosetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification but suggests that the variant is more likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | Uncertain | 1 | 6-33438455-C-T | 1 | 6.20e-7 | -13.235 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.725 | Likely Pathogenic | 0.1231 | 0.2785 | 1.44 | Ambiguous | 0.4 | -0.92 | Ambiguous | 0.26 | Likely Benign | 0.56 | Ambiguous | -7.56 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.45 | Pathogenic | 0.00 | Affected | 3.39 | 28 | 2 | -3 | 3.6 | 30.03 | 266.9 | 39.6 | 0.0 | 0.0 | 0.0 | 0.1 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation.In the variant simulations, Trp475 moves and stacks with Arg479 on the proceeding α-α loop, disrupting the terminal end of the α-helix. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||
| c.1424G>A | R475Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475Q is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438456‑G‑A). Prediction tools that indicate a benign effect include AlphaMissense‑Optimized, Foldetta, and Rosetta. Those that predict a pathogenic effect comprise SGM Consensus, SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points toward a pathogenic impact, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | Uncertain | 2 | 6-33438456-G-A | 5 | 3.10e-6 | -12.087 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 0.632 | Likely Pathogenic | 0.2190 | 0.1926 | 0.71 | Ambiguous | 0.1 | 0.12 | Likely Benign | 0.42 | Likely Benign | 0.82 | Ambiguous | -3.65 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.39 | 28 | 1 | 1 | 1.0 | -28.06 | 253.6 | 52.7 | 0.0 | 0.0 | -0.8 | 0.0 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation. In the variant simulations, Asn475 forms a hydrogen bond with Arg479 on the proceeding α-α loop. The absence of Phe476/Arg475 stacking and the Arg475-Glu472 salt bridge weakens the integrity of the terminal end of the α-helix during the variant simulations. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||
| c.1424G>C | R475P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: benign‑predicting algorithms are not present, while pathogenic‑predicting tools—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all classify the substitution as pathogenic. High‑accuracy assessments corroborate this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. Consequently, the variant is most likely pathogenic based on the available computational evidence, and this assessment does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | -16.637 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.835 | Likely Pathogenic | 0.1943 | 0.3295 | 2.93 | Destabilizing | 0.4 | 5.40 | Destabilizing | 4.17 | Destabilizing | 1.02 | Destabilizing | -6.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.43 | Pathogenic | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.1424G>T | R475L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R475L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, whereas only Rosetta predicts a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. With the preponderance of pathogenic calls and no conflicting evidence from ClinVar or population databases, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | -13.074 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 0.806 | Likely Pathogenic | 0.1580 | 0.3428 | 1.49 | Ambiguous | 0.4 | -0.47 | Likely Benign | 0.51 | Ambiguous | 0.55 | Ambiguous | -6.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.40 | Pathogenic | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.1852C>A | Q618K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618K is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33440904‑C‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while ESM1b is uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign result; and Foldetta also predicts benign stability. No predictions or folding stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict 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 | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | 6-33440904-C-A | 24 | 1.49e-5 | -7.708 | In-Between | 0.229 | Likely Benign | Likely Benign | 0.281 | Likely Benign | 0.1413 | 0.2750 | 0.02 | Likely Benign | 0.0 | 0.16 | Likely Benign | 0.09 | Likely Benign | -0.46 | Likely Benign | -0.05 | Neutral | 0.338 | Benign | 0.111 | Benign | -1.21 | Pathogenic | 0.29 | Tolerated | 3.37 | 35 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||
| c.1852C>G | Q618E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, and there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -12.535 | Likely Pathogenic | 0.162 | Likely Benign | Likely Benign | 0.233 | Likely Benign | 0.1003 | 0.1469 | 0.46 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.48 | Likely Benign | 0.33 | Likely Benign | -1.16 | Neutral | 0.046 | Benign | 0.021 | Benign | -1.17 | Pathogenic | 0.26 | Tolerated | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||
| 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 | 0.449 | Likely Benign | 0.1990 | 0.4011 | -0.11 | Likely Benign | 0.1 | 3.41 | Destabilizing | 1.65 | Ambiguous | 0.23 | Likely Benign | -3.32 | Deleterious | 0.261 | Benign | 0.246 | Benign | -1.35 | Pathogenic | 0.08 | Tolerated | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||
| c.1853A>G | Q618R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618R is 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, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -2.513 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.285 | Likely Benign | 0.1218 | 0.1163 | -0.43 | Likely Benign | 0.1 | 0.60 | Ambiguous | 0.09 | Likely Benign | -0.66 | Ambiguous | 1.22 | Neutral | 0.005 | Benign | 0.009 | Benign | -1.24 | Pathogenic | 1.00 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||
| c.1853A>T | Q618L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. AlphaMissense‑Default is uncertain, whereas AlphaMissense‑Optimized predicts benign. High‑accuracy methods give the following results: AlphaMissense‑Optimized – benign; SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) – Likely Pathogenic; Foldetta – benign. Overall, the majority of tools (nine benign vs. five pathogenic) predict a benign impact. Thus, the variant is most likely benign based on current predictions, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -8.561 | Likely Pathogenic | 0.423 | Ambiguous | Likely Benign | 0.479 | Likely Benign | 0.0612 | 0.4146 | -0.07 | Likely Benign | 0.1 | 0.20 | Likely Benign | 0.07 | Likely Benign | 0.31 | Likely Benign | -3.94 | Deleterious | 0.712 | Possibly Damaging | 0.268 | Benign | -1.28 | Pathogenic | 0.09 | Tolerated | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||
| c.1854G>C | Q618H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q618H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Four tools (FoldX, Foldetta, ESM1b, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and Foldetta is uncertain. Overall, the majority of evidence points toward a benign effect, and this conclusion does not contradict the lack of ClinVar annotation or gnomAD presence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -7.092 | In-Between | 0.489 | Ambiguous | Likely Benign | 0.475 | Likely Benign | 0.1015 | 0.2655 | 0.59 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.52 | Ambiguous | 0.34 | Likely Benign | -1.99 | Neutral | 0.946 | Possibly Damaging | 0.638 | Possibly Damaging | -1.35 | Pathogenic | 0.04 | Affected | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||
| c.1854G>T | Q618H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Four tools (FoldX, Foldetta, ESM1b, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also uncertain. Overall, the balance of evidence leans toward a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -7.092 | In-Between | 0.489 | Ambiguous | Likely Benign | 0.475 | Likely Benign | 0.1015 | 0.2655 | 0.59 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.52 | Ambiguous | 0.34 | Likely Benign | -1.99 | Neutral | 0.946 | Possibly Damaging | 0.638 | Possibly Damaging | -1.35 | Pathogenic | 0.04 | Affected | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||
| c.1867C>A | L623I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L623I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come only from REVEL and PROVEAN, while pathogenic calls are made by FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which is derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Uncertain results are reported by Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.060667 | Uncertain | 0.962 | 0.211 | 0.000 | -11.952 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.398 | Likely Benign | 0.1109 | 0.3767 | 3.15 | Destabilizing | 0.5 | 1.90 | Ambiguous | 2.53 | Destabilizing | 1.13 | Destabilizing | -1.99 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.63 | Pathogenic | 0.02 | Affected | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||
| c.1867C>G | L623V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L623V is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and AlphaMissense‑Optimized give uncertain results. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic, and AlphaMissense‑Optimized remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. 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 | -12.802 | Likely Pathogenic | 0.896 | Likely Pathogenic | Ambiguous | 0.416 | Likely Benign | 0.1653 | 0.3588 | 3.96 | Destabilizing | 0.3 | 1.84 | Ambiguous | 2.90 | Destabilizing | 1.45 | Destabilizing | -2.99 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 1.60 | Pathogenic | 0.01 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1867C>T | L623F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L623F is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN)—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No predictions are missing or inconclusive. Based on the overwhelming agreement among pathogenic predictions and the lack of a benign signal, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.060667 | Uncertain | 0.962 | 0.211 | 0.000 | -11.655 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.440 | Likely Benign | 0.0838 | 0.3016 | 1.22 | Ambiguous | 0.2 | 0.92 | Ambiguous | 1.07 | Ambiguous | 0.57 | Ambiguous | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.02 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1868T>A | L623H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L623H 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 unanimous computational 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 | 0.175930 | Structured | 0.060667 | Uncertain | 0.962 | 0.211 | 0.000 | -14.631 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.793 | Likely Pathogenic | 0.1099 | 0.0541 | 2.76 | Destabilizing | 0.3 | 2.22 | Destabilizing | 2.49 | Destabilizing | 2.40 | Destabilizing | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.55 | Pathogenic | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||
| 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 | 0.788 | Likely Pathogenic | 0.3961 | 0.1474 | 6.70 | Destabilizing | 0.2 | 11.18 | Destabilizing | 8.94 | Destabilizing | 2.26 | Destabilizing | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.56 | Pathogenic | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| 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 | 0.795 | Likely Pathogenic | 0.1327 | 0.0615 | 4.08 | Destabilizing | 1.4 | 3.28 | Destabilizing | 3.68 | Destabilizing | 2.31 | Destabilizing | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.55 | Pathogenic | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.2053T>A | L685M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from premPS, Foldetta, Rosetta, and AlphaMissense‑Optimized. High‑accuracy methods give inconclusive results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑to‑2 tie and therefore uncertain; Foldetta also reports an uncertain stability change. Consequently, the overall computational evidence is mixed, with a slight tilt toward pathogenicity. Thus, the variant is most likely pathogenic based on predictions, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -10.790 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.281 | Likely Benign | 0.0814 | 0.2758 | 0.35 | Likely Benign | 0.1 | 1.01 | Ambiguous | 0.68 | Ambiguous | 0.83 | Ambiguous | -2.00 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.29 | Benign | 0.01 | Affected | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||
| c.2053T>G | L685V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other folding‑stability methods provide definitive evidence. Overall, the preponderance of pathogenic predictions, including the SGM Consensus, suggests that the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -11.418 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 0.214 | Likely Benign | 0.1414 | 0.3010 | 1.87 | Ambiguous | 0.0 | 1.15 | Ambiguous | 1.51 | Ambiguous | 0.97 | Ambiguous | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.694 | Possibly Damaging | 3.33 | Benign | 0.02 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| 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 | 0.520 | Likely Pathogenic | 0.2844 | 0.0505 | 3.08 | Destabilizing | 0.2 | 2.95 | Destabilizing | 3.02 | Destabilizing | 1.24 | Destabilizing | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||
| c.2054T>G | L685W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar 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 | -15.885 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.509 | Likely Pathogenic | 0.0700 | 0.2328 | 1.53 | Ambiguous | 0.2 | 1.14 | Ambiguous | 1.34 | Ambiguous | 1.14 | Destabilizing | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.984 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||
| c.2055G>C | L685F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685F is not reported in ClinVar and has no gnomAD entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the change as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. FoldX and Rosetta predictions are uncertain and are treated as unavailable. Overall, the preponderance of evidence points to a pathogenic impact for the variant, 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 | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -12.304 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.300 | Likely Benign | 0.0724 | 0.2367 | 1.62 | Ambiguous | 0.2 | 1.80 | Ambiguous | 1.71 | Ambiguous | 0.50 | Likely Benign | -3.99 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.33 | Benign | 0.01 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.2055G>T | L685F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685F is not reported in ClinVar and has no gnomAD entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the change as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. FoldX and Rosetta predictions are uncertain and are treated as unavailable. Overall, the preponderance of evidence points to a pathogenic impact for the variant, 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 | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -12.304 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.300 | Likely Benign | 0.0724 | 0.2367 | 1.62 | Ambiguous | 0.2 | 1.80 | Ambiguous | 1.71 | Ambiguous | 0.50 | Likely Benign | -3.99 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.33 | Benign | 0.01 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.2089T>A | W697R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W697R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic effect: SGM‑Consensus, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, and premPS. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence from multiple pathogenic‑predicting tools indicates that W697R 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 | 0.175930 | Structured | 0.400169 | Uncertain | 0.945 | 0.297 | 0.000 | -10.020 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.401 | Likely Benign | 0.3944 | 0.0612 | 1.14 | Ambiguous | 0.1 | 1.18 | Ambiguous | 1.16 | Ambiguous | 1.25 | Destabilizing | -9.50 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.45 | Benign | 0.02 | Affected | 3.46 | 13 | 2 | -3 | -3.6 | -30.03 | 254.4 | -41.2 | 0.0 | 0.0 | -0.7 | 0.0 | X | Potentially Benign | The indole ring of Trp697, located on the outer surface of an α-helix (res. Leu685-Val699), is not involved in any long-lasting interactions in the WT simulations. In the variant simulations, the positively charged guanidinium side chain of Arg697 occasionally forms hydrogen bonds with nearby residues, such as Ser722 and Asn719. However, similar to Trp697 in the WT, Arg697 does not form any long-lasting interactions and thus does not induce any negative structural effects in the simulations. | ||||||||||||||
| c.2089T>C | W697R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W697R is listed in ClinVar as Benign (ClinVar ID 703213.0) and is present in the gnomAD database (gnomAD ID 6‑33441348‑T‑C). Functional prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence from multiple pathogenic‑predicting tools suggests that the variant is most likely pathogenic, which contradicts its current ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.400169 | Uncertain | 0.945 | 0.297 | 0.000 | Likely Benign | 1 | 6-33441348-T-C | 1 | 6.20e-7 | -10.020 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.401 | Likely Benign | 0.3944 | 0.0612 | 1.14 | Ambiguous | 0.1 | 1.18 | Ambiguous | 1.16 | Ambiguous | 1.25 | Destabilizing | -9.50 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.45 | Benign | 0.02 | Affected | 3.46 | 13 | 2 | -3 | -3.6 | -30.03 | 254.4 | -41.2 | 0.0 | 0.0 | -0.7 | 0.0 | X | Potentially Benign | The indole ring of Trp697, located on the outer surface of an α-helix (res. Leu685-Val699), is not involved in any long-lasting interactions in the WT simulations. In the variant simulations, the positively charged guanidinium side chain of Arg697 occasionally forms hydrogen bonds with nearby residues, such as Ser722 and Asn719. However, similar to Trp697 in the WT, Arg697 does not form any long-lasting interactions and thus does not induce any negative structural effects in the simulations. | |||||||||
| 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 | 0.485 | Likely Benign | 0.3965 | 0.1482 | 2.57 | Destabilizing | 0.1 | 2.38 | Destabilizing | 2.48 | Destabilizing | 1.21 | Destabilizing | -8.93 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 3.44 | Benign | 0.06 | Tolerated | -7 | -2 | 0.5 | -129.16 | ||||||||||||||||||||||||||
| c.2090G>C | W697S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W697S is not 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as unavailable due to uncertainty. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.400169 | Uncertain | 0.945 | 0.297 | 0.000 | -4.900 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.322 | Likely Benign | 0.3738 | 0.1089 | 1.90 | Ambiguous | 0.1 | 1.58 | Ambiguous | 1.74 | Ambiguous | 1.13 | Destabilizing | -8.89 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 3.53 | Benign | 0.13 | Tolerated | -2 | -3 | 0.1 | -99.14 | ||||||||||||||||||||||||||
| c.2090G>T | W697L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W697L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. No predictions are missing or inconclusive. Overall, the majority of tools (seven pathogenic vs. six benign) lean toward a pathogenic interpretation, and this does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.400169 | Uncertain | 0.945 | 0.297 | 0.000 | -9.057 | Likely Pathogenic | 0.676 | Likely Pathogenic | Likely Benign | 0.280 | Likely Benign | 0.2222 | 0.2848 | 0.20 | Likely Benign | 0.1 | -0.17 | Likely Benign | 0.02 | Likely Benign | 0.90 | Ambiguous | -8.48 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.58 | Benign | 0.02 | Affected | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||
| c.2091G>C | W697C 2D  3DClick to see structure in 3D Viewer AISynGAP1 W697C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The remaining tools—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized—return uncertain or inconclusive results. High‑accuracy assessments are likewise ambiguous: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, the evidence does not favor either outcome; the variant’s impact remains indeterminate. This lack of consensus 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 | 0.175930 | Structured | 0.400169 | Uncertain | 0.945 | 0.297 | 0.000 | -5.683 | Likely Benign | 0.811 | Likely Pathogenic | Ambiguous | 0.318 | Likely Benign | 0.3575 | 0.1015 | 1.84 | Ambiguous | 0.1 | 1.01 | Ambiguous | 1.43 | Ambiguous | 0.98 | Ambiguous | -8.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.48 | Benign | 0.10 | Tolerated | -8 | -2 | 3.4 | -83.07 | ||||||||||||||||||||||||||
| c.2091G>T | W697C 2D 3DClick to see structure in 3D Viewer AISynGAP1 W697C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) yield uncertain or missing results. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑vs‑2 tie; and Foldetta is uncertain. Consequently, the evidence does not strongly favor either outcome. The variant is therefore best classified as of uncertain significance; this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.400169 | Uncertain | 0.945 | 0.297 | 0.000 | -5.683 | Likely Benign | 0.811 | Likely Pathogenic | Ambiguous | 0.318 | Likely Benign | 0.3575 | 0.1015 | 1.84 | Ambiguous | 0.1 | 1.01 | Ambiguous | 1.43 | Ambiguous | 0.98 | Ambiguous | -8.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.48 | Benign | 0.10 | Tolerated | -8 | -2 | 3.4 | -83.07 | ||||||||||||||||||||||||||
| c.961C>A | R321S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Two tools—FoldX and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -10.146 | Likely Pathogenic | 0.497 | Ambiguous | Likely Benign | 0.379 | Likely Benign | 0.2958 | 0.2785 | 0.66 | Ambiguous | 0.1 | -0.30 | Likely Benign | 0.18 | Likely Benign | 0.24 | Likely Benign | -2.27 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.00 | Pathogenic | 0.10 | Tolerated | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||
| c.961C>G | R321G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, while the high‑accuracy subset is mixed, with one benign, one pathogenic, and one uncertain result. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -10.554 | Likely Pathogenic | 0.293 | Likely Benign | Likely Benign | 0.430 | Likely Benign | 0.3224 | 0.2898 | 0.90 | Ambiguous | 0.1 | 0.28 | Likely Benign | 0.59 | Ambiguous | 0.49 | Likely Benign | -3.70 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.92 | Pathogenic | 0.04 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.961C>T | R321C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437866‑C‑T). Prediction tools that agree on a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Five tools (SGM‑Consensus, FoldX, Rosetta, AlphaMissense‑Default, and Foldetta) report uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (six out of eleven) support a pathogenic impact, while three support benign and five are inconclusive. Thus, the variant is most likely pathogenic based on current computational evidence, and this does not contradict its ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | Conflicting | 2 | 6-33437866-C-T | 9 | 5.58e-6 | -10.025 | Likely Pathogenic | 0.387 | Ambiguous | Likely Benign | 0.495 | Likely Benign | 0.3313 | 0.2516 | 0.57 | Ambiguous | 0.1 | 0.56 | Ambiguous | 0.57 | Ambiguous | 0.18 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.89 | Pathogenic | 0.01 | Affected | 3.38 | 23 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||
| c.962G>A | R321H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R321H is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6‑33437867‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM, while premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions support a benign impact, and this consensus does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | Uncertain | 1 | 6-33437867-G-A | 8 | 4.96e-6 | -8.751 | Likely Pathogenic | 0.136 | Likely Benign | Likely Benign | 0.323 | Likely Benign | 0.2930 | 0.0936 | 0.48 | Likely Benign | 0.1 | -0.36 | Likely Benign | 0.06 | Likely Benign | 0.59 | Ambiguous | -1.43 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.92 | Pathogenic | 0.25 | Tolerated | 3.38 | 23 | 2 | 0 | 1.3 | -19.05 | 218.5 | 86.9 | 1.1 | 0.0 | 0.3 | 0.0 | X | Potentially Benign | The guanidinium group of Arg321, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), faces outward without forming any stable interactions in the WT simulations. Similarly, in the variant simulations, the imidazole ring of His321 also points outward without making any stable intra-protein interactions. Thus, the residue swap does not seem to cause adverse effects on the protein structure based on the simulations. However, β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. | ||||||||||
| c.962G>C | R321P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (8/12) predict pathogenicity, whereas 4/12 predict benign, with two high‑accuracy tools supporting benign and one supporting pathogenic. Thus, the variant is most likely pathogenic based on the preponderance of evidence, and this assessment does not contradict ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -11.576 | Likely Pathogenic | 0.740 | Likely Pathogenic | Likely Benign | 0.488 | Likely Benign | 0.2186 | 0.3661 | 1.22 | Ambiguous | 0.3 | -0.77 | Ambiguous | 0.23 | Likely Benign | 0.41 | Likely Benign | -3.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.92 | Pathogenic | 0.03 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.962G>T | R321L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SIFT, polyPhen‑2 (HumDiv and HumVar), PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign; FoldX and Rosetta individually are inconclusive. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -11.709 | Likely Pathogenic | 0.551 | Ambiguous | Likely Benign | 0.451 | Likely Benign | 0.1745 | 0.4048 | 0.54 | Ambiguous | 0.0 | -0.58 | Ambiguous | -0.02 | Likely Benign | 0.18 | Likely Benign | -4.06 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.93 | Pathogenic | 0.03 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.964G>A | A322T 2D  AIThe SynGAP1 missense variant A322T is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors classifies the change as benign: SGM‑Consensus (Likely Benign), REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect. Only FATHMM indicates a pathogenic signal, while FoldX and premPS are inconclusive. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign impact on protein stability. Overall, the majority of evidence supports a benign effect for A322T, 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 | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -2.252 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.112 | Likely Benign | 0.1367 | 0.6432 | 0.58 | Ambiguous | 0.9 | 0.22 | Likely Benign | 0.40 | Likely Benign | -0.52 | Ambiguous | 0.20 | Neutral | 0.010 | Benign | 0.005 | Benign | 1.95 | Pathogenic | 0.73 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| 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 | 0.343 | Likely Benign | 0.2064 | 0.5400 | 1.26 | Ambiguous | 1.3 | 5.43 | Destabilizing | 3.35 | Destabilizing | 0.40 | Likely Benign | -1.72 | Neutral | 0.784 | Possibly Damaging | 0.390 | Benign | 1.90 | Pathogenic | 0.18 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.964G>T | A322S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. Grouping by consensus, the benign‑predicting tools outnumber the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates a benign effect. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -1.424 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.127 | Likely Benign | 0.2696 | 0.5253 | 0.41 | Likely Benign | 0.2 | 0.38 | Likely Benign | 0.40 | Likely Benign | -0.44 | Likely Benign | 1.09 | Neutral | 0.010 | Benign | 0.010 | Benign | 2.00 | Pathogenic | 0.67 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.965C>A | A322D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A322D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The remaining tools—FoldX, Rosetta, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta indicates no significant stability change (uncertain). Overall, the preponderance of evidence (seven benign predictions versus one pathogenic) suggests the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -7.184 | In-Between | 0.411 | Ambiguous | Likely Benign | 0.246 | Likely Benign | 0.1646 | 0.1660 | 0.65 | Ambiguous | 0.1 | 1.35 | Ambiguous | 1.00 | Ambiguous | 0.34 | Likely Benign | -0.95 | Neutral | 0.270 | Benign | 0.136 | Benign | 1.96 | Pathogenic | 0.32 | Tolerated | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||
| c.965C>G | A322G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only FATHMM predicts a pathogenic outcome. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain or inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Based on the preponderance of benign predictions and the lack of contradictory evidence, the variant is most likely benign; this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -5.230 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.054 | Likely Benign | 0.2513 | 0.4683 | 0.84 | Ambiguous | 0.1 | 1.43 | Ambiguous | 1.14 | Ambiguous | 0.64 | Ambiguous | -1.07 | Neutral | 0.139 | Benign | 0.088 | Benign | 1.94 | Pathogenic | 0.19 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.965C>T | A322V 2D  AIThe SynGAP1 missense variant A322V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No predictions or stability results are missing or inconclusive. Based on the overwhelming consensus of the available tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -4.905 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.052 | Likely Benign | 0.1279 | 0.6126 | 0.02 | Likely Benign | 1.0 | -0.42 | Likely Benign | -0.20 | Likely Benign | 0.19 | Likely Benign | -1.63 | Neutral | 0.270 | Benign | 0.136 | Benign | 1.96 | Pathogenic | 0.22 | Tolerated | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.1048G>A | V350M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The remaining tools (FoldX, premPS, ESM1b) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. Taken together, the majority of evidence supports a benign classification. There is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -7.493 | In-Between | 0.273 | Likely Benign | Likely Benign | 0.075 | Likely Benign | 0.1005 | 0.4359 | -0.65 | Ambiguous | 0.1 | 0.40 | Likely Benign | -0.13 | Likely Benign | 0.69 | Ambiguous | -1.95 | Neutral | 0.868 | Possibly Damaging | 0.383 | Benign | 1.63 | Pathogenic | 0.06 | Tolerated | 2 | 1 | -2.3 | 32.06 | ||||||||||||||||||||||||||
| c.1048G>C | V350L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -5.941 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.042 | Likely Benign | 0.1173 | 0.4958 | -1.31 | Ambiguous | 0.1 | -0.34 | Likely Benign | -0.83 | Ambiguous | 0.36 | Likely Benign | -1.63 | Neutral | 0.068 | Benign | 0.022 | Benign | 2.37 | Pathogenic | 0.27 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1048G>T | V350L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No other tools provide conflicting evidence. Based on the preponderance of predictions, V350L is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -5.941 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.042 | Likely Benign | 0.1173 | 0.4958 | -1.31 | Ambiguous | 0.1 | -0.34 | Likely Benign | -0.83 | Ambiguous | 0.36 | Likely Benign | -1.63 | Neutral | 0.068 | Benign | 0.022 | Benign | 2.37 | Pathogenic | 0.27 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1049T>A | V350E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign effect include REVEL and SIFT, whereas a majority of tools predict pathogenicity: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, Foldetta, and Rosetta. Two tools give inconclusive results: FoldX (Uncertain) and AlphaMissense‑Optimized (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for V350E. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -15.975 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.304 | Likely Benign | 0.1078 | 0.1568 | 1.73 | Ambiguous | 0.2 | 2.61 | Destabilizing | 2.17 | Destabilizing | 1.93 | Destabilizing | -4.67 | Deleterious | 0.976 | Probably Damaging | 0.559 | Possibly Damaging | 1.61 | Pathogenic | 0.08 | Tolerated | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||
| c.1049T>C | V350A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V350A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), premPS, PROVEAN, ESM1b, and FATHMM. Stability‑based methods FoldX, Rosetta, and Foldetta give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as unavailable. Overall, the predictions are split, with a slight edge toward pathogenicity from the consensus and high‑accuracy tools. Therefore, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -8.323 | Likely Pathogenic | 0.280 | Likely Benign | Likely Benign | 0.096 | Likely Benign | 0.3207 | 0.2967 | 1.42 | Ambiguous | 0.0 | 1.97 | Ambiguous | 1.70 | Ambiguous | 2.07 | Destabilizing | -2.73 | Deleterious | 0.435 | Benign | 0.115 | Benign | 1.64 | Pathogenic | 0.55 | Tolerated | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||
| 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 | 0.330 | Likely Benign | 0.2316 | 0.2522 | 2.57 | Destabilizing | 0.0 | 4.25 | Destabilizing | 3.41 | Destabilizing | 1.93 | Destabilizing | -5.46 | Deleterious | 0.435 | Benign | 0.920 | Probably Damaging | 1.61 | Pathogenic | 0.02 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| 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 | 0.288 | Likely Benign | 0.2532 | 0.1071 | 2.90 | Destabilizing | 0.1 | 2.88 | Destabilizing | 2.89 | Destabilizing | 1.58 | Destabilizing | -7.11 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 3.78 | Benign | 0.02 | Affected | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| c.1216T>C | Y406H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y406H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors—FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently classify the substitution as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Taken together, the preponderance of evidence indicates that Y406H is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -9.015 | Likely Pathogenic | 0.858 | Likely Pathogenic | Ambiguous | 0.239 | Likely Benign | 0.2666 | 0.0811 | 2.13 | Destabilizing | 0.1 | 2.15 | Destabilizing | 2.14 | Destabilizing | 1.03 | Destabilizing | -4.21 | Deleterious | 0.997 | Probably Damaging | 0.966 | Probably Damaging | 3.80 | Benign | 0.03 | Affected | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||
| 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 | 0.347 | Likely Benign | 0.4439 | 0.0903 | 3.82 | Destabilizing | 0.3 | 4.28 | Destabilizing | 4.05 | Destabilizing | 0.98 | Ambiguous | -7.64 | Deleterious | 0.999 | Probably Damaging | 0.950 | Probably Damaging | 3.77 | Benign | 0.01 | Affected | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||
| 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 | 0.190 | Likely Benign | 0.4719 | 0.2817 | 3.51 | Destabilizing | 0.3 | 4.08 | Destabilizing | 3.80 | Destabilizing | 1.40 | Destabilizing | -6.72 | Deleterious | 0.991 | Probably Damaging | 0.886 | Possibly Damaging | 3.80 | Benign | 0.06 | Tolerated | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| 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 | 0.229 | Likely Benign | 0.3026 | 0.2861 | 2.47 | Destabilizing | 0.2 | 3.22 | Destabilizing | 2.85 | Destabilizing | 1.27 | Destabilizing | -6.72 | Deleterious | 0.998 | Probably Damaging | 0.851 | Possibly Damaging | 3.78 | Benign | 0.01 | Affected | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||
| c.1217A>T | Y406F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign or likely benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -3.427 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.2673 | 0.3952 | -0.01 | Likely Benign | 0.2 | 0.40 | Likely Benign | 0.20 | Likely Benign | 0.15 | Likely Benign | -0.93 | Neutral | 0.002 | Benign | 0.002 | Benign | 3.96 | Benign | 0.31 | Tolerated | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||
| 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 | 0.561 | Likely Pathogenic | 0.2482 | 0.0728 | 3.94 | Destabilizing | 0.2 | 3.69 | Destabilizing | 3.82 | Destabilizing | 2.60 | Destabilizing | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.97 | Benign | 0.00 | Affected | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| 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 | 0.513 | Likely Pathogenic | 0.2596 | 0.0668 | 3.22 | Destabilizing | 0.1 | 2.80 | Destabilizing | 3.01 | Destabilizing | 1.54 | Destabilizing | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.97 | Benign | 0.00 | Affected | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||
| 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 | 0.688 | Likely Pathogenic | 0.4388 | 0.0400 | 5.13 | Destabilizing | 0.1 | 5.37 | Destabilizing | 5.25 | Destabilizing | 2.43 | Destabilizing | -9.55 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||
| 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 | 0.593 | Likely Pathogenic | 0.4408 | 0.1961 | 4.36 | Destabilizing | 0.1 | 5.32 | Destabilizing | 4.84 | Destabilizing | 2.17 | Destabilizing | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| 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 | 0.597 | Likely Pathogenic | 0.2960 | 0.2005 | 4.03 | Destabilizing | 0.1 | 3.81 | Destabilizing | 3.92 | Destabilizing | 2.52 | Destabilizing | -8.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||
| c.1250A>T | Y417F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y417F variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized and premPS. High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta) as Benign, and AlphaMissense‑Optimized as Uncertain. Overall, the majority of tools and the SGM‑Consensus score suggest a pathogenic effect, while Foldetta indicates a benign effect; the variant’s status is not contradicted by ClinVar (no entry). Thus, based on the available predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -11.368 | Likely Pathogenic | 0.852 | Likely Pathogenic | Ambiguous | 0.367 | Likely Benign | 0.2617 | 0.3098 | 0.47 | Likely Benign | 0.1 | -0.09 | Likely Benign | 0.19 | Likely Benign | 0.97 | Ambiguous | -3.82 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.03 | Benign | 0.06 | Tolerated | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||
| c.1381G>A | A461T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A461T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta is also inconclusive. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -10.885 | Likely Pathogenic | 0.323 | Likely Benign | Likely Benign | 0.214 | Likely Benign | 0.1083 | 0.5930 | 1.21 | Ambiguous | 0.2 | 0.51 | Ambiguous | 0.86 | Ambiguous | 0.65 | Ambiguous | -3.27 | Deleterious | 0.508 | Possibly Damaging | 0.042 | Benign | 3.40 | Benign | 0.13 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||
| c.1381G>C | A461P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and FATHMM, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS remains uncertain. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is pathogenic. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -13.869 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.451 | Likely Benign | 0.1748 | 0.3949 | -0.35 | Likely Benign | 0.1 | 5.09 | Destabilizing | 2.37 | Destabilizing | 0.84 | Ambiguous | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.849 | Possibly Damaging | 3.32 | Benign | 0.03 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1381G>T | A461S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 (HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv), SIFT, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta’s stability analysis is also unavailable. Overall, the balance of evidence leans toward a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -10.663 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 0.236 | Likely Benign | 0.2401 | 0.4551 | 0.87 | Ambiguous | 0.0 | 1.18 | Ambiguous | 1.03 | Ambiguous | 0.63 | Ambiguous | -2.74 | Deleterious | 0.600 | Possibly Damaging | 0.289 | Benign | 3.36 | Benign | 0.02 | Affected | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||
| c.1382C>A | A461D 2D AIThe SynGAP1 missense variant A461D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. The majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that A461D is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -14.918 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.477 | Likely Benign | 0.1533 | 0.2016 | 0.89 | Ambiguous | 1.1 | 2.18 | Destabilizing | 1.54 | Ambiguous | 1.09 | Destabilizing | -5.47 | Deleterious | 0.997 | Probably Damaging | 0.792 | Possibly Damaging | 3.32 | Benign | 0.01 | Affected | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||
| c.1382C>G | A461G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461G has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into three groups: benign predictions come from REVEL, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; the remaining tools (FoldX, premPS, AlphaMissense‑Default, Foldetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect, with no ClinVar record to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -11.360 | Likely Pathogenic | 0.556 | Ambiguous | Likely Benign | 0.276 | Likely Benign | 0.1988 | 0.3317 | 1.46 | Ambiguous | 0.1 | 2.06 | Destabilizing | 1.76 | Ambiguous | 0.83 | Ambiguous | -3.79 | Deleterious | 0.991 | Probably Damaging | 0.628 | Possibly Damaging | 3.32 | Benign | 0.00 | Affected | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||
| c.1382C>T | A461V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Because the majority of standard predictors (nine benign vs. three pathogenic) favor a benign outcome, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -9.968 | Likely Pathogenic | 0.436 | Ambiguous | Likely Benign | 0.141 | Likely Benign | 0.0819 | 0.5078 | -0.08 | Likely Benign | 0.3 | 0.34 | Likely Benign | 0.13 | Likely Benign | 0.02 | Likely Benign | -3.05 | Deleterious | 0.983 | Probably Damaging | 0.273 | Benign | 3.43 | Benign | 0.66 | Tolerated | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||
| c.1597G>A | A533T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533T is catalogued in gnomAD (6-33438840‑G‑A) but has no ClinVar entry. In silico predictors overwhelmingly favor a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, whereas only FATHMM predicts pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, the SGM Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts a benign stability change. Overall, the evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | 6-33438840-G-A | 2 | 1.24e-6 | -5.396 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.147 | Likely Benign | 0.1413 | 0.6541 | 0.30 | Likely Benign | 0.1 | 0.31 | Likely Benign | 0.31 | Likely Benign | 0.19 | Likely Benign | -0.48 | Neutral | 0.002 | Benign | 0.001 | Benign | -1.26 | Pathogenic | 0.11 | Tolerated | 3.37 | 35 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||
| c.1597G>C | A533P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict benign. Only FATHMM predicts pathogenic. Stability‑based methods are inconclusive: FoldX, Rosetta, and the combined Foldetta output are listed as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as unavailable. Overall, the consensus of the majority of tools indicates a benign impact. This prediction does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.951 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.187 | Likely Benign | 0.1925 | 0.5299 | -0.93 | Ambiguous | 0.3 | -0.92 | Ambiguous | -0.93 | Ambiguous | -0.18 | Likely Benign | -0.48 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.26 | Pathogenic | 0.09 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1597G>T | A533S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. When predictions are grouped by consensus, the benign group contains all tools except FATHMM, which stands alone in the pathogenic group. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates a benign effect. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.740 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.193 | Likely Benign | 0.2612 | 0.5334 | 0.24 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.10 | Likely Benign | -0.14 | Likely Benign | 0.33 | Neutral | 0.009 | Benign | 0.039 | Benign | -1.14 | Pathogenic | 0.45 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1598C>A | A533E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -10.810 | Likely Pathogenic | 0.553 | Ambiguous | Likely Benign | 0.314 | Likely Benign | 0.1147 | 0.1498 | -0.13 | Likely Benign | 0.0 | -0.26 | Likely Benign | -0.20 | Likely Benign | 0.43 | Likely Benign | -1.89 | Neutral | 0.259 | Benign | 0.107 | Benign | -1.18 | Pathogenic | 0.18 | Tolerated | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||
| c.1598C>G | A533G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533G resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome; Rosetta is uncertain and therefore not counted as evidence. High‑accuracy assessments—all of which are available—show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Benign, reinforcing the benign consensus. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.412 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.185 | Likely Benign | 0.2348 | 0.4737 | 0.32 | Likely Benign | 0.1 | 0.64 | Ambiguous | 0.48 | Likely Benign | 0.33 | Likely Benign | -1.94 | Neutral | 0.258 | Benign | 0.099 | Benign | -1.23 | Pathogenic | 0.23 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1598C>T | A533V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are SIFT and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as benign, all supporting a non‑pathogenic interpretation. No prediction or folding‑stability result is missing or inconclusive. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar evidence exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -6.948 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.170 | Likely Benign | 0.1243 | 0.6205 | 0.23 | Likely Benign | 0.0 | 0.51 | Ambiguous | 0.37 | Likely Benign | 0.25 | Likely Benign | -2.41 | Neutral | 0.149 | Benign | 0.024 | Benign | -1.28 | Pathogenic | 0.05 | Affected | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.1825G>A | G609R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that remain uncertain are Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) predict a pathogenic impact for G609R. 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 | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.172 | Likely Pathogenic | 0.543 | Ambiguous | Likely Benign | 0.520 | Likely Pathogenic | 0.1158 | 0.4348 | 2.09 | Destabilizing | 0.1 | 0.37 | Likely Benign | 1.23 | Ambiguous | 0.60 | Ambiguous | -2.68 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.41 | Pathogenic | 0.07 | Tolerated | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.1825G>C | G609R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that remain uncertain are Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) predict a pathogenic impact for G609R. 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 | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.172 | Likely Pathogenic | 0.543 | Ambiguous | Likely Benign | 0.520 | Likely Pathogenic | 0.1158 | 0.4348 | 2.09 | Destabilizing | 0.1 | 0.37 | Likely Benign | 1.23 | Ambiguous | 0.60 | Ambiguous | -2.68 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.41 | Pathogenic | 0.07 | Tolerated | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.1825G>T | G609W 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant G609W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are premPS and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM) uniformly predict a pathogenic outcome. Two tools report inconclusive results (Foldetta and AlphaMissense‑Default) and are treated as unavailable evidence. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates a benign change, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports pathogenicity, and Foldetta’s stability assessment is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for G609W, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -13.074 | Likely Pathogenic | 0.525 | Ambiguous | Likely Benign | 0.566 | Likely Pathogenic | 0.0935 | 0.3181 | 3.14 | Destabilizing | 0.7 | -0.87 | Ambiguous | 1.14 | Ambiguous | 0.28 | Likely Benign | -4.70 | Deleterious | 0.999 | Probably Damaging | 0.976 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||
| c.1826G>A | G609E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609E has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools (Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.470 | Likely Pathogenic | 0.421 | Ambiguous | Likely Benign | 0.531 | Likely Pathogenic | 0.1709 | 0.4491 | 2.95 | Destabilizing | 0.4 | -1.65 | Ambiguous | 0.65 | Ambiguous | 0.61 | Ambiguous | -2.28 | Neutral | 0.916 | Possibly Damaging | 0.588 | Possibly Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||
| c.1826G>C | G609A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, PROVEAN, and FATHMM. One tool, Foldetta, yields an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -6.790 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.494 | Likely Benign | 0.3812 | 0.3896 | 2.38 | Destabilizing | 0.3 | 0.01 | Likely Benign | 1.20 | Ambiguous | 0.43 | Likely Benign | -2.65 | Deleterious | 0.282 | Benign | 0.164 | Benign | -1.43 | Pathogenic | 0.10 | Tolerated | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||
| 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 | 0.734 | Likely Pathogenic | 0.1269 | 0.3317 | 4.17 | Destabilizing | 0.3 | 3.77 | Destabilizing | 3.97 | Destabilizing | 0.34 | Likely Benign | -4.47 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.48 | Pathogenic | 0.02 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||
| c.685A>C | K229Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K229Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, FATHMM, and Foldetta; pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment does not conflict with ClinVar status, which currently has no entry for K229Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -9.606 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.813 | Likely Pathogenic | 0.4456 | 0.1057 | 0.41 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.18 | Likely Benign | 0.55 | Ambiguous | -3.03 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.84 | Benign | 0.02 | Affected | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||
| c.685A>G | K229E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K229E is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that classify the variant as benign include FoldX, Rosetta, premPS, SIFT, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall distribution of predictions, the variant is most likely pathogenic; this conclusion does not contradict the ClinVar status, which currently has no entry for K229E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -12.828 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.816 | Likely Pathogenic | 0.3915 | 0.0793 | 0.47 | Likely Benign | 0.0 | 0.24 | Likely Benign | 0.36 | Likely Benign | 0.18 | Likely Benign | -3.10 | Deleterious | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.84 | Benign | 0.09 | Tolerated | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.686A>C | K229T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K229T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, Foldetta, premPS, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. High‑accuracy methods give a pathogenic result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a benign outcome from Foldetta. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -12.639 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.813 | Likely Pathogenic | 0.1890 | 0.3029 | 0.83 | Ambiguous | 0.0 | -0.08 | Likely Benign | 0.38 | Likely Benign | 0.00 | Likely Benign | -4.77 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.86 | Benign | 0.01 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.686A>G | K229R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229R missense variant is catalogued in gnomAD (ID 6‑33435537‑A‑G) but has no entry in ClinVar. Functional prediction tools largely agree on a benign effect: FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. In contrast, REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar predict pathogenic. AlphaMissense‑Default is uncertain and is treated as unavailable. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | 6-33435537-A-G | 1 | 6.20e-7 | -5.651 | Likely Benign | 0.437 | Ambiguous | Likely Benign | 0.628 | Likely Pathogenic | 0.4921 | 0.0972 | 0.09 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.06 | Likely Benign | 0.40 | Likely Benign | -2.00 | Neutral | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.84 | Benign | 0.19 | Tolerated | 3.43 | 12 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||
| c.686A>T | K229I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K229I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from FoldX, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports benign. No prediction is inconclusive. Overall, the majority of tools, including the high‑accuracy ones, lean toward pathogenicity, and this does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -15.276 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.833 | Likely Pathogenic | 0.1202 | 0.3711 | -0.03 | Likely Benign | 0.1 | -0.63 | Ambiguous | -0.33 | Likely Benign | -0.19 | Likely Benign | -6.52 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.92 | Benign | 0.00 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||
| c.687A>C | K229N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -13.620 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.590 | Likely Pathogenic | 0.3682 | 0.1013 | 0.82 | Ambiguous | 0.1 | 0.64 | Ambiguous | 0.73 | Ambiguous | 0.61 | Ambiguous | -3.79 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.83 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.687A>T | K229N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining nine tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain and therefore not considered evidence for or against pathogenicity. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -13.620 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.588 | Likely Pathogenic | 0.3682 | 0.1013 | 0.82 | Ambiguous | 0.1 | 0.64 | Ambiguous | 0.73 | Ambiguous | 0.61 | Ambiguous | -3.79 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.83 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.955G>A | A319T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are polyPhen2_HumDiv and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of reliable predictors classify the variant as benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -7.841 | In-Between | 0.098 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.1274 | 0.6083 | 0.55 | Ambiguous | 0.3 | 0.70 | Ambiguous | 0.63 | Ambiguous | 0.30 | Likely Benign | -1.35 | Neutral | 0.775 | Possibly Damaging | 0.306 | Benign | 1.92 | Pathogenic | 0.09 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||
| c.955G>C | A319P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319P is catalogued in gnomAD (ID 6‑33437860‑G‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive are Rosetta, ESM1b, and Foldetta. 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, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | 6-33437860-G-C | 3 | 1.86e-6 | -7.213 | In-Between | 0.109 | Likely Benign | Likely Benign | 0.286 | Likely Benign | 0.1839 | 0.5067 | -0.02 | Likely Benign | 0.9 | -1.18 | Ambiguous | -0.60 | Ambiguous | 0.22 | Likely Benign | 0.11 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 1.97 | Pathogenic | 1.00 | Tolerated | 3.38 | 23 | -1 | 1 | -3.4 | 26.04 | |||||||||||||||||||||
| c.955G>T | A319S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -7.109 | In-Between | 0.093 | Likely Benign | Likely Benign | 0.165 | Likely Benign | 0.2537 | 0.4703 | 0.16 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.09 | Likely Benign | 0.13 | Likely Benign | -0.58 | Neutral | 0.978 | Probably Damaging | 0.754 | Possibly Damaging | 2.02 | Pathogenic | 0.12 | Tolerated | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||
| c.956C>A | A319D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A319D missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a likely pathogenic verdict (3/4 pathogenic votes). High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, whereas the SGM‑Consensus remains pathogenic. Foldetta, which integrates FoldX‑MD (benign) and Rosetta (uncertain), is considered unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -11.144 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | 0.373 | Likely Benign | 0.1504 | 0.1360 | -0.02 | Likely Benign | 0.2 | -0.84 | Ambiguous | -0.43 | Likely Benign | 0.30 | Likely Benign | -2.38 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 2.01 | Pathogenic | 0.20 | Tolerated | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||
| c.956C>G | A319G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenicity, while Rosetta remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -6.505 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.219 | Likely Benign | 0.2345 | 0.4532 | 0.11 | Likely Benign | 0.4 | 0.56 | Ambiguous | 0.34 | Likely Benign | 0.39 | Likely Benign | -1.83 | Neutral | 0.994 | Probably Damaging | 0.900 | Possibly Damaging | 1.89 | Pathogenic | 0.09 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.956C>T | A319V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A319V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is also inconclusive. Overall, the majority of evidence points to a benign effect, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -8.179 | Likely Pathogenic | 0.141 | Likely Benign | Likely Benign | 0.329 | Likely Benign | 0.1094 | 0.6390 | 0.58 | Ambiguous | 0.4 | 0.63 | Ambiguous | 0.61 | Ambiguous | 0.23 | Likely Benign | -2.32 | Neutral | 0.989 | Probably Damaging | 0.824 | Possibly Damaging | 1.88 | Pathogenic | 0.10 | Tolerated | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||
| 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 | 0.399 | Likely Benign | 0.1516 | 0.1885 | 5.62 | Destabilizing | 0.2 | 5.62 | Destabilizing | 5.62 | Destabilizing | 1.33 | Destabilizing | -5.70 | Deleterious | 0.894 | Possibly Damaging | 0.332 | Benign | 2.74 | Benign | 0.00 | Affected | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||
| c.1450T>C | F484L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic vs. 1 benign) and therefore also indicates pathogenicity. AlphaMissense‑Optimized independently predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, seven tools predict pathogenicity versus four predicting benign, and the high‑accuracy consensus supports a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -11.052 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.275 | Likely Benign | 0.1737 | 0.2956 | 1.52 | Ambiguous | 0.0 | 1.32 | Ambiguous | 1.42 | Ambiguous | 1.20 | Destabilizing | -5.64 | Deleterious | 0.054 | Benign | 0.022 | Benign | 3.20 | Benign | 0.04 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.1450T>G | F484V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -15.492 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.455 | Likely Benign | 0.1696 | 0.1902 | 6.08 | Destabilizing | 0.1 | 6.07 | Destabilizing | 6.08 | Destabilizing | 1.28 | Destabilizing | -6.70 | Deleterious | 0.859 | Possibly Damaging | 0.526 | Possibly Damaging | 2.75 | Benign | 0.00 | Affected | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||
| c.1451T>A | F484Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FATHMM, and polyPhen‑2 HumVar, whereas the majority of other in silico predictors (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic effect. Stability‑based methods FoldX and Rosetta are inconclusive, and Foldetta likewise reports no definitive change. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence supports a pathogenic classification for F484Y, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -14.223 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.356 | Likely Benign | 0.1056 | 0.1595 | 1.70 | Ambiguous | 0.1 | 0.92 | Ambiguous | 1.31 | Ambiguous | 1.26 | Destabilizing | -2.92 | Deleterious | 0.733 | Possibly Damaging | 0.344 | Benign | 2.66 | Benign | 0.02 | Affected | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||
| c.1451T>C | F484S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -15.666 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.705 | Likely Pathogenic | 0.3993 | 0.0200 | 4.68 | Destabilizing | 0.1 | 4.42 | Destabilizing | 4.55 | Destabilizing | 2.26 | Destabilizing | -7.76 | Deleterious | 1.000 | Probably Damaging | 0.986 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||
| c.1451T>G | F484C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -14.988 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.675 | Likely Pathogenic | 0.2449 | 0.0902 | 4.01 | Destabilizing | 0.0 | 3.54 | Destabilizing | 3.78 | Destabilizing | 2.07 | Destabilizing | -7.73 | Deleterious | 1.000 | Probably Damaging | 0.969 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||
| c.1452C>A | F484L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic vs. 1 benign) and therefore also indicates pathogenicity. AlphaMissense‑Optimized independently predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, seven tools predict pathogenicity versus four predicting benign, and the high‑accuracy consensus supports a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -11.052 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.214 | Likely Benign | 0.1737 | 0.2956 | 1.52 | Ambiguous | 0.0 | 1.32 | Ambiguous | 1.42 | Ambiguous | 1.20 | Destabilizing | -5.64 | Deleterious | 0.054 | Benign | 0.022 | Benign | 3.20 | Benign | 0.04 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.1452C>G | F484L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Overall, seven tools predict pathogenicity versus four predicting benign, and the high‑accuracy methods reinforce the pathogenic signal. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -11.052 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.214 | Likely Benign | 0.1737 | 0.2956 | 1.52 | Ambiguous | 0.0 | 1.32 | Ambiguous | 1.42 | Ambiguous | 1.20 | Destabilizing | -5.64 | Deleterious | 0.054 | Benign | 0.022 | Benign | 3.20 | Benign | 0.04 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| 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 | 0.557 | Likely Pathogenic | 0.2098 | 0.5395 | 3.05 | Destabilizing | 0.2 | 5.36 | Destabilizing | 4.21 | Destabilizing | 0.78 | Ambiguous | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.06 | Tolerated | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||
| c.1372A>G | T458A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T458A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign. Overall, the majority of reliable predictors (six pathogenic vs. five benign) indicate a pathogenic effect. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -10.734 | Likely Pathogenic | 0.924 | Likely Pathogenic | Ambiguous | 0.358 | Likely Benign | 0.4137 | 0.4257 | 0.36 | Likely Benign | 0.0 | 0.31 | Likely Benign | 0.34 | Likely Benign | 0.56 | Ambiguous | -4.27 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.40 | Benign | 0.15 | Tolerated | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||
| c.1372A>T | T458S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T458S missense variant has no ClinVar entry and is not present in gnomAD. Functional prediction tools cluster into two groups: benign calls from REVEL, FoldX, Rosetta, SIFT, and FATHMM; pathogenic calls from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments further split the signal: AlphaMissense‑Optimized remains uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Because the majority of standard predictors are evenly divided and the high‑accuracy methods disagree, the variant’s effect cannot be confidently classified as benign or pathogenic. Thus, the variant is of uncertain significance, and this uncertainty does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -8.465 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 0.260 | Likely Benign | 0.3525 | 0.4349 | 0.44 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.40 | Likely Benign | 0.55 | Ambiguous | -3.49 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.48 | Benign | 0.13 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.1373C>A | T458K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T458K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results from FoldX and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting pathogenicity, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicting pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting benign stability. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -13.734 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.373 | Likely Benign | 0.1153 | 0.3326 | -0.59 | Ambiguous | 0.1 | -0.26 | Likely Benign | -0.43 | Likely Benign | 0.80 | Ambiguous | -5.23 | Deleterious | 0.999 | Probably Damaging | 0.973 | Probably Damaging | 3.40 | Benign | 0.14 | Tolerated | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||
| c.1373C>G | T458R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T458R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, and FATHMM, whereas a larger set—SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. Uncertain results come from FoldX and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -12.984 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.390 | Likely Benign | 0.1016 | 0.3013 | -0.81 | Ambiguous | 0.1 | -0.11 | Likely Benign | -0.46 | Likely Benign | 0.61 | Ambiguous | -5.26 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.52 | Benign | 0.20 | Tolerated | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||
| c.1373C>T | T458I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T458I missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (seven versus six) and the two high‑accuracy pathogenic predictions suggest the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -9.436 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.337 | Likely Benign | 0.0724 | 0.6128 | -0.40 | Likely Benign | 0.1 | 0.29 | Likely Benign | -0.06 | Likely Benign | 0.50 | Likely Benign | -4.76 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.09 | Tolerated | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||
| c.1375G>A | G459S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from REVEL and FATHMM, while pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -10.979 | Likely Pathogenic | 0.873 | Likely Pathogenic | Ambiguous | 0.414 | Likely Benign | 0.2340 | 0.5197 | 2.34 | Destabilizing | 0.1 | 0.77 | Ambiguous | 1.56 | Ambiguous | 0.60 | Ambiguous | -5.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.09 | Benign | 0.05 | Affected | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||
| c.1375G>C | G459R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G459R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM Consensus score (Likely Pathogenic) all indicate a pathogenic impact. Stability‑based methods (FoldX, Rosetta, premPS) are inconclusive, and Foldetta likewise reports an uncertain effect. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as Likely Pathogenic, and Foldetta as unavailable. Taken together, the consensus of the majority of tools points to a pathogenic effect for G459R. This prediction is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -12.958 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.486 | Likely Benign | 0.0903 | 0.4248 | 1.84 | Ambiguous | 0.2 | 0.79 | Ambiguous | 1.32 | Ambiguous | 0.79 | Ambiguous | -7.41 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.1375G>T | G459C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the majority of algorithms (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence points to a pathogenic effect for G459C, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -12.109 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.586 | Likely Pathogenic | 0.0960 | 0.4103 | 2.46 | Destabilizing | 0.2 | 1.49 | Ambiguous | 1.98 | Ambiguous | 0.65 | Ambiguous | -8.46 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||
| c.1376G>A | G459D 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant G459D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate benign effects include REVEL and FATHMM, while the majority of tools predict pathogenicity: FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as inconclusive. Overall, the evidence points to a pathogenic effect for G459D, and this conclusion does not conflict with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -11.258 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.454 | Likely Benign | 0.1466 | 0.1905 | 2.21 | Destabilizing | 0.1 | 0.56 | Ambiguous | 1.39 | Ambiguous | 0.93 | Ambiguous | -6.18 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.07 | Benign | 0.05 | Affected | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||
| c.1376G>C | G459A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G459A missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled Uncertain (Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is Uncertain and therefore not considered evidence. Overall, the majority of reliable tools indicate a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -11.684 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.469 | Likely Benign | 0.3529 | 0.5161 | 2.44 | Destabilizing | 0.1 | 0.90 | Ambiguous | 1.67 | Ambiguous | 0.72 | Ambiguous | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.06 | Benign | 0.01 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.1376G>T | G459V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; premPS is inconclusive and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for G459V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -13.606 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.605 | Likely Pathogenic | 0.0997 | 0.4240 | 3.79 | Destabilizing | 0.1 | 5.01 | Destabilizing | 4.40 | Destabilizing | 0.71 | Ambiguous | -8.46 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.99 | Benign | 0.00 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||
| c.706G>A | A236T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A236T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and thus unavailable. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, six tools favor pathogenicity versus three favor benign, and no high‑confidence consensus tool contradicts this trend. Therefore, the variant is most likely pathogenic, and this assessment does not conflict with any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -8.319 | Likely Pathogenic | 0.240 | Likely Benign | Likely Benign | 0.811 | Likely Pathogenic | 0.1342 | 0.6926 | 0.73 | Ambiguous | 0.2 | 1.58 | Ambiguous | 1.16 | Ambiguous | 0.83 | Ambiguous | -3.35 | Deleterious | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 5.79 | Benign | 0.03 | Affected | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||
| c.706G>C | A236P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A236P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include Foldetta, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas those that predict a pathogenic outcome are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Default; the remaining tools (FoldX, Rosetta, premPS, ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. No prediction or stability result is missing or inconclusive. Overall, the majority of individual tools lean toward pathogenicity, but the two most reliable high‑accuracy methods (AlphaMissense‑Optimized and Foldetta) suggest a benign effect, while the SGM Consensus indicates pathogenicity. Given the mixed evidence, the variant is most likely benign based on the strongest high‑accuracy predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -7.932 | In-Between | 0.621 | Likely Pathogenic | Likely Benign | 0.862 | Likely Pathogenic | 0.1980 | 0.4897 | -0.99 | Ambiguous | 0.1 | 1.44 | Ambiguous | 0.23 | Likely Benign | 0.67 | Ambiguous | -4.31 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.78 | Benign | 0.12 | Tolerated | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||
| c.706G>T | A236S 2D AIThe SynGAP1 A236S variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, premPS, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for A236S, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -7.845 | In-Between | 0.106 | Likely Benign | Likely Benign | 0.648 | Likely Pathogenic | 0.2641 | 0.5547 | 0.40 | Likely Benign | 0.5 | 1.24 | Ambiguous | 0.82 | Ambiguous | 0.65 | Ambiguous | -2.30 | Neutral | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.83 | Benign | 0.13 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.707C>A | A236E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236E is not reported in ClinVar and is present in gnomAD (ID 6‑33435558‑C‑A). Functional prediction tools show a split assessment: benign calls come from FATHMM, Rosetta, and the protein‑folding stability method Foldetta; pathogenic calls come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. When grouped by agreement, the benign‑predicting tools (FATHMM, Rosetta, Foldetta) represent one consensus, while the pathogenic‑predicting tools (REVEL, premPS, PROVEAN, polyPhen‑2, SIFT, ESM1b, AlphaMissense‑Default, SGM‑Consensus) form the opposing consensus. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely pathogenic; Foldetta, combining FoldX‑MD and Rosetta outputs, is benign. Overall, the majority of predictions lean toward pathogenicity, and this does not contradict the ClinVar status, which has no reported classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | 6-33435558-C-A | 1 | 6.20e-7 | -10.844 | Likely Pathogenic | 0.835 | Likely Pathogenic | Ambiguous | 0.844 | Likely Pathogenic | 0.1075 | 0.1970 | -0.75 | Ambiguous | 0.2 | 0.28 | Likely Benign | -0.24 | Likely Benign | 1.08 | Destabilizing | -4.24 | Deleterious | 0.998 | Probably Damaging | 0.900 | Possibly Damaging | 6.06 | Benign | 0.02 | Affected | 3.40 | 14 | -1 | 0 | -5.3 | 58.04 | ||||||||||||||||||||
| c.707C>G | A236G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A236G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, premPS, and PROVEAN. Four tools (FoldX, Rosetta, Foldetta, and ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign, while Foldetta remains uncertain. Overall, the majority of available predictions support a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -7.412 | In-Between | 0.162 | Likely Benign | Likely Benign | 0.615 | Likely Pathogenic | 0.2200 | 0.3899 | 0.92 | Ambiguous | 0.1 | 1.15 | Ambiguous | 1.04 | Ambiguous | 1.09 | Destabilizing | -3.35 | Deleterious | 0.067 | Benign | 0.028 | Benign | 5.74 | Benign | 0.07 | Tolerated | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||
| c.707C>T | A236V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236V is listed in ClinVar as Benign (ID 469162.0) and is present in gnomAD (6‑33435558‑C‑T). Prediction tools that report benign include polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b. Four tools give uncertain or inconclusive results: FoldX, Rosetta, Foldetta, and premPS. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are evenly split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as uncertain, and the SGM Consensus as unavailable. Consequently, the overall prediction profile is mixed, but the most reliable high‑accuracy evidence points toward a benign effect. Therefore, the variant is most likely benign, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | Benign/Likely benign | 2 | 6-33435558-C-T | 6 | 3.72e-6 | -8.752 | Likely Pathogenic | 0.267 | Likely Benign | Likely Benign | 0.777 | Likely Pathogenic | 0.0913 | 0.5859 | 0.61 | Ambiguous | 0.2 | 1.08 | Ambiguous | 0.85 | Ambiguous | 0.64 | Ambiguous | -3.55 | Deleterious | 0.981 | Probably Damaging | 0.446 | Benign | 5.79 | Benign | 0.03 | Affected | 3.40 | 14 | 0 | 0 | 2.4 | 28.05 | 213.8 | -44.7 | 0.0 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | The methyl side chain of Ala236, located on an α helix (residues Ala236-Val250) facing an anti-parallel β sheet strand (residues Ile205-Val209), interacts hydrophobically with nearby residues such as Arg239 and Phe218. In the variant simulations, the isopropyl branched hydrocarbon side chain of Val236 maintains similar hydrophobic interactions as alanine in the WT, with an overall arrangement remarkably similar to Ala236. The residue swap does not affect the protein structure based on the simulations. | ||||||||||
| c.790C>A | L264I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L264I is not reported in ClinVar and is present in gnomAD (ID 6‑33437695‑C‑A). Prediction tools that indicate a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the balance of evidence—six pathogenic versus three benign predictions, a pathogenic SGM Consensus, and an uncertain Foldetta—suggests that the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | 6-33437695-C-A | 1 | 6.20e-7 | -10.945 | Likely Pathogenic | 0.638 | Likely Pathogenic | Likely Benign | 0.418 | Likely Benign | 0.0764 | 0.2630 | 1.90 | Ambiguous | 0.5 | 0.84 | Ambiguous | 1.37 | Ambiguous | 0.95 | Ambiguous | -1.84 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 0.66 | Pathogenic | 0.02 | Affected | 3.38 | 18 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||
| c.790C>G | L264V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized; all other evaluated algorithms (SGM‑Consensus, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic or likely pathogenic outcome, while Rosetta remains uncertain. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies the variant as Pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for L264V, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | -10.621 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | 0.444 | Likely Benign | 0.1280 | 0.2289 | 2.55 | Destabilizing | 0.1 | 1.62 | Ambiguous | 2.09 | Destabilizing | 1.24 | Destabilizing | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 0.73 | Pathogenic | 0.01 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.791T>A | L264Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264Q is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | Uncertain | 1 | -15.729 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.678 | Likely Pathogenic | 0.0942 | 0.0558 | 3.43 | Destabilizing | 0.1 | 2.41 | Destabilizing | 2.92 | Destabilizing | 2.48 | Destabilizing | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | 3.38 | 18 | -2 | -2 | -7.3 | 14.97 | 254.7 | -7.6 | 0.0 | 0.0 | 0.0 | 0.3 | X | X | X | Potentially Pathogenic | The iso-butyl branched hydrocarbon side chain of Leu264, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), packs against multiple hydrophobic residues such as Leu266, Phe314, Leu317, and Leu323 in the WT simulations. In the variant simulations, the hydrophilic carboxamide group of the Gln264 side chain is not suitable for the hydrophobic niche, causing the hydrophobic residues to make room for the swapped residue. Additionally, the carboxamide group of Gln264 forms hydrogen bonds with the backbone amide groups of Arg405 and Lys256 in the β sheet and the carbonyl group of Val350 in an α helical section of a nearby loop (res. Pro359-Phe358). The residue swap disrupts the packing of the C2 domain, which could adversely affect the C2 domain structure during folding. This disruption could potentially weaken the stability of the SynGAP-membrane association. | ||||||||||
| c.791T>C | L264P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset reports a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | Uncertain | 1 | -12.285 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.767 | Likely Pathogenic | 0.3239 | 0.1053 | 5.73 | Destabilizing | 0.3 | 6.57 | Destabilizing | 6.15 | Destabilizing | 2.65 | Destabilizing | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||
| c.791T>G | L264R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264R is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | -16.976 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.742 | Likely Pathogenic | 0.1132 | 0.0558 | 4.25 | Destabilizing | 0.3 | 3.37 | Destabilizing | 3.81 | Destabilizing | 2.28 | Destabilizing | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.958G>A | V320I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta remains inconclusive. High‑accuracy assessments corroborate the benign trend: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence points to a benign effect for V320I, and this conclusion does not conflict with the current ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | Uncertain | 1 | -5.220 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.0514 | 0.3207 | -0.27 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.20 | Likely Benign | 0.01 | Likely Benign | -0.21 | Neutral | 0.198 | Benign | 0.114 | Benign | 1.77 | Pathogenic | 0.45 | Tolerated | 3.38 | 23 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||||
| c.958G>C | V320L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437863‑G‑C). Functional prediction tools that agree on benign impact include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Pathogenic predictions come from polyPhen‑2 HumDiv and FATHMM, while Rosetta, Foldetta, premPS, and AlphaMissense‑Default are inconclusive. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a benign verdict. AlphaMissense‑Optimized also predicts benign, whereas Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | Uncertain | 2 | 6-33437863-G-C | 6 | 3.72e-6 | -6.207 | Likely Benign | 0.362 | Ambiguous | Likely Benign | 0.096 | Likely Benign | 0.0661 | 0.3863 | -0.26 | Likely Benign | 0.2 | 1.33 | Ambiguous | 0.54 | Ambiguous | 0.51 | Ambiguous | -1.02 | Neutral | 0.900 | Possibly Damaging | 0.373 | Benign | 1.78 | Pathogenic | 0.92 | Tolerated | 3.38 | 23 | 2 | 1 | -0.4 | 14.03 | 245.8 | -10.2 | 0.3 | 0.9 | 0.1 | 0.3 | X | Potentially Benign | The isopropyl side chain of Val310, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), hydrophobically packs with the side chains of nearby residues (e.g., Leu286, Val350, Pro318). The hydrophobic Leu320 side chain mostly forms the same interactions; hence, the residue swap does not seem to negatively affect the protein structure based on the variant simulations. | ||||||||||
| c.958G>T | V320F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V320F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on benign impact include REVEL, premPS, and SIFT, whereas tools that agree on pathogenic impact include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as inconclusive. Because the majority of available predictions and the SGM‑Consensus favor pathogenicity, the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for V320F. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | -9.958 | Likely Pathogenic | 0.877 | Likely Pathogenic | Ambiguous | 0.237 | Likely Benign | 0.0473 | 0.3064 | 1.49 | Ambiguous | 1.4 | 1.55 | Ambiguous | 1.52 | Ambiguous | 0.44 | Likely Benign | -3.26 | Deleterious | 0.994 | Probably Damaging | 0.944 | Probably Damaging | 1.79 | Pathogenic | 0.06 | Tolerated | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||
| c.959T>A | V320D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL and SIFT; pathogenic predictions from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods FoldX and Rosetta returned uncertain results, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also yielded an uncertain prediction. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect, which is consistent with the lack of ClinVar annotation and gnomAD absence. Thus, the variant is most likely pathogenic, and this prediction does not contradict ClinVar status because ClinVar has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | -11.269 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.405 | Likely Benign | 0.1101 | 0.0482 | 1.99 | Ambiguous | 1.0 | 1.67 | Ambiguous | 1.83 | Ambiguous | 1.50 | Destabilizing | -5.58 | Deleterious | 0.999 | Probably Damaging | 0.972 | Probably Damaging | 1.93 | Pathogenic | 0.07 | Tolerated | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||
| c.959T>C | V320A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V320A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Four tools (AlphaMissense‑Default, FoldX, Rosetta, Foldetta) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy consensus leans toward pathogenic. Thus, the variant is most likely pathogenic, with no contradiction to ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | -5.488 | Likely Benign | 0.545 | Ambiguous | Likely Benign | 0.179 | Likely Benign | 0.2405 | 0.1903 | 1.26 | Ambiguous | 0.7 | 1.48 | Ambiguous | 1.37 | Ambiguous | 1.27 | Destabilizing | -3.05 | Deleterious | 0.948 | Possibly Damaging | 0.761 | Possibly Damaging | 1.84 | Pathogenic | 0.35 | Tolerated | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||
| c.959T>G | V320G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools cluster into two agreement groups: the single benign prediction comes from REVEL, while the pathogenic group includes FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—returns pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. Overall, the preponderance of evidence indicates that V320G is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | -9.043 | Likely Pathogenic | 0.816 | Likely Pathogenic | Ambiguous | 0.438 | Likely Benign | 0.1688 | 0.1949 | 2.15 | Destabilizing | 1.1 | 1.87 | Ambiguous | 2.01 | Destabilizing | 1.48 | Destabilizing | -5.74 | Deleterious | 0.958 | Probably Damaging | 0.999 | Probably Damaging | 1.89 | Pathogenic | 0.02 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1363C>A | L455M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L455M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. No folding‑stability method provides a definitive result. Consequently, the computational evidence does not favor either benign or pathogenic classification. The variant’s status is therefore inconclusive, and this lack of consensus does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -10.086 | Likely Pathogenic | 0.802 | Likely Pathogenic | Ambiguous | 0.147 | Likely Benign | 0.0606 | 0.3362 | 0.88 | Ambiguous | 0.0 | 1.27 | Ambiguous | 1.08 | Ambiguous | 0.59 | Ambiguous | -1.64 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.11 | Tolerated | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||
| c.1363C>G | L455V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, whereas the remaining 11 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict pathogenicity. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -12.773 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.276 | Likely Benign | 0.1149 | 0.3056 | 2.89 | Destabilizing | 0.1 | 2.38 | Destabilizing | 2.64 | Destabilizing | 1.41 | Destabilizing | -2.83 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.29 | Benign | 0.02 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1364T>A | L455Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455Q is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -13.075 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.655 | Likely Pathogenic | 0.0871 | 0.0958 | 2.84 | Destabilizing | 0.0 | 3.42 | Destabilizing | 3.13 | Destabilizing | 2.24 | Destabilizing | -5.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1364T>C | L455P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -14.150 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.695 | Likely Pathogenic | 0.3211 | 0.1221 | 7.45 | Destabilizing | 0.2 | 11.99 | Destabilizing | 9.72 | Destabilizing | 2.19 | Destabilizing | -6.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1364T>G | L455R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455R resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -16.347 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.648 | Likely Pathogenic | 0.1126 | 0.0600 | 6.36 | Destabilizing | 0.2 | 4.96 | Destabilizing | 5.66 | Destabilizing | 2.08 | Destabilizing | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1453C>A | R485S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that return uncertain results are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for R485S, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | Uncertain | 1 | -15.603 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.609 | Likely Pathogenic | 0.2968 | 0.3266 | 0.40 | Likely Benign | 0.1 | 1.07 | Ambiguous | 0.74 | Ambiguous | 0.82 | Ambiguous | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||
| c.1453C>G | R485G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485G is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33438485‑C‑G). Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tools predict a benign outcome. Uncertain or inconclusive predictions come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Overall, the evidence strongly favors a pathogenic classification, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | 6-33438485-C-G | 1 | 6.20e-7 | -15.777 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.631 | Likely Pathogenic | 0.3140 | 0.2678 | 0.84 | Ambiguous | 0.1 | 1.60 | Ambiguous | 1.22 | Ambiguous | 0.98 | Ambiguous | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.92 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||
| c.1453C>T | R485C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485C (gnomAD ID 6‑33438485‑C‑T) is listed in ClinVar with an uncertain significance. Functional prediction tools largely disagree: benign calls come from Rosetta and premPS, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus is labeled likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. With the majority of evidence pointing to pathogenicity and no contradictory data from ClinVar, the variant is most likely pathogenic, although ClinVar has not yet reached a definitive classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | Uncertain | 2 | 6-33438485-C-T | 9 | 5.58e-6 | -14.294 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.597 | Likely Pathogenic | 0.3350 | 0.2762 | 1.00 | Ambiguous | 0.1 | 0.26 | Likely Benign | 0.63 | Ambiguous | 0.44 | Likely Benign | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.90 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -4 | -3 | 7.0 | -53.05 | 225.5 | 99.6 | -0.1 | 0.0 | -0.3 | 0.2 | X | Uncertain | The guanidinium group of Arg485 is located in a short helical structure (res. Glu480-Leu482) within an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. The side chain of Arg485 acts as the “arginine finger” of SynGAP, playing a crucial role in Ras-GTPase activation. Consequently, the residue swap inhibits the conversion of GTP to GDP at the enzyme’s active site. Although no negative effects on the protein structure are observed during the simulations, no definite conclusions can be drawn due to the critical role of Arg485 in GTPase activation. | |||||||||
| c.1454G>A | R485H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R485H missense variant is listed in ClinVar as Benign (ClinVar ID 3707943.0) and is present in the gnomAD database (gnomAD ID 6‑33438486‑G‑A). Functional prediction tools that agree on a benign effect are Rosetta and Foldetta, while the majority of tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | Likely Benign | 1 | 6-33438486-G-A | 13 | 8.05e-6 | -13.628 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.618 | Likely Pathogenic | 0.2990 | 0.1602 | 0.77 | Ambiguous | 0.1 | 0.12 | Likely Benign | 0.45 | Likely Benign | 1.13 | Destabilizing | -4.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0 | 2 | 1.3 | -19.05 | ||||||||||||||||||
| c.1454G>C | R485P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485P is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic scores. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | -16.356 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.692 | Likely Pathogenic | 0.2059 | 0.3941 | 5.26 | Destabilizing | 0.3 | 6.86 | Destabilizing | 6.06 | Destabilizing | 0.56 | Ambiguous | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.94 | Pathogenic | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.1454G>T | R485L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485L is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which is currently unreported. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | -15.807 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.631 | Likely Pathogenic | 0.1715 | 0.3784 | 0.23 | Likely Benign | 0.2 | 0.14 | Likely Benign | 0.19 | Likely Benign | 0.39 | Likely Benign | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.92 | Pathogenic | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.172A>C | M58L 2D  AIThe SynGAP1 missense variant M58L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. Only SIFT predicts a deleterious impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus result is benign; Foldetta data are not available. Consequently, the aggregate evidence points to a benign effect for M58L, 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 | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | -0.661 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.208 | Likely Benign | 0.1514 | 0.4621 | -0.11 | Neutral | 0.006 | Benign | 0.039 | Benign | 4.77 | Benign | 0.00 | Affected | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.172A>G | M58V 2D  AIThe SynGAP1 missense variant M58V is listed in ClinVar (ID 2962156.0) with an uncertain significance status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The high‑accuracy consensus from AlphaMissense‑Optimized, SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta (protein‑folding stability) is available only for the first two; Foldetta data are missing. The SGM Consensus, based on a majority of benign predictions, indicates a likely benign outcome. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | Uncertain | 1 | -2.211 | Likely Benign | 0.688 | Likely Pathogenic | Likely Benign | 0.160 | Likely Benign | 0.2951 | 0.3917 | -0.71 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||
| c.172A>T | M58L 2D AIThe SynGAP1 missense variant M58L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | -0.661 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.208 | Likely Benign | 0.1514 | 0.4621 | -0.11 | Neutral | 0.006 | Benign | 0.039 | Benign | 4.77 | Benign | 0.00 | Affected | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.173T>A | M58K 2D  AIThe SynGAP1 missense variant M58K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | -6.059 | Likely Benign | 0.939 | Likely Pathogenic | Ambiguous | 0.199 | Likely Benign | 0.1615 | 0.1163 | -1.52 | Neutral | 0.018 | Benign | 0.184 | Benign | 4.08 | Benign | 0.00 | Affected | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||
| c.173T>C | M58T 2D  AIThe SynGAP1 missense variant M58T is listed in gnomAD (ID 6‑33423582‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | 6-33423582-T-C | 1 | 6.20e-7 | -4.308 | Likely Benign | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.159 | Likely Benign | 0.1999 | 0.2357 | -1.58 | Neutral | 0.018 | Benign | 0.184 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||
| c.173T>G | M58R 2D  AIThe SynGAP1 missense variant M58R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments therefore indicate a benign likelihood: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus is benign, and Foldetta data are missing. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | -5.035 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.237 | Likely Benign | 0.1745 | 0.1113 | -1.78 | Neutral | 0.042 | Benign | 0.184 | Benign | 4.07 | Benign | 0.00 | Affected | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||
| c.174G>A | M58I 2D  AIThe SynGAP1 missense variant M58I is not reported in ClinVar (ClinVar ID = None) but is present in gnomAD (ID = 6‑33423583‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status. Thus, based on the available evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | 6-33423583-G-A | 1 | 6.20e-7 | -2.153 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.078 | Likely Benign | 0.1397 | 0.3848 | -0.55 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.21 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.174G>C | M58I 2D AIThe SynGAP1 missense variant M58I is 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 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | -2.153 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.078 | Likely Benign | 0.1397 | 0.3848 | -0.55 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.21 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||
| c.174G>T | M58I 2D AIThe SynGAP1 missense variant M58I is 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 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of predictions (seven benign vs. three pathogenic) suggest the variant is most likely benign, 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 Benign | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | -2.153 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.078 | Likely Benign | 0.1397 | 0.3848 | -0.55 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.21 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||
| c.1318A>C | N440H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenicity is suggested only by polyPhen‑2 HumDiv and ESM1b, while FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -8.064 | Likely Pathogenic | 0.226 | Likely Benign | Likely Benign | 0.140 | Likely Benign | 0.0935 | 0.3270 | 1.12 | Ambiguous | 0.1 | 0.83 | Ambiguous | 0.98 | Ambiguous | 0.00 | Likely Benign | -2.48 | Neutral | 0.835 | Possibly Damaging | 0.217 | Benign | 3.40 | Benign | 0.19 | Tolerated | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||
| c.1318A>G | N440D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -9.335 | Likely Pathogenic | 0.407 | Ambiguous | Likely Benign | 0.074 | Likely Benign | 0.1544 | 0.2025 | -0.62 | Ambiguous | 0.0 | -0.41 | Likely Benign | -0.52 | Ambiguous | 0.47 | Likely Benign | -1.71 | Neutral | 0.229 | Benign | 0.045 | Benign | 3.43 | Benign | 0.43 | Tolerated | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||
| c.1318A>T | N440Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yielding an uncertain stability change. Overall, the majority of predictions lean toward a benign interpretation, and this is consistent with the lack of ClinVar annotation. Therefore, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.586 | Likely Pathogenic | 0.674 | Likely Pathogenic | Likely Benign | 0.135 | Likely Benign | 0.0535 | 0.3624 | 0.81 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.03 | Ambiguous | 0.20 | Likely Benign | -3.81 | Deleterious | 0.931 | Possibly Damaging | 0.230 | Benign | 3.43 | Benign | 0.07 | Tolerated | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||
| c.1319A>C | N440T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly favor a benign effect: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, REVEL, premPS, Rosetta, Foldetta, and the SGM‑Consensus (majority vote) all predict benign or likely benign. No tool predicts pathogenicity; the only inconclusive result is from FoldX, which is listed as uncertain. High‑accuracy methods corroborate the benign assessment: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Therefore, based on the available predictions, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -5.371 | Likely Benign | 0.143 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.0969 | 0.3341 | 0.58 | Ambiguous | 0.0 | 0.16 | Likely Benign | 0.37 | Likely Benign | 0.11 | Likely Benign | -1.27 | Neutral | 0.007 | Benign | 0.005 | Benign | 3.48 | Benign | 0.14 | Tolerated | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||
| c.1319A>G | N440S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or likely benign. Only FoldX and premPS returned uncertain results, which are treated as unavailable. High‑accuracy methods corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Consequently, 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 | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -1.753 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.2024 | 0.3556 | 0.52 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.30 | Likely Benign | -0.50 | Ambiguous | 1.15 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.53 | Benign | 0.92 | Tolerated | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||
| c.1319A>T | N440I 2D  AISynGAP1 missense variant N440I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic; Foldetta remains inconclusive. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.365 | Likely Pathogenic | 0.778 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | 0.0554 | 0.3772 | 0.97 | Ambiguous | 0.9 | 1.10 | Ambiguous | 1.04 | Ambiguous | 0.10 | Likely Benign | -4.07 | Deleterious | 0.322 | Benign | 0.109 | Benign | 3.47 | Benign | 0.03 | Affected | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||
| c.1320T>A | N440K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Based on the overall distribution of predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.114 | Likely Pathogenic | 0.895 | Likely Pathogenic | Ambiguous | 0.058 | Likely Benign | 0.1660 | 0.2550 | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||
| c.1320T>G | N440K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Based on the overall distribution of predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.114 | Likely Pathogenic | 0.895 | Likely Pathogenic | Ambiguous | 0.057 | Likely Benign | 0.1660 | 0.2550 | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||
| c.1333G>A | E445K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E445K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic calls arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. When high‑accuracy methods are considered separately, 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 benign. Overall, the majority of evidence—including the high‑accuracy tools—supports a pathogenic effect. This conclusion does not conflict with ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -15.371 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.524 | Likely Pathogenic | 0.1784 | 0.5311 | 0.02 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.02 | Likely Benign | 0.46 | Likely Benign | -3.82 | Deleterious | 0.991 | Probably Damaging | 0.951 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1333G>C | E445Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E445Q is reported in gnomAD (ID 6‑33438238‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, Rosetta, SIFT, FATHMM) and pathogenic predictions (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, ESM1b). Two tools remain inconclusive (premPS, AlphaMissense‑Optimized). High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign impact. Overall, the balance of evidence tilts toward pathogenicity, with the high‑accuracy consensus supporting this view, and there is no conflict with ClinVar status because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | 6-33438238-G-C | 1 | 6.19e-7 | -12.430 | Likely Pathogenic | 0.790 | Likely Pathogenic | Ambiguous | 0.240 | Likely Benign | 0.0787 | 0.5018 | -0.03 | Likely Benign | 0.0 | 0.20 | Likely Benign | 0.09 | Likely Benign | 0.70 | Ambiguous | -2.86 | Deleterious | 0.987 | Probably Damaging | 0.946 | Probably Damaging | 3.40 | Benign | 0.12 | Tolerated | 3.38 | 31 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||
| c.1334A>C | E445A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E445A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as Benign. Overall, the majority of predictions lean toward pathogenicity, and the high‑accuracy consensus supports a likely pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -12.659 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.476 | Likely Benign | 0.2846 | 0.4876 | 0.09 | Likely Benign | 0.0 | -0.34 | Likely Benign | -0.13 | Likely Benign | 0.56 | Ambiguous | -5.73 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.34 | Benign | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1334A>G | E445G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E445G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Predictions that are inconclusive or uncertain are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E445G, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -12.294 | Likely Pathogenic | 0.823 | Likely Pathogenic | Ambiguous | 0.523 | Likely Pathogenic | 0.2446 | 0.4202 | 0.80 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.80 | Ambiguous | 0.69 | Ambiguous | -6.68 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1334A>T | E445V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E445V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, 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 Benign. Overall, the majority of evidence points toward a pathogenic effect. 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 | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -14.830 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.572 | Likely Pathogenic | 0.0414 | 0.5233 | 0.34 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.17 | Likely Benign | 0.32 | Likely Benign | -6.68 | Deleterious | 0.992 | Probably Damaging | 0.967 | Probably Damaging | 3.34 | Benign | 0.01 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1335G>C | E445D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E445D is reported in gnomAD (ID 6‑33438240‑G‑C) but has no ClinVar entry. Functional prediction tools show a split verdict: benign calls come from REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence, especially the SGM Consensus, points to a pathogenic effect for E445D. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | 6-33438240-G-C | 4 | 2.48e-6 | -10.238 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.136 | Likely Benign | 0.1437 | 0.3526 | 0.81 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.65 | Ambiguous | 0.91 | Ambiguous | -2.86 | Deleterious | 0.977 | Probably Damaging | 0.921 | Probably Damaging | 3.54 | Benign | 0.09 | Tolerated | 3.38 | 31 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||
| c.1335G>T | E445D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E445D is not reported in ClinVar (status: none) and is absent from gnomAD. Prediction tools that agree on benign include REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized; those that agree on pathogenic include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain or unavailable results come from FoldX, Foldetta, and premPS. High‑accuracy methods give a split view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta is uncertain. Overall, the predictions are inconclusive, with an equal number of benign and pathogenic calls. Thus, the variant is most likely benign based on the current evidence, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -10.238 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.136 | Likely Benign | 0.1437 | 0.3526 | 0.81 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.65 | Ambiguous | 0.91 | Ambiguous | -2.86 | Deleterious | 0.977 | Probably Damaging | 0.921 | Probably Damaging | 3.54 | Benign | 0.09 | Tolerated | 3.38 | 31 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||
| c.1417G>A | V473I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438449‑G‑A). Functional prediction tools that agree on benign impact include REVEL, FoldX, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Pathogenic predictions are provided by both polyPhen‑2 HumDiv and HumVar. Predictions that are inconclusive are AlphaMissense‑Default, ESM1b, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority, and Foldetta is uncertain. Overall, the balance of evidence favors a benign effect for V473I, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | Uncertain | 1 | 6-33438449-G-A | 1 | 6.20e-7 | -7.481 | In-Between | 0.418 | Ambiguous | Likely Benign | 0.203 | Likely Benign | 0.0568 | 0.3335 | -0.12 | Likely Benign | 0.0 | 1.20 | Ambiguous | 0.54 | Ambiguous | -0.06 | Likely Benign | -0.91 | Neutral | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.74 | Benign | 0.18 | Tolerated | 3.37 | 34 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||
| c.1417G>C | V473L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and Foldetta, while those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of tools (seven pathogenic vs. six benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -9.073 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.336 | Likely Benign | 0.0708 | 0.3921 | -0.29 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.41 | Likely Benign | 0.35 | Likely Benign | -2.85 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.43 | Benign | 0.21 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1417G>T | V473L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and Foldetta, while those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of tools (seven pathogenic vs. six benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -9.073 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.335 | Likely Benign | 0.0708 | 0.3921 | -0.29 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.41 | Likely Benign | 0.35 | Likely Benign | -2.85 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.43 | Benign | 0.21 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1418T>A | V473E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: all evaluated algorithms except FATHMM predict pathogenicity, while FATHMM alone predicts benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the consensus of the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -15.296 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.664 | Likely Pathogenic | 0.0903 | 0.1396 | 3.20 | Destabilizing | 0.2 | 2.24 | Destabilizing | 2.72 | Destabilizing | 2.22 | Destabilizing | -5.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||
| c.1418T>C | V473A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V473A missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are all uncertain or unavailable, providing no decisive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions support a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation (no contradiction). Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -10.867 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.485 | Likely Benign | 0.2529 | 0.2521 | 1.88 | Ambiguous | 0.0 | 1.76 | Ambiguous | 1.82 | Ambiguous | 2.17 | Destabilizing | -3.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||
| c.1418T>G | V473G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473G has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) votes pathogenic, and Foldetta also predicts pathogenic. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective evidence, and this conclusion does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -14.782 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.683 | Likely Pathogenic | 0.1885 | 0.2567 | 3.45 | Destabilizing | 0.0 | 3.40 | Destabilizing | 3.43 | Destabilizing | 2.69 | Destabilizing | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1465C>A | L489I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions come from REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is indeterminate due to a tie between pathogenic and benign signals, and Foldetta reports an uncertain stability change. Overall, the preponderance of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -7.333 | In-Between | 0.342 | Ambiguous | Likely Benign | 0.490 | Likely Benign | 0.1069 | 0.4080 | 1.01 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.77 | Ambiguous | 0.90 | Ambiguous | -1.55 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.42 | Pathogenic | 0.21 | Tolerated | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1465C>G | L489V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM, while only AlphaMissense‑Optimized predicts a benign outcome. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for L489V. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database record. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -9.345 | Likely Pathogenic | 0.467 | Ambiguous | Likely Benign | 0.586 | Likely Pathogenic | 0.1665 | 0.4108 | 2.09 | Destabilizing | 0.0 | 1.70 | Ambiguous | 1.90 | Ambiguous | 1.25 | Destabilizing | -2.55 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1465C>T | L489F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489F is listed in ClinVar with an uncertain significance (ClinVar ID 522018.0) and is present in the gnomAD database (gnomAD ID 6‑33438497‑C‑T). In silico prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while no tool predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No prediction or folding‑stability result is missing or ambiguous. **Thus, the variant is most likely pathogenic based on the collective predictions, and this does not contradict the ClinVar uncertain status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | Uncertain | 2 | 6-33438497-C-T | 1 | 6.20e-7 | -12.066 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.724 | Likely Pathogenic | 0.0791 | 0.3729 | 1.72 | Ambiguous | 0.5 | 1.14 | Ambiguous | 1.43 | Ambiguous | 0.56 | Ambiguous | -3.76 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.51 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 2 | 0 | -1.0 | 34.02 | 246.4 | -17.8 | 0.0 | 0.0 | 0.6 | 0.1 | X | Potentially Benign | The iso-butyl side chain of Leu489, located in the α-helix (res. Leu489-Glu519) within an inter-helix space of four helices (res. Ala461-Phe476, res. Val441-Ser457, and res. Met414-Glu436), packs with hydrophobic residues (e.g., Cys432, Ala448, Lys444, Ala493, Val447, Met468) in the inter-helix space. In the variant simulations, the phenyl ring of the Phe489 side chain can also pack favorably in the hydrophobic region. However, due to the size difference, the aromatic side chain of Phe489 tends to reposition to escape the tight region to accommodate the larger side chain, stacking with Lys444. Although no apparent negative changes are observed during the variant simulation, the size difference between the swapped residues could affect the protein folding process. | |||||||||
| c.1466T>A | L489H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489H is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -15.946 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.919 | Likely Pathogenic | 0.1132 | 0.0871 | 3.12 | Destabilizing | 0.2 | 2.13 | Destabilizing | 2.63 | Destabilizing | 1.99 | Destabilizing | -6.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.60 | Pathogenic | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||
| c.1466T>C | L489P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | Conflicting | 2 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.939 | Likely Pathogenic | 0.3673 | 0.1474 | 2.50 | Destabilizing | 0.1 | 4.69 | Destabilizing | 3.60 | Destabilizing | 1.73 | Destabilizing | -6.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.56 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -3 | -3 | -5.4 | -16.04 | 209.9 | 61.9 | 0.1 | 0.0 | 0.6 | 0.1 | X | Potentially Pathogenic | The iso-butyl side chain of Leu489, located in the α-helix (res. Leu489-Glu519) within an inter-helix space of four helices (res. Ala461-Phe476, res. Val441-Ser457, and res. Met414-Glu436), packs with hydrophobic residues (e.g., Cys432, Ala448, Lys444, Ala493, Val447, Met468). In the variant simulations, Pro489 is located near the beginning of the α-helix, so the residue swap with Leu489 does not affect the continuity of the secondary structure element. However, the side chain of proline is not as optimal as that of leucine for maintaining hydrophobic packing with nearby residues (e.g., Ala448, Lys444). Additionally, the consistently maintained hydrogen bond interaction between the backbone amide group of Leu489 and the carbonyl of Glu436 is lost due to the residue swap, potentially affecting the tertiary structure integrity. | ||||||||||||
| c.1466T>G | L489R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -15.365 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.949 | Likely Pathogenic | 0.1306 | 0.1145 | 4.32 | Destabilizing | 0.3 | 4.90 | Destabilizing | 4.61 | Destabilizing | 1.74 | Destabilizing | -5.86 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.61 | Pathogenic | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.2011G>A | D671N 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant D671N is reported in gnomAD (6‑33441270‑G‑A) but has no ClinVar entry. Functional prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus remains pathogenic. Overall, the predictions are split, with a slight bias toward benign outcomes from the majority of tools, but the consensus pathogenic signal from SGM and several high‑confidence predictors suggests uncertainty. The variant is most likely benign based on the preponderance of benign predictions, and this 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 | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | 6-33441270-G-A | -10.347 | Likely Pathogenic | 0.685 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | 0.1298 | 0.6463 | 0.18 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.29 | Likely Benign | 0.19 | Likely Benign | -3.19 | Deleterious | 0.887 | Possibly Damaging | 0.592 | Possibly Damaging | 3.36 | Benign | 0.02 | Affected | 3.39 | 27 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||
| c.2011G>C | D671H 2D  3DClick to see structure in 3D Viewer AISynGAP1 D671H is not reported in ClinVar and is absent from gnomAD. Benign predictions are provided by REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy tools give mixed results: AlphaMissense‑Optimized is uncertain, SGM Consensus predicts pathogenic, and Foldetta predicts benign. Overall, the balance of evidence leans toward pathogenicity, and this does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -11.501 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | 0.300 | Likely Benign | 0.1627 | 0.6509 | 0.49 | Likely Benign | 0.0 | 0.29 | Likely Benign | 0.39 | Likely Benign | 0.09 | Likely Benign | -4.35 | Deleterious | 0.999 | Probably Damaging | 0.939 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.2011G>T | D671Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D671Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split consensus: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized and the SGM‑Consensus both indicate pathogenicity, while Foldetta predicts a benign effect on protein stability. Because the majority of standard predictors lean toward pathogenicity and the two high‑confidence tools also favor a deleterious outcome, the variant is most likely pathogenic. This assessment does not contradict ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -13.107 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.385 | Likely Benign | 0.0564 | 0.6376 | 0.31 | Likely Benign | 0.1 | 0.05 | Likely Benign | 0.18 | Likely Benign | 0.11 | Likely Benign | -6.05 | Deleterious | 1.000 | Probably Damaging | 0.961 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.2012A>C | D671A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D671A missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic interpretation, with seven tools supporting pathogenicity versus four supporting benignity. This conclusion does not conflict with ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -11.709 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.245 | Likely Benign | 0.4056 | 0.5895 | 0.25 | Likely Benign | 0.1 | 0.79 | Ambiguous | 0.52 | Ambiguous | 0.10 | Likely Benign | -5.08 | Deleterious | 0.980 | Probably Damaging | 0.804 | Possibly Damaging | 3.34 | Benign | 0.03 | Affected | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||
| c.2012A>G | D671G 2D  AIThe SynGAP1 D671G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. No evidence from these tools contradicts the pathogenic prediction. Overall, the balance of evidence favors a pathogenic classification for D671G, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -10.346 | Likely Pathogenic | 0.857 | Likely Pathogenic | Ambiguous | 0.279 | Likely Benign | 0.4032 | 0.5823 | 0.50 | Ambiguous | 0.5 | 1.53 | Ambiguous | 1.02 | Ambiguous | 0.00 | Likely Benign | -4.78 | Deleterious | 0.995 | Probably Damaging | 0.946 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||
| c.2012A>T | D671V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D671V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the majority of predictions (seven pathogenic vs. three benign) support a pathogenic classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -12.376 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.379 | Likely Benign | 0.0820 | 0.6651 | 0.63 | Ambiguous | 0.1 | 0.51 | Ambiguous | 0.57 | Ambiguous | 0.14 | Likely Benign | -6.08 | Deleterious | 0.975 | Probably Damaging | 0.885 | Possibly Damaging | 3.31 | Benign | 0.01 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| c.2013C>A | D671E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D671E is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the substitution as benign. The only inconclusive result is AlphaMissense‑Default, which is listed as uncertain; all other high‑accuracy predictors support a benign outcome. In particular, AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -3.657 | Likely Benign | 0.371 | Ambiguous | Likely Benign | 0.066 | Likely Benign | 0.1520 | 0.6388 | -0.17 | Likely Benign | 0.1 | 0.22 | Likely Benign | 0.03 | Likely Benign | 0.03 | Likely Benign | -0.83 | Neutral | 0.013 | Benign | 0.009 | Benign | 3.47 | Benign | 0.53 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.2013C>G | D671E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D671E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized indicates Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. With all available evidence pointing to a benign effect and no ClinVar record to contradict this, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -3.657 | Likely Benign | 0.371 | Ambiguous | Likely Benign | 0.066 | Likely Benign | 0.1520 | 0.6388 | -0.17 | Likely Benign | 0.1 | 0.22 | Likely Benign | 0.03 | Likely Benign | 0.03 | Likely Benign | -0.83 | Neutral | 0.013 | Benign | 0.009 | Benign | 3.47 | Benign | 0.53 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.2029A>C | S677R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Those that predict a pathogenic effect are FoldX, ESM1b, and AlphaMissense‑Default. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is also inconclusive. Overall, the majority of tools and the high‑accuracy benign prediction suggest the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -9.388 | Likely Pathogenic | 0.714 | Likely Pathogenic | Likely Benign | 0.104 | Likely Benign | 0.1120 | 0.4195 | 2.59 | Destabilizing | 0.1 | 0.73 | Ambiguous | 1.66 | Ambiguous | 0.71 | Ambiguous | -2.49 | Neutral | 0.385 | Benign | 0.037 | Benign | 3.31 | Benign | 0.12 | Tolerated | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||
| c.2029A>G | S677G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. Predictions that are inconclusive—FoldX, Rosetta, Foldetta, and premPS—are treated as unavailable. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the evidence supports a benign classification for S677G, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -5.126 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.126 | Likely Benign | 0.2885 | 0.5325 | 0.98 | Ambiguous | 0.1 | 1.20 | Ambiguous | 1.09 | Ambiguous | 0.64 | Ambiguous | -1.38 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.30 | Benign | 0.26 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||
| c.2029A>T | S677C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677C is reported in ClinVar as Benign (ClinVar ID 2825814.0) and is not present in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv, SIFT, and ESM1b predict a pathogenic impact. High‑accuracy predictors all support a benign outcome: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction or folding‑stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this assessment aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | Benign | 1 | -8.496 | Likely Pathogenic | 0.076 | Likely Benign | Likely Benign | 0.153 | Likely Benign | 0.1375 | 0.6697 | -0.51 | Ambiguous | 0.3 | -0.30 | Likely Benign | -0.41 | Likely Benign | 0.15 | Likely Benign | -2.41 | Neutral | 0.932 | Possibly Damaging | 0.222 | Benign | 3.25 | Benign | 0.04 | Affected | 3.41 | 23 | -1 | 0 | 3.3 | 16.06 | |||||||||||||||||||||
| c.2030G>A | S677N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677N is catalogued in gnomAD (6‑33441289‑G‑A) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while premPS and ESM1b are uncertain. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Thus, all available evidence supports a benign classification, and there is no conflict with ClinVar status (which is absent). The variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | 6-33441289-G-A | 1 | 6.20e-7 | -7.955 | In-Between | 0.111 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.1763 | 0.5688 | 0.17 | Likely Benign | 0.5 | -0.15 | Likely Benign | 0.01 | Likely Benign | 0.89 | Ambiguous | -2.05 | Neutral | 0.038 | Benign | 0.007 | Benign | 3.28 | Benign | 0.15 | Tolerated | 3.41 | 23 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||
| c.2030G>C | S677T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and FATHMM all classify it as benign. No tool predicts pathogenicity. The only inconclusive results come from Rosetta (Uncertain) and Foldetta (Uncertain), which are treated as unavailable evidence. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta remains Uncertain. Overall, the consensus of available predictions indicates that S677T is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -4.760 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 0.1775 | 0.6985 | -0.17 | Likely Benign | 0.3 | -0.85 | Ambiguous | -0.51 | Ambiguous | 0.15 | Likely Benign | -0.97 | Neutral | 0.008 | Benign | 0.007 | Benign | 3.32 | Benign | 0.30 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.2030G>T | S677I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, premPS, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenicity is suggested only by PROVEAN and SIFT, while Foldetta and ESM1b give uncertain results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -7.942 | In-Between | 0.156 | Likely Benign | Likely Benign | 0.097 | Likely Benign | 0.1040 | 0.6463 | -0.09 | Likely Benign | 0.0 | -2.25 | Stabilizing | -1.17 | Ambiguous | -0.01 | Likely Benign | -2.81 | Deleterious | 0.002 | Benign | 0.002 | Benign | 3.34 | Benign | 0.05 | Affected | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||
| c.2031T>A | S677R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677R is not 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, SIFT, and FATHMM. Those that predict a pathogenic effect are FoldX, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is uncertain. Overall, the majority of consensus tools (six benign vs. three pathogenic) lean toward a benign interpretation. This prediction does not contradict any ClinVar status, as none is available. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -9.388 | Likely Pathogenic | 0.714 | Likely Pathogenic | Likely Benign | 0.150 | Likely Benign | 0.1120 | 0.4195 | 2.59 | Destabilizing | 0.1 | 0.73 | Ambiguous | 1.66 | Ambiguous | 0.71 | Ambiguous | -2.49 | Neutral | 0.385 | Benign | 0.037 | Benign | 3.31 | Benign | 0.12 | Tolerated | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||
| c.2031T>G | S677R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677R is not 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, SIFT, and FATHMM. Those that predict a pathogenic effect are FoldX, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is uncertain. Overall, the majority of consensus tools (six benign vs. three pathogenic) lean toward a benign interpretation. This prediction does not contradict any ClinVar status, as none is available. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -9.388 | Likely Pathogenic | 0.714 | Likely Pathogenic | Likely Benign | 0.150 | Likely Benign | 0.1120 | 0.4195 | 2.59 | Destabilizing | 0.1 | 0.73 | Ambiguous | 1.66 | Ambiguous | 0.71 | Ambiguous | -2.49 | Neutral | 0.385 | Benign | 0.037 | Benign | 3.31 | Benign | 0.12 | Tolerated | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||
| c.712G>A | E238K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238K missense change is not reported in ClinVar and is absent from gnomAD. In silico predictors cluster into two groups: a single benign call from FATHMM, and a consensus of pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are not considered evidence. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E238K. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -13.475 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.858 | Likely Pathogenic | 0.2812 | 0.5524 | 0.56 | Ambiguous | 0.4 | 1.83 | Ambiguous | 1.20 | Ambiguous | 0.83 | Ambiguous | -3.63 | Deleterious | 0.995 | Probably Damaging | 0.695 | Possibly Damaging | 5.46 | Benign | 0.01 | Affected | 4.29 | 391 | 0 | 1 | -0.4 | -0.94 | 209.0 | 55.9 | 0.0 | 0.0 | -0.1 | 0.0 | X | Potentially Pathogenic | The negatively charged residue Glu238, located in an α helix (res. Ala236-Val250), is replaced by the positively charged residue Lys238. This charge reversal removes the periodically formed salt bridge between the carboxylate group of Glu238 and the guanidinium group of Arg234 observed in the WT simulations. In the variant simulations, both Lys238 and Arg234 form alternative salt bridges with the carboxylate group of Glu680 in the GAP domain loop. Although not visible in the simulations, the absence of the Glu238-Arg234 salt bridge could weaken the integrity of the α helix (residues Ala236-Val250) and potentially affect the tertiary assembly between the PH and GAP domains. | ||||||||||||||
| c.712G>C | E238Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two consensus groups: benign predictions come from SIFT and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods (FoldX, Rosetta, premPS) and Foldetta give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -11.476 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.723 | Likely Pathogenic | 0.1372 | 0.5412 | 0.63 | Ambiguous | 0.5 | 0.59 | Ambiguous | 0.61 | Ambiguous | 0.52 | Ambiguous | -2.72 | Deleterious | 0.996 | Probably Damaging | 0.891 | Possibly Damaging | 5.44 | Benign | 0.06 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.713A>C | E238A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E238A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM predicts benign, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results and are treated as unavailable. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence indicates that E238A is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -13.252 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.879 | Likely Pathogenic | 0.4164 | 0.5610 | 0.91 | Ambiguous | 0.3 | 1.89 | Ambiguous | 1.40 | Ambiguous | 0.57 | Ambiguous | -5.44 | Deleterious | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 5.44 | Benign | 0.04 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.713A>G | E238G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238G is reported in gnomAD (variant ID 6‑33435564‑A‑G) but has no entry in ClinVar. Functional prediction tools largely agree on a deleterious effect: the benign‑predicting tool FATHMM is the only one that classifies it as benign, whereas the pathogenic‑predicting tools (REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Pathogenic” call) all predict a harmful impact. Predictions of uncertain status (FoldX, premPS) are treated as unavailable. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among high‑confidence tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | 6-33435564-A-G | 1 | 6.19e-7 | -12.582 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.889 | Likely Pathogenic | 0.3137 | 0.4833 | 1.09 | Ambiguous | 0.2 | 3.42 | Destabilizing | 2.26 | Destabilizing | 0.87 | Ambiguous | -6.35 | Deleterious | 0.970 | Probably Damaging | 0.607 | Possibly Damaging | 5.39 | Benign | 0.00 | Affected | 3.40 | 14 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||
| c.713A>T | E238V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E238V. This conclusion is not contradicted by ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -14.329 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.890 | Likely Pathogenic | 0.0848 | 0.6093 | 0.88 | Ambiguous | 0.4 | 0.75 | Ambiguous | 0.82 | Ambiguous | 0.45 | Likely Benign | -6.35 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.714A>C | E238D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -7.861 | In-Between | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.691 | Likely Pathogenic | 0.1975 | 0.3619 | 1.25 | Ambiguous | 0.4 | 1.72 | Ambiguous | 1.49 | Ambiguous | 0.78 | Ambiguous | -2.72 | Deleterious | 0.868 | Possibly Damaging | 0.504 | Possibly Damaging | 5.57 | Benign | 0.05 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.714A>T | E238D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -7.861 | In-Between | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.691 | Likely Pathogenic | 0.1975 | 0.3619 | 1.25 | Ambiguous | 0.4 | 1.72 | Ambiguous | 1.49 | Ambiguous | 0.78 | Ambiguous | -2.72 | Deleterious | 0.868 | Possibly Damaging | 0.504 | Possibly Damaging | 5.57 | Benign | 0.05 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.1456G>A | E486K 2D 3DClick to see structure in 3D Viewer AISynGAP1 E486K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a benign effect. Because the predictions are split evenly and the high‑accuracy tools are contradictory, the variant’s impact remains uncertain; thus, the variant is most likely pathogenic based on the high‑accuracy predictions, a conclusion that contradicts its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | Uncertain | 2 | -14.545 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.435 | Likely Benign | 0.1940 | 0.6392 | 0.06 | Likely Benign | 0.1 | 0.37 | Likely Benign | 0.22 | Likely Benign | 0.41 | Likely Benign | -3.58 | Deleterious | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 3.40 | Benign | 0.12 | Tolerated | 3.37 | 35 | 0 | 1 | -0.4 | -0.94 | 206.8 | 52.1 | -0.3 | 0.1 | 0.2 | 0.0 | X | X | Uncertain | Glu486 is located in an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. It is adjacent to the arginine finger (Arg485) and is expected to closely interact with Ras. The residue swap could affect complex formation with the GTPase and its activation. In the WT simulations, the carboxylate group of Glu486 forms salt bridges with Arg485 and Arg475 on the preceding α-helix (res. Ala461-Phe476). In the variant simulations, Lys486 does not form any specific interactions. Although the amino group of the Lys486 side chain cannot form these salt bridges, no negative effects on the protein structure are observed. Nevertheless, the potential role of Glu486 in SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations, and no definite conclusions can be drawn. | |||||||||||
| c.1456G>C | E486Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E486Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as benign, and AlphaMissense‑Optimized as uncertain. No prediction or stability result is missing or inconclusive beyond the stated uncertainty. Overall, the evidence is balanced, with an equal number of benign and pathogenic calls, and the high‑accuracy tools provide opposing conclusions. Thus, the variant is most likely benign based on the preponderance of benign predictions, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -10.549 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.334 | Likely Benign | 0.0888 | 0.5880 | 0.12 | Likely Benign | 0.1 | 0.00 | Likely Benign | 0.06 | Likely Benign | 0.24 | Likely Benign | -2.68 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.38 | Benign | 0.09 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1457A>C | E486A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E486A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, premPS, SIFT, and FATHMM, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore unavailable. Overall, the majority of evidence supports a pathogenic effect. The prediction aligns with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -11.902 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.398 | Likely Benign | 0.3561 | 0.5859 | 0.63 | Ambiguous | 0.0 | 0.32 | Likely Benign | 0.48 | Likely Benign | -0.03 | Likely Benign | -5.17 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.44 | Benign | 0.39 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1457A>G | E486G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E486G missense change is not listed in ClinVar and has no gnomAD entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM. Those that predict a damaging outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is consistent with the absence of a ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -12.488 | Likely Pathogenic | 0.924 | Likely Pathogenic | Ambiguous | 0.328 | Likely Benign | 0.2918 | 0.5385 | 1.09 | Ambiguous | 0.1 | 1.59 | Ambiguous | 1.34 | Ambiguous | -0.14 | Likely Benign | -5.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.80 | Benign | 0.40 | Tolerated | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1457A>T | E486V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E486V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, SIFT, FATHMM, and Foldetta. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Uncertain results from FoldX and Rosetta are treated as unavailable. Overall, the majority of predictions support a pathogenic classification, and this conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -15.115 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.490 | Likely Benign | 0.0493 | 0.6445 | 0.54 | Ambiguous | 0.1 | -0.65 | Ambiguous | -0.06 | Likely Benign | 0.31 | Likely Benign | -6.36 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 3.37 | Benign | 0.06 | Tolerated | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1458G>C | E486D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E486D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls (REVEL, FoldX, Rosetta, SIFT, FATHMM) and pathogenic calls (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Two tools are uncertain (premPS, AlphaMissense‑Optimized). High‑accuracy assessments give mixed results: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Because the majority of standard predictors lean toward pathogenic and the SGM‑Consensus also indicates pathogenic, the variant is most likely pathogenic, although the Foldetta benign prediction and the presence of uncertain calls leave room for ambiguity. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -10.363 | Likely Pathogenic | 0.914 | Likely Pathogenic | Ambiguous | 0.166 | Likely Benign | 0.1453 | 0.4115 | 0.19 | Likely Benign | 0.0 | 0.38 | Likely Benign | 0.29 | Likely Benign | 0.54 | Ambiguous | -2.58 | Deleterious | 0.994 | Probably Damaging | 0.979 | Probably Damaging | 3.43 | Benign | 0.16 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1458G>T | E486D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E486D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls (REVEL, FoldX, Rosetta, SIFT, FATHMM) and pathogenic calls (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Two tools are uncertain (premPS, AlphaMissense‑Optimized). High‑accuracy assessments give mixed results: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Because the majority of standard predictors lean toward pathogenic and the SGM‑Consensus also indicates pathogenic, the variant is most likely pathogenic, although the Foldetta benign prediction and the presence of uncertain calls leave room for ambiguity. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -10.363 | Likely Pathogenic | 0.914 | Likely Pathogenic | Ambiguous | 0.166 | Likely Benign | 0.1453 | 0.4115 | 0.19 | Likely Benign | 0.0 | 0.38 | Likely Benign | 0.29 | Likely Benign | 0.54 | Ambiguous | -2.58 | Deleterious | 0.994 | Probably Damaging | 0.979 | Probably Damaging | 3.43 | Benign | 0.16 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.160A>C | N54H 2D AISynGAP1 missense variant N54H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -7.646 | In-Between | 0.236 | Likely Benign | Likely Benign | 0.112 | Likely Benign | 0.1377 | 0.7334 | -1.18 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.14 | Benign | 0.00 | Affected | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||
| c.160A>G | N54D 2D AIThe SynGAP1 missense variant N54D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is labeled “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -6.980 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.074 | Likely Benign | 0.1826 | 0.4496 | -0.75 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.22 | Benign | 0.00 | Affected | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.160A>T | N54Y 2D AIThe SynGAP1 missense variant N54Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). High‑accuracy methods show AlphaMissense‑Optimized as benign; the SGM Consensus is unavailable, and Foldetta results are not provided, so its stability prediction is also unavailable. Overall, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy benign prediction is outweighed by the majority of pathogenic calls. Thus, the variant is most likely pathogenic based on current computational predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -9.313 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 0.183 | Likely Benign | 0.0512 | 0.6687 | -1.57 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.16 | Benign | 0.00 | Affected | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||||||
| c.161A>C | N54T 2D AIThe SynGAP1 missense variant N54T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign impact, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -5.808 | Likely Benign | 0.386 | Ambiguous | Likely Benign | 0.070 | Likely Benign | 0.1268 | 0.7498 | -0.47 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.20 | Benign | 0.00 | Affected | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||
| c.161A>G | N54S 2D AIThe SynGAP1 missense variant N54S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -5.358 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 0.3740 | 0.7048 | -0.17 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.31 | Benign | 0.00 | Affected | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||
| c.161A>T | N54I 2D AIThe SynGAP1 missense variant N54I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -9.919 | Likely Pathogenic | 0.890 | Likely Pathogenic | Ambiguous | 0.201 | Likely Benign | 0.0637 | 0.6793 | -1.70 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.15 | Benign | 0.00 | Affected | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||
| c.162C>A | N54K 2D AIThe SynGAP1 missense variant N54K is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign) and is treated as unavailable. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are not provided, so its stability prediction is unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions) suggests the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -8.252 | Likely Pathogenic | 0.779 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | 0.2010 | 0.5987 | -0.82 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||
| c.162C>G | N54K 2D AIThe SynGAP1 missense variant N54K is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign) and is treated as unavailable. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are not provided, so its stability prediction is unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions) suggests the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -8.252 | Likely Pathogenic | 0.779 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | 0.2010 | 0.5987 | -0.82 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||
| c.721A>C | K241Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K241Q missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, FATHMM, and Foldetta, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, nine tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict these findings. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.593 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.767 | Likely Pathogenic | 0.4225 | 0.1527 | 0.33 | Likely Benign | 0.0 | 0.46 | Likely Benign | 0.40 | Likely Benign | 0.63 | Ambiguous | -3.33 | Deleterious | 0.995 | Probably Damaging | 0.914 | Probably Damaging | 5.83 | Benign | 0.04 | Affected | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||
| c.721A>G | K241E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K241E missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include SIFT and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -12.582 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.878 | Likely Pathogenic | 0.3610 | 0.1179 | 0.75 | Ambiguous | 0.1 | 1.36 | Ambiguous | 1.06 | Ambiguous | 0.68 | Ambiguous | -3.43 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 6.00 | Benign | 0.10 | Tolerated | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.722A>C | K241T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are reported by Rosetta and FATHMM. Two tools (Foldetta and premPS) give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta remains uncertain. Overall, the consensus of the majority of evidence points to a pathogenic effect for K241T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.911 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.853 | Likely Pathogenic | 0.2021 | 0.3951 | 2.00 | Destabilizing | 0.4 | 0.06 | Likely Benign | 1.03 | Ambiguous | 0.60 | Ambiguous | -5.14 | Deleterious | 0.995 | Probably Damaging | 0.747 | Possibly Damaging | 5.74 | Benign | 0.03 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.722A>G | K241R 2D AIThe SynGAP1 missense variant K241R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -4.615 | Likely Benign | 0.444 | Ambiguous | Likely Benign | 0.602 | Likely Pathogenic | 0.4571 | 0.1242 | -0.23 | Likely Benign | 0.5 | -0.03 | Likely Benign | -0.13 | Likely Benign | 0.43 | Likely Benign | -2.12 | Neutral | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 5.89 | Benign | 0.14 | Tolerated | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.722A>T | K241I 2D 3DClick to see structure in 3D Viewer AISynGAP1 K241I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, premPS, and FATHMM. Those that predict a damaging effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta return uncertain results. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized reports pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -14.370 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.852 | Likely Pathogenic | 0.1176 | 0.3868 | 1.31 | Ambiguous | 0.5 | 0.28 | Likely Benign | 0.80 | Ambiguous | 0.41 | Likely Benign | -6.96 | Deleterious | 0.985 | Probably Damaging | 0.704 | Possibly Damaging | 5.71 | Benign | 0.01 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||
| c.723A>C | K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.198 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.663 | Likely Pathogenic | 0.3426 | 0.1872 | 0.92 | Ambiguous | 0.1 | 1.13 | Ambiguous | 1.03 | Ambiguous | 0.89 | Ambiguous | -4.23 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.81 | Benign | 0.03 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.723A>T | K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported for FoldX, Rosetta, Foldetta, and premPS and are not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.198 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.663 | Likely Pathogenic | 0.3426 | 0.1872 | 0.92 | Ambiguous | 0.1 | 1.13 | Ambiguous | 1.03 | Ambiguous | 0.89 | Ambiguous | -4.23 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.81 | Benign | 0.03 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.2047A>C | I683L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b. Remaining methods (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the balance of evidence favors a benign impact for I683L, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -9.988 | Likely Pathogenic | 0.488 | Ambiguous | Likely Benign | 0.286 | Likely Benign | 0.0957 | 0.3185 | 0.63 | Ambiguous | 0.1 | 0.76 | Ambiguous | 0.70 | Ambiguous | 0.69 | Ambiguous | -2.00 | Neutral | 0.011 | Benign | 0.056 | Benign | 3.43 | Benign | 0.04 | Affected | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.2047A>G | I683V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683V is listed in ClinVar with an uncertain significance and is present in gnomAD (6‑33441306‑A‑G). Across a panel of in silico predictors, the majority indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (derived from a majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only polyPhen‑2 HumDiv classifies the change as pathogenic. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote) is benign, and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is inconclusive and therefore not considered evidence. No other tool provides a pathogenic signal. Consequently, the variant is most likely benign, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | Uncertain | 1 | 6-33441306-A-G | 2 | 1.24e-6 | -7.588 | In-Between | 0.138 | Likely Benign | Likely Benign | 0.112 | Likely Benign | 0.1021 | 0.2898 | 0.90 | Ambiguous | 0.0 | 0.60 | Ambiguous | 0.75 | Ambiguous | 0.76 | Ambiguous | -0.78 | Neutral | 0.538 | Possibly Damaging | 0.080 | Benign | 3.35 | Benign | 0.14 | Tolerated | 3.42 | 17 | 4 | 3 | -0.3 | -14.03 | 215.6 | 29.1 | 0.0 | 0.0 | -0.7 | 0.1 | X | Potentially Benign | The sec-butyl side chain of Ile683, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is sterically packed against His453 and Glu688. In the variant simulations, the iso-propyl side chain of Val683 has similar size and physicochemical properties as Ile630 in the WT, and thus, it is able to maintain similar interactions in the inter-helix space. Consequently, no negative structural effects are observed during the simulations due to the residue swap. | |||||||||
| c.2047A>T | I683F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, while AlphaMissense‑Optimized and Foldetta are inconclusive and thus treated as unavailable evidence. Overall, the balance of evidence favors a pathogenic classification for I683F, and this assessment does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -12.781 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 0.481 | Likely Benign | 0.0770 | 0.2307 | 1.38 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.58 | Ambiguous | 0.59 | Ambiguous | -3.99 | Deleterious | 0.971 | Probably Damaging | 0.499 | Possibly Damaging | 3.27 | Benign | 0.01 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.2048T>A | I683N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683N 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 the pathogenic signal: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) also indicates pathogenicity. 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 | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -12.120 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.546 | Likely Pathogenic | 0.0978 | 0.1133 | 2.18 | Destabilizing | 0.1 | 2.08 | Destabilizing | 2.13 | Destabilizing | 1.46 | Destabilizing | -6.87 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.2048T>C | I683T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683T has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools predict pathogenicity: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support this pattern: AlphaMissense‑Optimized classifies the variant as benign, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates it is likely pathogenic; the Foldetta stability analysis is inconclusive and therefore unavailable. Taken together, the preponderance of evidence points to a pathogenic effect for I683T. This conclusion does not contradict ClinVar status, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -9.891 | Likely Pathogenic | 0.775 | Likely Pathogenic | Likely Benign | 0.548 | Likely Pathogenic | 0.1090 | 0.0880 | 1.67 | Ambiguous | 0.1 | 1.35 | Ambiguous | 1.51 | Ambiguous | 1.25 | Destabilizing | -4.77 | Deleterious | 0.999 | Probably Damaging | 0.981 | Probably Damaging | 3.29 | Benign | 0.08 | Tolerated | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.2048T>G | I683S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683S 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 majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. No prediction or folding stability result is missing or inconclusive; all available evidence points to a deleterious effect. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -11.443 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.552 | Likely Pathogenic | 0.1936 | 0.1320 | 2.53 | Destabilizing | 0.2 | 1.94 | Ambiguous | 2.24 | Destabilizing | 1.35 | Destabilizing | -5.88 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 3.29 | Benign | 0.05 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||
| c.2049C>G | I683M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I683M variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of definitive predictions (five pathogenic vs. three benign) point to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -9.010 | Likely Pathogenic | 0.424 | Ambiguous | Likely Benign | 0.296 | Likely Benign | 0.0933 | 0.2662 | 0.69 | Ambiguous | 0.1 | 0.68 | Ambiguous | 0.69 | Ambiguous | 0.74 | Ambiguous | -2.88 | Deleterious | 0.999 | Probably Damaging | 0.986 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||
| c.2086C>A | L696I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L696I missense change is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is unavailable. Overall, the majority of conventional tools lean toward pathogenicity, and the high‑accuracy prediction that is available (AlphaMissense‑Optimized) indicates benign, leaving the evidence mixed. Thus, the variant is most likely pathogenic based on the preponderance of predictions, and this does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | -10.652 | Likely Pathogenic | 0.698 | Likely Pathogenic | Likely Benign | 0.250 | Likely Benign | 0.0921 | 0.2542 | 1.01 | Ambiguous | 0.1 | 0.58 | Ambiguous | 0.80 | Ambiguous | 0.85 | Ambiguous | -1.86 | Neutral | 0.996 | Probably Damaging | 0.989 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||
| c.2086C>G | L696V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L696V variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) report a pathogenic outcome; Rosetta remains inconclusive. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for the variant, 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 | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | Uncertain | 1 | -11.909 | Likely Pathogenic | 0.745 | Likely Pathogenic | Likely Benign | 0.351 | Likely Benign | 0.1307 | 0.2830 | 2.35 | Destabilizing | 0.1 | 1.85 | Ambiguous | 2.10 | Destabilizing | 1.46 | Destabilizing | -2.79 | Deleterious | 0.992 | Probably Damaging | 0.970 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 3.46 | 13 | 1 | 2 | 0.4 | -14.03 | |||||||||||||||||||||
| c.2086C>T | L696F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L696F has no ClinVar entry and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | -9.651 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.422 | Likely Benign | 0.0667 | 0.2008 | 0.14 | Likely Benign | 0.1 | 0.74 | Ambiguous | 0.44 | Likely Benign | 0.55 | Ambiguous | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.05 | Benign | 0.00 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| 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 | 0.569 | Likely Pathogenic | 0.1009 | 0.0488 | 2.56 | Destabilizing | 0.0 | 2.55 | Destabilizing | 2.56 | Destabilizing | 2.07 | Destabilizing | -6.58 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||
| 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 | 0.678 | Likely Pathogenic | 0.3065 | 0.1995 | 6.66 | Destabilizing | 0.2 | 10.84 | Destabilizing | 8.75 | Destabilizing | 2.13 | Destabilizing | -6.58 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 3.46 | 13 | -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.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 | 0.624 | Likely Pathogenic | 0.1200 | 0.0688 | 3.67 | Destabilizing | 0.0 | 5.36 | Destabilizing | 4.52 | Destabilizing | 2.44 | Destabilizing | -5.68 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.01 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.2116G>A | E706K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E706K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all classify the change as benign. In contrast, ESM1b and AlphaMissense‑Default predict a pathogenic impact. Tools that return uncertain results—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—do not provide decisive evidence. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign calls). High‑accuracy assessments are likewise ambiguous: AlphaMissense‑Optimized is uncertain, Foldetta is uncertain, and the SGM Consensus remains inconclusive. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | Uncertain | 1 | -10.519 | Likely Pathogenic | 0.833 | Likely Pathogenic | Ambiguous | 0.080 | Likely Benign | 0.2065 | 0.4511 | 1.17 | Ambiguous | 0.1 | 0.51 | Ambiguous | 0.84 | Ambiguous | 0.08 | Likely Benign | -1.51 | Neutral | 0.345 | Benign | 0.028 | Benign | 4.15 | Benign | 0.52 | Tolerated | 3.47 | 10 | 0 | 1 | -0.4 | -0.94 | 187.1 | 49.2 | 0.0 | 0.0 | 0.4 | 0.1 | X | Uncertain | The carboxylate side chain of Glu706, located at the end and outer surface of an α-helix (res. Thr704-Gly712), forms a salt bridge with Lys710 and a hydrogen bond with its own backbone amino group at the helix end in the WT simulations. Although Lys706 is unable to make these transient interactions in the variant simulations, there is no apparent negative effect on the protein structure due to the residue swap. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | |||||||||||||
| c.2116G>C | E706Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E706Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are AlphaMissense‑Default and ESM1b. Rosetta and Foldetta provide uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta also yields an uncertain outcome. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | -8.171 | Likely Pathogenic | 0.588 | Likely Pathogenic | Likely Benign | 0.059 | Likely Benign | 0.0941 | 0.3831 | 0.44 | Likely Benign | 0.0 | 0.61 | Ambiguous | 0.53 | Ambiguous | -0.14 | Likely Benign | -1.00 | Neutral | 0.433 | Benign | 0.051 | Benign | 4.13 | Benign | 0.31 | Tolerated | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.2117A>C | E706A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E706A has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only polyPhen2_HumDiv suggests pathogenicity, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of ClinVar classification or gnomAD observation. Thus, the variant is most likely benign, and this is consistent with the lack of ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | -4.604 | Likely Benign | 0.443 | Ambiguous | Likely Benign | 0.117 | Likely Benign | 0.3413 | 0.4089 | 0.80 | Ambiguous | 0.0 | 0.48 | Likely Benign | 0.64 | Ambiguous | -0.12 | Likely Benign | -0.81 | Neutral | 0.613 | Possibly Damaging | 0.180 | Benign | 4.20 | Benign | 0.65 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.2117A>G | E706G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E706G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar all classify the substitution as benign or tolerated. Only polyPhen2_HumDiv predicts a pathogenic effect. Tools with uncertain outcomes—AlphaMissense‑Default, FoldX, Rosetta, and Foldetta—do not provide a definitive assessment. High‑accuracy predictors reinforce the benign consensus: AlphaMissense‑Optimized reports a benign change; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the majority of evidence supports a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this is not contradictory to ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | -5.289 | Likely Benign | 0.535 | Ambiguous | Likely Benign | 0.071 | Likely Benign | 0.2781 | 0.3614 | 1.22 | Ambiguous | 0.0 | 1.32 | Ambiguous | 1.27 | Ambiguous | 0.12 | Likely Benign | -1.71 | Neutral | 0.931 | Possibly Damaging | 0.138 | Benign | 4.07 | Benign | 0.23 | Tolerated | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.2117A>T | E706V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E706V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Foldetta, give uncertain or inconclusive results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of predictions lean toward a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | -9.306 | Likely Pathogenic | 0.667 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | 0.0528 | 0.4275 | 1.05 | Ambiguous | 0.0 | 0.30 | Likely Benign | 0.68 | Ambiguous | 0.05 | Likely Benign | -2.63 | Deleterious | 0.555 | Possibly Damaging | 0.109 | Benign | 4.07 | Benign | 0.16 | Tolerated | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.2118A>C | E706D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E706D is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the consensus SGM score (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign effect. No tool predicts pathogenicity. High‑accuracy assessments likewise support a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. **Thus, the variant is most likely benign, and this prediction does not contradict any ClinVar status (none is available).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | -4.216 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.182 | Likely Benign | 0.1681 | 0.2726 | 0.22 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.12 | Likely Benign | -0.16 | Likely Benign | -0.01 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.17 | Benign | 0.41 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.2118A>T | E706D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E706D is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the consensus SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments further support a benign effect: AlphaMissense‑Optimized predicts benign, the SGM Consensus indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. With all evidence pointing to a neutral impact and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | -4.216 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.182 | Likely Benign | 0.1681 | 0.2726 | 0.22 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.12 | Likely Benign | -0.16 | Likely Benign | -0.01 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.17 | Benign | 0.41 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.709G>A | A237T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A237T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split; Foldetta also yields an inconclusive stability assessment. Overall, the majority of evidence leans toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -8.664 | Likely Pathogenic | 0.213 | Likely Benign | Likely Benign | 0.539 | Likely Pathogenic | 0.0975 | 0.5737 | 0.74 | Ambiguous | 0.3 | 0.55 | Ambiguous | 0.65 | Ambiguous | 0.71 | Ambiguous | -2.66 | Deleterious | 0.900 | Possibly Damaging | 0.348 | Benign | 5.80 | Benign | 0.06 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||
| 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 | 0.752 | Likely Pathogenic | 0.1593 | 0.3724 | 0.10 | Likely Benign | 0.5 | 4.20 | Destabilizing | 2.15 | Destabilizing | 1.04 | Destabilizing | -3.68 | Deleterious | 0.995 | Probably Damaging | 0.832 | Possibly Damaging | 5.77 | Benign | 0.03 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.709G>T | A237S 2D AIThe SynGAP1 missense variant A237S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM. No tool predicts a pathogenic outcome; the only inconclusive results come from premPS and ESM1b, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -7.696 | In-Between | 0.112 | Likely Benign | Likely Benign | 0.421 | Likely Benign | 0.2209 | 0.4357 | 0.48 | Likely Benign | 0.6 | 0.34 | Likely Benign | 0.41 | Likely Benign | 0.61 | Ambiguous | -1.41 | Neutral | 0.259 | Benign | 0.048 | Benign | 5.82 | Benign | 0.31 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| 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 | 0.769 | Likely Pathogenic | 0.1419 | 0.2302 | 1.23 | Ambiguous | 0.4 | 3.49 | Destabilizing | 2.36 | Destabilizing | 1.20 | Destabilizing | -3.97 | Deleterious | 0.969 | Probably Damaging | 0.704 | Possibly Damaging | 5.88 | Benign | 0.05 | Affected | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||
| c.710C>G | A237G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Given the balance of evidence, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -6.647 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.538 | Likely Pathogenic | 0.1809 | 0.2910 | 1.00 | Ambiguous | 0.0 | 2.01 | Destabilizing | 1.51 | Ambiguous | 1.14 | Destabilizing | -2.91 | Deleterious | 0.900 | Possibly Damaging | 0.430 | Benign | 5.81 | Benign | 0.05 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.710C>T | A237V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237V is not reported in ClinVar and is absent from gnomAD. Standard in‑silico predictors are divided: benign calls come from premPS, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) are uncertain. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic outcome from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain result from Foldetta. Because the majority of conventional predictors and the optimized AlphaMissense model favor benign, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -8.927 | Likely Pathogenic | 0.397 | Ambiguous | Likely Benign | 0.565 | Likely Pathogenic | 0.0771 | 0.4853 | 0.87 | Ambiguous | 0.4 | 0.97 | Ambiguous | 0.92 | Ambiguous | 0.18 | Likely Benign | -3.26 | Deleterious | 0.900 | Possibly Damaging | 0.430 | Benign | 5.87 | Benign | 0.10 | Tolerated | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||
| c.1060G>A | A354T 2D AIThe SynGAP1 missense variant A354T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic effect. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign result. No predictions or folding‑stability analyses are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -2.812 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.097 | Likely Benign | 0.1731 | 0.6496 | 0.37 | Likely Benign | 0.7 | 0.11 | Likely Benign | 0.24 | Likely Benign | -0.52 | Ambiguous | 1.72 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.75 | Pathogenic | 0.45 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.1060G>C | A354P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A354P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, SIFT, and FATHMM, while Rosetta and premPS are inconclusive. The high‑accuracy consensus from AlphaMissense‑Optimized and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) both indicate a benign outcome, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Overall, the majority of evidence points to a benign effect for A354P, 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 Benign | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -5.971 | Likely Benign | 0.239 | Likely Benign | Likely Benign | 0.241 | Likely Benign | 0.2259 | 0.5884 | 2.66 | Destabilizing | 0.2 | 1.55 | Ambiguous | 2.11 | Destabilizing | 0.57 | Ambiguous | -1.66 | Neutral | 0.001 | Benign | 0.002 | Benign | 1.76 | Pathogenic | 0.04 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1060G>T | A354S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A354S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Taken together, the overwhelming majority of evidence indicates that A354S is most likely benign, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -3.005 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.2829 | 0.5117 | 0.02 | Likely Benign | 0.1 | 0.27 | Likely Benign | 0.15 | Likely Benign | -0.10 | Likely Benign | 0.28 | Neutral | 0.005 | Benign | 0.001 | Benign | 1.76 | Pathogenic | 0.21 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1061C>A | A354D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A354D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Those that predict a pathogenic effect are FATHMM and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, and Rosetta) return uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors a pathogenic interpretation. Foldetta’s stability prediction is uncertain. Overall, the majority of consensus tools lean toward a benign effect, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -7.914 | In-Between | 0.725 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | 0.1759 | 0.1345 | 0.22 | Likely Benign | 0.1 | 1.10 | Ambiguous | 0.66 | Ambiguous | 0.57 | Ambiguous | -1.49 | Neutral | 0.255 | Benign | 0.053 | Benign | 1.75 | Pathogenic | 0.07 | Tolerated | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||
| c.1061C>G | A354G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A354G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. Predictions marked uncertain (Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a benign impact for A354G, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -4.285 | Likely Benign | 0.113 | Likely Benign | Likely Benign | 0.037 | Likely Benign | 0.2563 | 0.4777 | 0.41 | Likely Benign | 0.0 | 1.24 | Ambiguous | 0.83 | Ambiguous | 0.65 | Ambiguous | -1.87 | Neutral | 0.146 | Benign | 0.038 | Benign | 1.75 | Pathogenic | 0.05 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1061C>T | A354V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A354V is not reported in ClinVar and is present in the gnomAD database (variant ID 6‑33437966‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The high‑accuracy consensus methods support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Predictions from FoldX and Rosetta are inconclusive and are treated as unavailable. Overall, the majority of evidence indicates that A354V is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | 6-33437966-C-T | 1 | 6.26e-7 | -6.223 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.1429 | 0.6388 | 0.65 | Ambiguous | 0.1 | -1.02 | Ambiguous | -0.19 | Likely Benign | 0.18 | Likely Benign | -1.11 | Neutral | 0.146 | Benign | 0.038 | Benign | 1.81 | Pathogenic | 0.05 | Affected | 3.38 | 24 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||
| c.1069C>A | H357N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H357N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the overwhelming majority of evidence points to a benign impact. There is no ClinVar annotation to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -7.617 | In-Between | 0.103 | Likely Benign | Likely Benign | 0.126 | Likely Benign | 0.2052 | 0.3266 | 0.14 | Likely Benign | 0.2 | 0.31 | Likely Benign | 0.23 | Likely Benign | 0.31 | Likely Benign | -1.47 | Neutral | 0.495 | Possibly Damaging | 0.169 | Benign | 4.25 | Benign | 0.15 | Tolerated | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||
| c.1069C>G | H357D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H357D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta also predicts a benign outcome. No prediction or folding‑stability result is missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -12.013 | Likely Pathogenic | 0.559 | Ambiguous | Likely Benign | 0.208 | Likely Benign | 0.2782 | 0.1976 | -0.23 | Likely Benign | 0.4 | -0.27 | Likely Benign | -0.25 | Likely Benign | 0.48 | Likely Benign | -1.90 | Neutral | 0.495 | Possibly Damaging | 0.169 | Benign | 4.22 | Benign | 0.08 | Tolerated | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||
| c.1069C>T | H357Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H357Y is reported in gnomAD (variant ID 6‑33437974‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | 6-33437974-C-T | 1 | 6.21e-7 | -5.888 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.140 | Likely Benign | 0.1010 | 0.4658 | -0.33 | Likely Benign | 0.2 | 0.08 | Likely Benign | -0.13 | Likely Benign | -0.07 | Likely Benign | -1.71 | Neutral | 0.936 | Possibly Damaging | 0.388 | Benign | 4.19 | Benign | 0.14 | Tolerated | 3.39 | 22 | 2 | 0 | 1.9 | 26.03 | ||||||||||||||||||||
| c.1070A>C | H357P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H357P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Two tools give uncertain results: Foldetta (protein‑folding stability) and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect. Thus, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -7.953 | In-Between | 0.267 | Likely Benign | Likely Benign | 0.197 | Likely Benign | 0.2433 | 0.4468 | 0.17 | Likely Benign | 0.9 | 3.52 | Destabilizing | 1.85 | Ambiguous | -0.06 | Likely Benign | -2.70 | Deleterious | 0.936 | Possibly Damaging | 0.469 | Possibly Damaging | 4.18 | Benign | 0.17 | Tolerated | 0 | -2 | 1.6 | -40.02 | ||||||||||||||||||||||||||
| c.1070A>G | H357R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H357R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. Two tools remain uncertain: Rosetta and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority; and Foldetta also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -9.212 | Likely Pathogenic | 0.348 | Ambiguous | Likely Benign | 0.107 | Likely Benign | 0.2147 | 0.2818 | -0.10 | Likely Benign | 0.3 | 1.07 | Ambiguous | 0.49 | Likely Benign | 0.32 | Likely Benign | -1.03 | Neutral | 0.495 | Possibly Damaging | 0.095 | Benign | 4.22 | Benign | 0.59 | Tolerated | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||
| c.1070A>T | H357L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H357L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv, while polyPhen‑2 HumVar and ESM1b are benign or uncertain, respectively. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign (3 benign vs 1 pathogenic), and Foldetta also predicts benign. No predictions are missing or inconclusive. Overall, the variant is most likely benign based on the majority of computational evidence, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -7.281 | In-Between | 0.140 | Likely Benign | Likely Benign | 0.203 | Likely Benign | 0.1084 | 0.5971 | -0.18 | Likely Benign | 0.1 | 0.14 | Likely Benign | -0.02 | Likely Benign | 0.10 | Likely Benign | -3.39 | Deleterious | 0.704 | Possibly Damaging | 0.169 | Benign | 4.20 | Benign | 0.25 | Tolerated | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||
| c.1071C>A | H357Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H357Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess sequence conservation, structural impact, or functional effect all converge on a benign outcome: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Based on the uniform predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -4.370 | Likely Benign | 0.163 | Likely Benign | Likely Benign | 0.025 | Likely Benign | 0.1716 | 0.3850 | 0.06 | Likely Benign | 0.2 | -0.03 | Likely Benign | 0.02 | Likely Benign | -0.35 | Likely Benign | 1.42 | Neutral | 0.013 | Benign | 0.007 | Benign | 4.49 | Benign | 1.00 | Tolerated | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| c.1071C>G | H357Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H357Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess sequence conservation, structural impact, or functional effect all converge on a benign outcome: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Based on the uniform predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -4.370 | Likely Benign | 0.163 | Likely Benign | Likely Benign | 0.025 | Likely Benign | 0.1716 | 0.3850 | 0.06 | Likely Benign | 0.2 | -0.03 | Likely Benign | 0.02 | Likely Benign | -0.35 | Likely Benign | 1.42 | Neutral | 0.013 | Benign | 0.007 | Benign | 4.49 | Benign | 1.00 | Tolerated | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| c.1330A>C | K444Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K444Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote) is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K444Q, and this conclusion does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -12.876 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.382 | Likely Benign | 0.4112 | 0.1057 | 1.34 | Ambiguous | 0.0 | 1.36 | Ambiguous | 1.35 | Ambiguous | 1.04 | Destabilizing | -3.82 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 3.43 | Benign | 0.07 | Tolerated | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||
| 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 | 0.437 | Likely Benign | 0.3486 | 0.0793 | 2.99 | Destabilizing | 0.1 | 3.75 | Destabilizing | 3.37 | Destabilizing | 1.10 | Destabilizing | -3.82 | Deleterious | 0.997 | Probably Damaging | 0.981 | Probably Damaging | 3.40 | Benign | 0.01 | Affected | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1331A>C | K444T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444T 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. Those that predict a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results are Foldetta, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain (treated as unavailable for pathogenicity inference). Overall, the majority of reliable predictions indicate a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -15.557 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.442 | Likely Benign | 0.1643 | 0.3416 | 2.12 | Destabilizing | 0.1 | 1.17 | Ambiguous | 1.65 | Ambiguous | 0.96 | Ambiguous | -5.73 | Deleterious | 0.999 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.1331A>G | K444R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K444R is not reported in ClinVar and has no gnomAD allele. Prediction tools cluster into benign (REVEL, FoldX, SIFT, FATHMM, AlphaMissense‑Optimized) and pathogenic (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Two tools (Rosetta, premPS) give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. No prediction or folding stability result is missing. Overall, six tools favor pathogenicity while five favor benignity, and the high‑accuracy consensus leans toward benign. Thus the variant is most likely pathogenic based on the broader set of 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 | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -10.753 | Likely Pathogenic | 0.693 | Likely Pathogenic | Likely Benign | 0.213 | Likely Benign | 0.4597 | 0.0972 | -0.12 | Likely Benign | 0.1 | -0.61 | Ambiguous | -0.37 | Likely Benign | 0.77 | Ambiguous | -2.86 | Deleterious | 0.972 | Probably Damaging | 0.926 | Probably Damaging | 3.45 | Benign | 0.12 | Tolerated | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.1331A>T | K444M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are returned by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further highlight the discrepancy: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Overall, the majority of tools lean toward a pathogenic interpretation, and this is not contradicted by any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -14.223 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.442 | Likely Benign | 0.0934 | 0.3890 | 0.39 | Likely Benign | 0.1 | -0.47 | Likely Benign | -0.04 | Likely Benign | 0.33 | Likely Benign | -5.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.41 | Benign | 0.00 | Affected | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||
| c.1332G>C | K444N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools (FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic; Foldetta’s stability assessment is uncertain and therefore not used as evidence. Overall, the preponderance of evidence points to a pathogenic effect for K444N. 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 | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -14.797 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.286 | Likely Benign | 0.3282 | 0.1213 | 2.41 | Destabilizing | 0.0 | 1.52 | Ambiguous | 1.97 | Ambiguous | 1.18 | Destabilizing | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1332G>T | K444N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444N 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. Tools that predict a pathogenic effect include FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact. There is no ClinVar annotation to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -14.797 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.286 | Likely Benign | 0.3282 | 0.1213 | 2.41 | Destabilizing | 0.0 | 1.52 | Ambiguous | 1.97 | Ambiguous | 1.18 | Destabilizing | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.2119G>A | A707T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A707T is reported in gnomAD (ID 6‑33441584‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. The Foldetta stability prediction is inconclusive and therefore not considered evidence. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | 6-33441584-G-A | 1 | 6.20e-7 | -0.836 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.252 | Likely Benign | 0.0880 | 0.4330 | 0.50 | Ambiguous | 0.0 | 2.36 | Destabilizing | 1.43 | Ambiguous | 0.10 | Likely Benign | -0.57 | Neutral | 0.980 | Probably Damaging | 0.947 | Probably Damaging | 3.52 | Benign | 0.44 | Tolerated | 3.50 | 9 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||
| 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 | 0.228 | Likely Benign | 0.1375 | 0.3095 | 0.28 | Likely Benign | 0.1 | 5.75 | Destabilizing | 3.02 | Destabilizing | 0.76 | Ambiguous | -2.92 | Deleterious | 0.996 | Probably Damaging | 0.983 | Probably Damaging | 3.41 | Benign | 0.09 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.2119G>T | A707S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A707S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign. In contrast, polyPhen‑2 HumDiv and HumVar classify the variant as pathogenic. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence supports a benign impact, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | -4.432 | Likely Benign | 0.113 | Likely Benign | Likely Benign | 0.150 | Likely Benign | 0.1825 | 0.2924 | 0.70 | Ambiguous | 0.1 | 0.63 | Ambiguous | 0.67 | Ambiguous | 0.28 | Likely Benign | -1.07 | Neutral | 0.848 | Possibly Damaging | 0.945 | Probably Damaging | 3.43 | Benign | 0.08 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.2120C>A | A707D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A707D is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are SGM‑Consensus, AlphaMissense‑Default, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools give uncertain results: premPS and Rosetta. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta predicts benign. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | -9.160 | Likely Pathogenic | 0.772 | Likely Pathogenic | Likely Benign | 0.225 | Likely Benign | 0.1376 | 0.1741 | 0.29 | Likely Benign | 0.0 | -0.61 | Ambiguous | -0.16 | Likely Benign | 0.89 | Ambiguous | -3.16 | Deleterious | 0.996 | Probably Damaging | 0.983 | Probably Damaging | 3.39 | Benign | 0.02 | Affected | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||
| c.2120C>G | A707G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A707G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) give uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign, while Foldetta remains uncertain. Overall, the majority of definitive predictions lean toward a benign effect, and there is no ClinVar status to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | -7.480 | In-Between | 0.224 | Likely Benign | Likely Benign | 0.198 | Likely Benign | 0.1678 | 0.2388 | 1.45 | Ambiguous | 0.0 | 1.52 | Ambiguous | 1.49 | Ambiguous | 0.62 | Ambiguous | -2.60 | Deleterious | 0.991 | Probably Damaging | 0.960 | Probably Damaging | 3.42 | Benign | 0.01 | Affected | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||
| c.2120C>T | A707V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A707V variant is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (variant ID 6‑33441585‑C‑T). Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign classification. Only three tools—Rosetta, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar—predict pathogenicity, while Foldetta reports an uncertain stability change. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact for A707V, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | 6-33441585-C-T | 1 | 6.20e-7 | -6.479 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.212 | Likely Benign | 0.0794 | 0.4048 | 0.05 | Likely Benign | 0.0 | 2.17 | Destabilizing | 1.11 | Ambiguous | -0.30 | Likely Benign | -1.62 | Neutral | 0.991 | Probably Damaging | 0.912 | Probably Damaging | 3.45 | Benign | 1.00 | Tolerated | 3.50 | 9 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||
| c.1447A>C | I483L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” In contrast, polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact, and premPS remains uncertain. High‑accuracy assessments are uniformly benign: AlphaMissense‑Optimized is benign, the SGM‑Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Taken together, the majority of evidence, including the high‑accuracy tools, supports a benign classification for I483L. This conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.258 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 0.341 | Likely Benign | 0.0664 | 0.2461 | 0.31 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.35 | Likely Benign | 0.67 | Ambiguous | -1.86 | Neutral | 0.879 | Possibly Damaging | 0.970 | Probably Damaging | 4.09 | Benign | 0.31 | Tolerated | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||
| c.1447A>G | I483V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions marked as uncertain include FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, whereas Foldetta remains uncertain. Overall, the balance of evidence from both general and high‑accuracy tools leans toward a benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | Conflicting | 2 | -10.121 | Likely Pathogenic | 0.523 | Ambiguous | Likely Benign | 0.228 | Likely Benign | 0.0876 | 0.2691 | 1.00 | Ambiguous | 0.0 | 0.27 | Likely Benign | 0.64 | Ambiguous | 1.02 | Destabilizing | -0.86 | Neutral | 0.914 | Possibly Damaging | 0.921 | Probably Damaging | 3.23 | Benign | 0.03 | Affected | 3.37 | 32 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||
| c.1447A>T | I483L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” In contrast, polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact, and premPS remains uncertain. High‑accuracy assessments are uniformly benign: AlphaMissense‑Optimized is benign, the SGM‑Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Taken together, the majority of evidence, including the high‑accuracy tools, supports a benign classification for I483L. This conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.258 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 0.342 | Likely Benign | 0.0664 | 0.2461 | 0.31 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.35 | Likely Benign | 0.67 | Ambiguous | -1.86 | Neutral | 0.879 | Possibly Damaging | 0.970 | Probably Damaging | 4.09 | Benign | 0.31 | Tolerated | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||
| c.1448T>A | I483K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -18.260 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.585 | Likely Pathogenic | 0.0868 | 0.0670 | 3.53 | Destabilizing | 0.1 | 5.15 | Destabilizing | 4.34 | Destabilizing | 2.01 | Destabilizing | -6.50 | Deleterious | 0.962 | Probably Damaging | 0.991 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | -2 | -3 | -8.4 | 15.01 | |||||||||||||||||||||||||
| c.1448T>C | I483T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.692 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.474 | Likely Benign | 0.0888 | 0.0840 | 2.32 | Destabilizing | 0.0 | 2.05 | Destabilizing | 2.19 | Destabilizing | 1.77 | Destabilizing | -4.24 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.15 | Benign | 0.05 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.1448T>G | I483R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -17.066 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.595 | Likely Pathogenic | 0.1120 | 0.0870 | 5.14 | Destabilizing | 0.4 | 4.09 | Destabilizing | 4.62 | Destabilizing | 1.97 | Destabilizing | -6.50 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | -2 | -3 | -9.0 | 43.03 | |||||||||||||||||||||||||
| c.1449A>G | I483M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I483M missense variant is not reported in ClinVar (ClinVar status: not present) but is catalogued in gnomAD (gnomAD ID: 6‑33438481‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta as benign. No conclusive folding‑stability result is available from Rosetta. Overall, the majority of high‑accuracy tools (two benign, one pathogenic) lean toward a benign interpretation, and this assessment is not contradicted by any ClinVar annotation. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | 6-33438481-A-G | 1 | 6.20e-7 | -8.839 | Likely Pathogenic | 0.777 | Likely Pathogenic | Likely Benign | 0.261 | Likely Benign | 0.0607 | 0.1959 | 0.02 | Likely Benign | 0.0 | 0.73 | Ambiguous | 0.38 | Likely Benign | 1.06 | Destabilizing | -2.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.05 | Affected | 3.37 | 32 | 1 | 2 | -2.6 | 18.03 | ||||||||||||||||||||
| 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 | 0.505 | Likely Pathogenic | 0.1518 | 0.3557 | 4.40 | Destabilizing | 0.7 | 5.68 | Destabilizing | 5.04 | Destabilizing | 0.68 | Ambiguous | -5.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||
| c.1462A>G | T488A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488A is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while the majority of tools (FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) predict pathogenicity; Rosetta and premPS are uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the preponderance of evidence indicates that T488A is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -11.341 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.497 | Likely Benign | 0.2871 | 0.2872 | 2.12 | Destabilizing | 0.2 | 1.99 | Ambiguous | 2.06 | Destabilizing | 0.57 | Ambiguous | -4.64 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | 3.24 | Benign | 0.01 | Affected | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||
| c.1462A>T | T488S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T488S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, and Rosetta) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of standard tools lean toward a benign interpretation, but the high‑accuracy consensus is split, leaving the variant’s impact ambiguous. No ClinVar annotation contradicts these predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -7.662 | In-Between | 0.745 | Likely Pathogenic | Likely Benign | 0.257 | Likely Benign | 0.2256 | 0.2813 | 0.35 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.63 | Ambiguous | 0.77 | Ambiguous | -3.51 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.73 | Benign | 0.31 | Tolerated | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||
| c.1463C>A | T488K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488K is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining eleven tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all classify the variant as pathogenic. The high‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs)—all predict pathogenicity. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -14.391 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.692 | Likely Pathogenic | 0.0871 | 0.2104 | 2.09 | Destabilizing | 0.2 | 2.33 | Destabilizing | 2.21 | Destabilizing | 0.90 | Ambiguous | -5.64 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||
| c.1463C>G | T488R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only FATHMM, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -14.353 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.726 | Likely Pathogenic | 0.0711 | 0.2048 | 1.29 | Ambiguous | 0.3 | 1.55 | Ambiguous | 1.42 | Ambiguous | 0.85 | Ambiguous | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.22 | Benign | 0.00 | Affected | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||
| c.1463C>T | T488M 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant T488M is listed in ClinVar with an uncertain significance (ClinVar ID 2824521.0) and is present in gnomAD (ID 6‑33438495‑C‑T). Prediction tools that indicate a benign effect include premPS and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as inconclusive. No other tools provide definitive evidence. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | Uncertain | 1 | 6-33438495-C-T | 2 | 1.24e-6 | -12.459 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.746 | Likely Pathogenic | 0.1027 | 0.4857 | 0.66 | Ambiguous | 0.3 | 1.62 | Ambiguous | 1.14 | Ambiguous | 0.46 | Likely Benign | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 3.37 | 35 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||
| c.1573G>A | E525K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E525K is reported in gnomAD (ID 6‑33438816‑G‑A) but has no ClinVar entry. Functional prediction tools show a split assessment: benign predictions come from FoldX, Rosetta, Foldetta, and FATHMM, whereas pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic, the SGM‑Consensus also indicates likely pathogenic, while the Foldetta stability analysis predicts a benign effect. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | 6-33438816-G-A | 1 | 6.20e-7 | -15.628 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.629 | Likely Pathogenic | 0.2349 | 0.4293 | -0.13 | Likely Benign | 0.5 | 0.34 | Likely Benign | 0.11 | Likely Benign | 0.96 | Ambiguous | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 2.71 | Benign | 0.00 | Affected | 3.37 | 35 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||
| c.1573G>C | E525Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E525Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign predictions come from Rosetta, Foldetta, and FATHMM, while pathogenic predictions are returned by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -13.722 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.516 | Likely Pathogenic | 0.1173 | 0.3962 | 1.05 | Ambiguous | 0.7 | -0.11 | Likely Benign | 0.47 | Likely Benign | 0.84 | Ambiguous | -2.98 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1574A>C | E525A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E525A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Foldetta, premPS, and FATHMM, whereas the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a pathogenic classification for E525A, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -12.627 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.680 | Likely Pathogenic | 0.3554 | 0.3960 | 1.23 | Ambiguous | 0.6 | -0.62 | Ambiguous | 0.31 | Likely Benign | 0.09 | Likely Benign | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1574A>G | E525G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E525G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized returns a pathogenic score, the SGM‑Consensus also indicates pathogenicity, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Taken together, the overwhelming majority of evidence points to a pathogenic impact for E525G. This conclusion is consistent with the absence of ClinVar annotation and gnomAD data, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -13.181 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.691 | Likely Pathogenic | 0.2947 | 0.3886 | 1.71 | Ambiguous | 0.6 | 0.90 | Ambiguous | 1.31 | Ambiguous | 0.78 | Ambiguous | -6.96 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1574A>T | E525V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E525V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Foldetta, premPS, and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome; FoldX and Rosetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for E525V, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -13.622 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.683 | Likely Pathogenic | 0.0721 | 0.4946 | 1.10 | Ambiguous | 0.7 | -0.69 | Ambiguous | 0.21 | Likely Benign | 0.00 | Likely Benign | -6.96 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1575G>C | E525D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E525D missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and Foldetta, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results and are therefore not used to weigh the overall assessment. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, while Foldetta predicts benign. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect for E525D. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -11.207 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | 0.1876 | 0.2197 | 0.78 | Ambiguous | 0.6 | -0.55 | Ambiguous | 0.12 | Likely Benign | 1.00 | Destabilizing | -2.98 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.90 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1575G>T | E525D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E525D missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and Foldetta, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results and are not counted as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the balance of evidence (nine pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -11.207 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | 0.1876 | 0.2197 | 0.78 | Ambiguous | 0.6 | -0.55 | Ambiguous | 0.12 | Likely Benign | 1.00 | Destabilizing | -2.98 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.90 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.2044T>A | Y682N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y682N 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 majority of tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact; FoldX and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as pathogenic. Overall, the evidence strongly favors 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. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -11.734 | Likely Pathogenic | 0.859 | Likely Pathogenic | Ambiguous | 0.564 | Likely Pathogenic | 0.2354 | 0.0928 | 1.86 | Ambiguous | 0.1 | 2.22 | Destabilizing | 2.04 | Destabilizing | 1.54 | Destabilizing | -8.61 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.34 | Benign | 0.02 | Affected | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| c.2044T>C | Y682H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y682H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and FATHMM, whereas the majority of other in silico predictors (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict it to be pathogenic. The high‑accuracy consensus method SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. AlphaMissense‑Optimized and the protein‑folding stability predictor Foldetta both return uncertain results, and FoldX and Rosetta individually are inconclusive. Overall, the preponderance of pathogenic predictions outweighs the benign ones, indicating that Y682H is most likely pathogenic. This assessment does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -9.255 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.399 | Likely Benign | 0.2405 | 0.0868 | 1.78 | Ambiguous | 0.0 | 0.56 | Ambiguous | 1.17 | Ambiguous | 1.23 | Destabilizing | -4.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.32 | Benign | 0.03 | Affected | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||
| 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 | 0.639 | Likely Pathogenic | 0.4191 | 0.0760 | 2.81 | Destabilizing | 0.4 | 3.06 | Destabilizing | 2.94 | Destabilizing | 0.96 | Ambiguous | -9.60 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.32 | Benign | 0.01 | Affected | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.2045A>C | Y682S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y682S has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). 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. Overall, the preponderance of evidence points to a pathogenic effect for Y682S, 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 | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -11.058 | Likely Pathogenic | 0.894 | Likely Pathogenic | Ambiguous | 0.552 | Likely Pathogenic | 0.4487 | 0.2343 | 2.12 | Destabilizing | 0.1 | 1.12 | Ambiguous | 1.62 | Ambiguous | 0.88 | Ambiguous | -8.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.42 | Benign | 0.12 | Tolerated | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| c.2045A>G | Y682C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y682C is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, while only FATHMM predicts a benign outcome. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) are uncertain. High‑accuracy assessments reinforce this trend: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; AlphaMissense‑Optimized is uncertain; and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic impact for Y682C. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -10.023 | Likely Pathogenic | 0.793 | Likely Pathogenic | Ambiguous | 0.559 | Likely Pathogenic | 0.2949 | 0.2399 | 1.79 | Ambiguous | 0.1 | 1.51 | Ambiguous | 1.65 | Ambiguous | 1.11 | Destabilizing | -8.71 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.33 | Benign | 0.01 | Affected | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||
| c.2045A>T | Y682F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y682F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The SGM Consensus, which is a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes) and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta (combining FoldX‑MD and Rosetta outputs) as benign, and the SGM Consensus remains unavailable. Overall, the balance of evidence—both from general predictors and from the high‑accuracy tools—leans toward a benign classification. 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. | GAP | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -9.740 | Likely Pathogenic | 0.225 | Likely Benign | Likely Benign | 0.278 | Likely Benign | 0.2452 | 0.3662 | 0.21 | Likely Benign | 0.1 | -0.09 | Likely Benign | 0.06 | Likely Benign | 0.42 | Likely Benign | -3.72 | Deleterious | 0.997 | Probably Damaging | 0.947 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||
| c.646C>A | Q216K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216K is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools lean toward a benign classification, but the presence of several pathogenic predictions and a high‑accuracy consensus that is pathogenic introduces uncertainty. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.908 | Likely Pathogenic | 0.826 | Likely Pathogenic | Ambiguous | 0.617 | Likely Pathogenic | 0.2431 | 0.4591 | -0.35 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.02 | Likely Benign | 0.17 | Likely Benign | -2.71 | Deleterious | 0.779 | Possibly Damaging | 0.351 | Benign | 5.92 | Benign | 0.12 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||
| c.646C>G | Q216E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. No predictions or stability results are missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -9.215 | Likely Pathogenic | 0.550 | Ambiguous | Likely Benign | 0.474 | Likely Benign | 0.1872 | 0.3117 | 0.49 | Likely Benign | 0.3 | 0.30 | Likely Benign | 0.40 | Likely Benign | 0.35 | Likely Benign | -1.89 | Neutral | 0.779 | Possibly Damaging | 0.351 | Benign | 5.85 | Benign | 0.13 | Tolerated | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||
| 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 | 0.830 | Likely Pathogenic | 0.2603 | 0.5736 | 4.35 | Destabilizing | 0.8 | 4.05 | Destabilizing | 4.20 | Destabilizing | 0.53 | Ambiguous | -4.69 | Deleterious | 0.989 | Probably Damaging | 0.737 | Possibly Damaging | 5.84 | Benign | 0.01 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||
| c.647A>G | Q216R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q216R is not reported in ClinVar and has no gnomAD entry. Prediction tools that call the variant benign include FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as Benign. Overall, the predictions are split, with a slight edge toward pathogenicity. The variant is therefore most likely pathogenic based on the current computational evidence, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.149 | Likely Pathogenic | 0.821 | Likely Pathogenic | Ambiguous | 0.513 | Likely Pathogenic | 0.1972 | 0.2748 | -0.42 | Likely Benign | 0.0 | 0.09 | Likely Benign | -0.17 | Likely Benign | -0.01 | Likely Benign | -2.70 | Deleterious | 0.963 | Probably Damaging | 0.549 | Possibly Damaging | 6.00 | Benign | 0.19 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||
| c.647A>T | Q216L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216L is not reported in ClinVar (ClinVar ID: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain (treated as unavailable), SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the majority of tools (8 pathogenic vs. 5 benign) and the consensus high‑accuracy prediction lean toward pathogenicity. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -11.303 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.797 | Likely Pathogenic | 0.1036 | 0.6410 | -0.17 | Likely Benign | 0.3 | 0.28 | Likely Benign | 0.06 | Likely Benign | 0.30 | Likely Benign | -5.58 | Deleterious | 0.963 | Probably Damaging | 0.452 | Possibly Damaging | 5.87 | Benign | 0.01 | Affected | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||
| c.648G>C | Q216H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas those that predict a pathogenic impact are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.532 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.638 | Likely Pathogenic | 0.1909 | 0.4660 | 0.29 | Likely Benign | 0.0 | 0.30 | Likely Benign | 0.30 | Likely Benign | 0.50 | Likely Benign | -3.84 | Deleterious | 0.989 | Probably Damaging | 0.809 | Possibly Damaging | 5.85 | Benign | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||
| c.648G>T | Q216H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.532 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.638 | Likely Pathogenic | 0.1909 | 0.4660 | 0.29 | Likely Benign | 0.0 | 0.30 | Likely Benign | 0.30 | Likely Benign | 0.50 | Likely Benign | -3.84 | Deleterious | 0.989 | Probably Damaging | 0.809 | Possibly Damaging | 5.85 | Benign | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||
| c.1459A>C | N487H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N487H has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus) predict a pathogenic or likely pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from these tools contradicts the lack of ClinVar annotation. Overall, the preponderance of pathogenic predictions indicates that the variant is most likely pathogenic, consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -11.403 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.548 | Likely Pathogenic | 0.1123 | 0.3411 | 1.15 | Ambiguous | 0.1 | 0.84 | Ambiguous | 1.00 | Ambiguous | 0.72 | Ambiguous | -4.97 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||
| c.1459A>G | N487D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX and premPS are inconclusive. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, while Foldetta indicates a benign folding stability change. Overall, the preponderance of evidence points to a pathogenic effect for this variant, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.330 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.513 | Likely Pathogenic | 0.1728 | 0.1815 | 0.80 | Ambiguous | 0.2 | -0.21 | Likely Benign | 0.30 | Likely Benign | 0.84 | Ambiguous | -4.97 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.81 | Benign | 0.01 | Affected | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||
| c.1459A>T | N487Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487Y has no ClinVar entry and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, premPS, and FATHMM, whereas the majority of algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—label it pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports it as likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for N487Y, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -14.921 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.652 | Likely Pathogenic | 0.0587 | 0.2946 | 1.15 | Ambiguous | 0.0 | -0.05 | Likely Benign | 0.55 | Ambiguous | 0.33 | Likely Benign | -7.96 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.69 | Benign | 0.00 | Affected | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||
| c.145T>A | C49S 2D  AIThe SynGAP1 missense variant C49S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs. 2 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard predictors lean toward pathogenicity, but the high‑accuracy tools do not provide definitive support. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -6.575 | Likely Benign | 0.704 | Likely Pathogenic | Likely Benign | 0.260 | Likely Benign | 0.3855 | 0.1686 | -3.07 | Deleterious | 0.462 | Possibly Damaging | 0.478 | Possibly Damaging | 3.91 | Benign | 0.00 | Affected | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||
| c.145T>C | C49R 2D  AIThe SynGAP1 missense variant C49R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain and no Foldetta (FoldX‑MD/Rosetta) result is available. Taken together, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -10.000 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.320 | Likely Benign | 0.1605 | 0.2120 | -3.53 | Deleterious | 0.676 | Possibly Damaging | 0.761 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||||||||
| c.145T>G | C49G 2D  AIThe SynGAP1 missense variant C49G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic versus four benign) lean toward a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -6.464 | Likely Benign | 0.674 | Likely Pathogenic | Likely Benign | 0.351 | Likely Benign | 0.2419 | 0.2528 | -3.64 | Deleterious | 0.462 | Possibly Damaging | 0.599 | Possibly Damaging | 3.87 | Benign | 0.00 | Affected | -3 | -3 | -2.9 | -46.09 | ||||||||||||||||||||||||||||||||||||
| c.1460A>C | N487T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as “Likely Pathogenic.” High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No evidence from FoldX, Rosetta, or premPS is available to alter this assessment. Overall, the preponderance of computational evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -12.618 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.481 | Likely Benign | 0.1200 | 0.3441 | 1.92 | Ambiguous | 0.1 | 1.94 | Ambiguous | 1.93 | Ambiguous | 0.68 | Ambiguous | -5.97 | Deleterious | 0.987 | Probably Damaging | 0.980 | Probably Damaging | 2.78 | Benign | 0.05 | Affected | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||
| c.1460A>G | N487S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N487S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is inconclusive, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is also inconclusive. Overall, the preponderance of evidence from multiple in silico predictors and the SGM Consensus indicates that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -10.297 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.459 | Likely Benign | 0.3065 | 0.3656 | 1.42 | Ambiguous | 0.0 | 1.49 | Ambiguous | 1.46 | Ambiguous | 0.65 | Ambiguous | -4.97 | Deleterious | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 2.74 | Benign | 0.01 | Affected | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||
| c.1460A>T | N487I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487I has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely disagree, but the majority indicate a deleterious effect. Benign predictions come from Rosetta, premPS, and FATHMM, whereas pathogenic predictions are reported by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are provided by FoldX and Foldetta. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenic; Foldetta remains inconclusive. Overall, the preponderance of evidence supports a pathogenic classification for N487I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -16.592 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.591 | Likely Pathogenic | 0.0633 | 0.3531 | 1.71 | Ambiguous | 0.1 | 0.13 | Likely Benign | 0.92 | Ambiguous | 0.33 | Likely Benign | -8.95 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.67 | Benign | 0.00 | Affected | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||
| c.1461C>A | N487K 2D AIThe SynGAP1 missense variant N487K lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. The remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability predictions are available. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.489 | Likely Benign | 0.1953 | 0.2721 | 1.10 | Ambiguous | 0.9 | 1.28 | Ambiguous | 1.19 | Ambiguous | 0.80 | Ambiguous | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||
| c.1461C>G | N487K 2D AIThe SynGAP1 missense variant N487K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑related methods (FoldX, Rosetta, premPS, Foldetta) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none is available). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.488 | Likely Benign | 0.1953 | 0.2721 | 1.10 | Ambiguous | 0.9 | 1.28 | Ambiguous | 1.19 | Ambiguous | 0.80 | Ambiguous | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||
| c.146G>A | C49Y 2D  AIThe SynGAP1 missense variant C49Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for C49Y. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -11.097 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.312 | Likely Benign | 0.1016 | 0.3172 | -3.38 | Deleterious | 0.676 | Possibly Damaging | 0.761 | Possibly Damaging | 3.85 | Benign | 0.00 | Affected | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||||||||
| c.146G>C | C49S 2D AIThe SynGAP1 missense variant C49S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of conventional tools (five pathogenic vs four benign) lean toward a pathogenic interpretation, but the single high‑accuracy benign prediction and the inconclusive SGM Consensus leave the assessment uncertain. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -6.575 | Likely Benign | 0.704 | Likely Pathogenic | Likely Benign | 0.224 | Likely Benign | 0.3855 | 0.1686 | -3.07 | Deleterious | 0.462 | Possibly Damaging | 0.478 | Possibly Damaging | 3.91 | Benign | 0.00 | Affected | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||
| c.146G>T | C49F 2D  AIThe SynGAP1 missense variant C49F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect are REVEL and FATHMM, while a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—classifies the variant as pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -7.194 | In-Between | 0.893 | Likely Pathogenic | Ambiguous | 0.301 | Likely Benign | 0.1199 | 0.3690 | -3.21 | Deleterious | 0.676 | Possibly Damaging | 0.695 | Possibly Damaging | 3.86 | Benign | 0.00 | Affected | -4 | -2 | 0.3 | 44.04 | ||||||||||||||||||||||||||||||||||||
| c.147C>G | C49W 2D  AIThe SynGAP1 missense variant C49W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic and the SGM‑Consensus is “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that C49W is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -12.247 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.291 | Likely Benign | 0.1380 | 0.3172 | -3.56 | Deleterious | 0.880 | Possibly Damaging | 0.914 | Probably Damaging | 3.83 | Benign | 0.00 | Affected | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||||||||
| c.2026A>C | S676R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, FATHMM, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing; all available data are reported. Overall, the balance of evidence (six benign versus four pathogenic predictions, with the high‑accuracy Foldetta supporting benign) indicates that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -10.665 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | 0.0962 | 0.3454 | 0.22 | Likely Benign | 0.3 | 0.74 | Ambiguous | 0.48 | Likely Benign | 0.45 | Likely Benign | -2.34 | Neutral | 0.891 | Possibly Damaging | 0.278 | Benign | 3.40 | Benign | 0.02 | Affected | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||
| c.2026A>G | S676G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. Two tools (ESM1b and premPS) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, and Foldetta predicts a benign stability change. No prediction or folding result is missing or inconclusive. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -7.249 | In-Between | 0.117 | Likely Benign | Likely Benign | 0.132 | Likely Benign | 0.2772 | 0.4342 | 0.38 | Likely Benign | 0.1 | 0.25 | Likely Benign | 0.32 | Likely Benign | 0.67 | Ambiguous | -2.74 | Deleterious | 0.855 | Possibly Damaging | 0.100 | Benign | 3.39 | Benign | 0.02 | Affected | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||
| c.2026A>T | S676C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen2_HumVar, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen2_HumDiv, SIFT, and ESM1b. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -9.230 | Likely Pathogenic | 0.132 | Likely Benign | Likely Benign | 0.164 | Likely Benign | 0.1113 | 0.6352 | 0.47 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.62 | Ambiguous | 0.15 | Likely Benign | -2.45 | Neutral | 0.959 | Probably Damaging | 0.431 | Benign | 3.35 | Benign | 0.01 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.2027G>A | S676N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote). Only SIFT predicts a pathogenic outcome. Predictions that are inconclusive (FoldX, premPS, ESM1b) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is unavailable because one component (FoldX) is uncertain. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -7.486 | In-Between | 0.282 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.1454 | 0.4599 | 0.60 | Ambiguous | 0.3 | -0.21 | Likely Benign | 0.20 | Likely Benign | 0.55 | Ambiguous | -1.63 | Neutral | 0.438 | Benign | 0.036 | Benign | 3.42 | Benign | 0.05 | Affected | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||
| c.2027G>C | S676T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (Uncertain) and Foldetta (Uncertain). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta remains Uncertain. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -5.621 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.098 | Likely Benign | 0.1575 | 0.6286 | 0.79 | Ambiguous | 0.1 | 0.34 | Likely Benign | 0.57 | Ambiguous | -0.36 | Likely Benign | 0.91 | Neutral | 0.050 | Benign | 0.017 | Benign | 3.52 | Benign | 1.00 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.2027G>T | S676I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b. FoldX, Rosetta, Foldetta, and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the balance of evidence (five benign versus three pathogenic predictions) indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -10.165 | Likely Pathogenic | 0.383 | Ambiguous | Likely Benign | 0.170 | Likely Benign | 0.0879 | 0.5720 | 1.25 | Ambiguous | 0.3 | 1.12 | Ambiguous | 1.19 | Ambiguous | 0.14 | Likely Benign | -2.46 | Neutral | 0.801 | Possibly Damaging | 0.063 | Benign | 3.38 | Benign | 0.02 | Affected | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||
| c.2028C>A | S676R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, FATHMM, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing; all available data are included. Overall, the balance of evidence (six benign versus four pathogenic predictions, with the high‑accuracy Foldetta supporting benign) indicates that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -10.665 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | 0.0962 | 0.3454 | 0.22 | Likely Benign | 0.3 | 0.74 | Ambiguous | 0.48 | Likely Benign | 0.45 | Likely Benign | -2.34 | Neutral | 0.891 | Possibly Damaging | 0.278 | Benign | 3.40 | Benign | 0.02 | Affected | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||
| c.2028C>G | S676R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, FATHMM, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing; all available data are included. Overall, the balance of evidence (six benign versus four pathogenic predictions, with the high‑accuracy Foldetta supporting benign) indicates that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -10.665 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | 0.0962 | 0.3454 | 0.22 | Likely Benign | 0.3 | 0.74 | Ambiguous | 0.48 | Likely Benign | 0.45 | Likely Benign | -2.34 | Neutral | 0.891 | Possibly Damaging | 0.278 | Benign | 3.40 | Benign | 0.02 | Affected | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||
| c.2038G>A | E680K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E680K missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are SIFT, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. With a majority of individual tools and the SGM‑Consensus indicating pathogenicity, 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 | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -12.728 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.417 | Likely Benign | 0.3048 | 0.7553 | -0.10 | Likely Benign | 0.4 | -0.15 | Likely Benign | -0.13 | Likely Benign | 0.33 | Likely Benign | -3.54 | Deleterious | 0.959 | Probably Damaging | 0.411 | Benign | 3.49 | Benign | 0.02 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.2038G>C | E680Q 2D AIThe SynGAP1 missense variant E680Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a benign impact for E680Q. This conclusion is not contradicted by ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -10.502 | Likely Pathogenic | 0.742 | Likely Pathogenic | Likely Benign | 0.239 | Likely Benign | 0.1751 | 0.7241 | -0.01 | Likely Benign | 0.7 | -0.01 | Likely Benign | -0.01 | Likely Benign | -0.10 | Likely Benign | -2.58 | Deleterious | 0.981 | Probably Damaging | 0.483 | Possibly Damaging | 3.47 | Benign | 0.15 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.2039A>C | E680A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E680A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. AlphaMissense‑Optimized remains inconclusive. Overall, the majority of predictions lean toward pathogenicity, but the conflicting high‑accuracy results leave the classification uncertain. The variant is most likely pathogenic based on the prevailing evidence, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -11.338 | Likely Pathogenic | 0.819 | Likely Pathogenic | Ambiguous | 0.444 | Likely Benign | 0.3931 | 0.6989 | 0.34 | Likely Benign | 0.2 | 0.59 | Ambiguous | 0.47 | Likely Benign | 0.30 | Likely Benign | -5.22 | Deleterious | 0.935 | Possibly Damaging | 0.490 | Possibly Damaging | 3.47 | Benign | 0.09 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.2039A>G | E680G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E680G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools lean toward a pathogenic effect, with high‑accuracy methods split but tipping toward pathogenicity. The variant’s status in ClinVar is unknown, so there is no contradiction between the predictions and existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -11.396 | Likely Pathogenic | 0.743 | Likely Pathogenic | Likely Benign | 0.411 | Likely Benign | 0.2708 | 0.6228 | 0.67 | Ambiguous | 0.2 | 0.11 | Likely Benign | 0.39 | Likely Benign | 0.44 | Likely Benign | -5.48 | Deleterious | 0.998 | Probably Damaging | 0.739 | Possibly Damaging | 3.47 | Benign | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.2039A>T | E680V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E680V missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, premPS, and Foldetta. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and Rosetta is inconclusive. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, more tools (seven) predict pathogenicity than benign (five), and the high‑accuracy consensus leans toward pathogenic. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -12.051 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.454 | Likely Benign | 0.1091 | 0.7518 | 0.46 | Likely Benign | 0.3 | -1.08 | Ambiguous | -0.31 | Likely Benign | 0.18 | Likely Benign | -6.21 | Deleterious | 0.988 | Probably Damaging | 0.606 | Possibly Damaging | 3.47 | Benign | 0.01 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.2040G>C | E680D 2D AIThe SynGAP1 missense variant E680D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -5.019 | Likely Benign | 0.289 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 0.2199 | 0.5208 | 0.21 | Likely Benign | 0.8 | 0.27 | Likely Benign | 0.24 | Likely Benign | -0.10 | Likely Benign | -0.64 | Neutral | 0.906 | Possibly Damaging | 0.295 | Benign | 3.66 | Benign | 0.32 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.2040G>T | E680D 2D AIThe SynGAP1 missense variant E680D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or likely benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, representing the sole discordant prediction. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction or folding‑stability result is missing or inconclusive. **Based on the aggregate predictions, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -5.019 | Likely Benign | 0.289 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 0.2199 | 0.5208 | 0.21 | Likely Benign | 0.8 | 0.27 | Likely Benign | 0.24 | Likely Benign | -0.10 | Likely Benign | -0.64 | Neutral | 0.906 | Possibly Damaging | 0.295 | Benign | 3.66 | Benign | 0.32 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.631A>C | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, and FATHMM, whereas a pathogenic signal is reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of tools predict a pathogenic effect, and the high‑accuracy predictions reinforce this conclusion. The variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.132 | Likely Benign | 0.1003 | 0.3592 | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.631A>G | S211G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, and ESM1b; Rosetta is uncertain. High‑accuracy methods give a benign result for AlphaMissense‑Optimized and for Foldetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs two pathogenic). No evidence from ClinVar contradicts these predictions. Overall, the balance of evidence—including the unanimous benign calls from the high‑accuracy tools—suggests that the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -9.895 | Likely Pathogenic | 0.265 | Likely Benign | Likely Benign | 0.067 | Likely Benign | 0.2560 | 0.4337 | 0.30 | Likely Benign | 0.2 | 0.54 | Ambiguous | 0.42 | Likely Benign | 1.07 | Destabilizing | -3.17 | Deleterious | 0.787 | Possibly Damaging | 0.404 | Benign | 3.92 | Benign | 0.07 | Tolerated | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||
| c.631A>T | S211C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, and premPS, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Two tools (Rosetta and AlphaMissense‑Default) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Because the consensus of the most reliable predictors is split (two benign, one pathogenic) and the overall tool distribution is evenly divided, the variant’s impact remains ambiguous. Based on the available predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -10.567 | Likely Pathogenic | 0.547 | Ambiguous | Likely Benign | 0.263 | Likely Benign | 0.1292 | 0.5638 | 0.28 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.46 | Likely Benign | 0.11 | Likely Benign | -4.14 | Deleterious | 0.999 | Probably Damaging | 0.908 | Possibly Damaging | 3.89 | Benign | 0.01 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||
| c.632G>A | S211N 2D AIThe SynGAP1 S211N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and premPS. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, the overall prediction leans toward pathogenicity, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -9.995 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 0.174 | Likely Benign | 0.1534 | 0.4863 | 0.60 | Ambiguous | 1.2 | 1.39 | Ambiguous | 1.00 | Ambiguous | 1.21 | Destabilizing | -2.22 | Neutral | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 3.95 | Benign | 0.09 | Tolerated | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||
| c.632G>C | S211T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Rosetta, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign and Foldetta as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -10.301 | Likely Pathogenic | 0.678 | Likely Pathogenic | Likely Benign | 0.157 | Likely Benign | 0.1678 | 0.5960 | 0.98 | Ambiguous | 0.5 | -0.78 | Ambiguous | 0.10 | Likely Benign | 0.50 | Likely Benign | -2.33 | Neutral | 0.948 | Possibly Damaging | 0.484 | Possibly Damaging | 3.95 | Benign | 0.07 | Tolerated | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||
| c.632G>T | S211I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S211I missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. No evidence from FoldX or Rosetta is available. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -17.090 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.251 | Likely Benign | 0.0909 | 0.5220 | 1.06 | Ambiguous | 1.1 | 1.05 | Ambiguous | 1.06 | Ambiguous | 0.12 | Likely Benign | -4.94 | Deleterious | 0.995 | Probably Damaging | 0.767 | Possibly Damaging | 3.90 | Benign | 0.01 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||
| c.633C>A | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, FATHMM, and Foldetta. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Pathogenic.” The premPS score is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions and the two high‑accuracy pathogenic calls suggest that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.144 | Likely Benign | 0.1003 | 0.3592 | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.633C>G | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, FATHMM, and the protein‑stability integrator Foldetta, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic, and premPS is uncertain. High‑accuracy assessments give conflicting signals: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus also predicts Likely Pathogenic, but Foldetta, which combines FoldX‑MD and Rosetta outputs, predicts Benign. Overall, the majority of tools and the consensus score point to a pathogenic effect, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.144 | Likely Benign | 0.1003 | 0.3592 | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.793A>C | K265Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K265Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Among standard in‑silico predictors, five tools (REVEL, FoldX, PROVEAN, AlphaMissense‑Optimized, Foldetta) predict a benign effect, while five (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM) predict pathogenicity. Three tools (premPS, AlphaMissense‑Default, Rosetta) are inconclusive. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a benign outcome from Foldetta. Overall, the predictions are mixed; the balance of evidence, including the two high‑confidence benign calls, suggests the variant is more likely benign, and this does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -8.533 | Likely Pathogenic | 0.505 | Ambiguous | Likely Benign | 0.386 | Likely Benign | 0.4401 | 0.1062 | 0.35 | Likely Benign | 0.1 | -1.15 | Ambiguous | -0.40 | Likely Benign | 0.80 | Ambiguous | -2.46 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.85 | Pathogenic | 0.05 | Affected | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||
| c.793A>G | K265E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265E missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and Foldetta. Those that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are AlphaMissense‑Optimized, FoldX, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -12.163 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.461 | Likely Benign | 0.3801 | 0.0882 | 0.63 | Ambiguous | 0.2 | 0.00 | Likely Benign | 0.32 | Likely Benign | 0.95 | Ambiguous | -2.79 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.94 | Pathogenic | 0.05 | Affected | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.794A>C | K265T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265T missense variant is reported in gnomAD (ID 6‑33437699‑A‑C) but has no ClinVar entry. Prediction tools that classify the variant as benign include REVEL, SIFT, and Rosetta. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools give uncertain results: FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | 6-33437699-A-C | 1 | 6.20e-7 | -9.425 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 0.441 | Likely Benign | 0.2042 | 0.3178 | 0.99 | Ambiguous | 0.1 | 0.37 | Likely Benign | 0.68 | Ambiguous | 0.83 | Ambiguous | -3.75 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.07 | Tolerated | 3.38 | 18 | -1 | 0 | 3.2 | -27.07 | ||||||||||||||||||||
| c.794A>G | K265R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K265R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster into two groups: benign predictions include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. No prediction or stability result is missing or inconclusive. Based on the aggregate evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -3.366 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.223 | Likely Benign | 0.4713 | 0.0976 | 0.04 | Likely Benign | 0.1 | -0.44 | Likely Benign | -0.20 | Likely Benign | 0.30 | Likely Benign | -1.08 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.90 | Pathogenic | 0.36 | Tolerated | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.794A>T | K265M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265M missense variant is not reported in ClinVar and has no entries in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify it as damaging. Benign predictions are limited to FoldX, Foldetta, and premPS. Uncertain results come from Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this view: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, while Foldetta predicts a benign folding‑stability change. Overall, the preponderance of evidence supports a pathogenic classification for K265M, and this conclusion is not contradicted by the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -10.885 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 0.516 | Likely Pathogenic | 0.1005 | 0.3695 | -0.22 | Likely Benign | 0.2 | -0.63 | Ambiguous | -0.43 | Likely Benign | 0.19 | Likely Benign | -3.78 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.79 | Pathogenic | 0.01 | Affected | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||
| c.795G>C | K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, whereas the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -8.759 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.350 | Likely Benign | 0.3691 | 0.1158 | 0.98 | Ambiguous | 0.1 | 0.16 | Likely Benign | 0.57 | Ambiguous | 0.85 | Ambiguous | -3.26 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.86 | Pathogenic | 0.03 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.795G>T | K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, while the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive results are reported only for FoldX, Foldetta, and premPS, and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -8.759 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.351 | Likely Benign | 0.3691 | 0.1158 | 0.98 | Ambiguous | 0.1 | 0.16 | Likely Benign | 0.57 | Ambiguous | 0.85 | Ambiguous | -3.26 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.86 | Pathogenic | 0.03 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.175C>A | L59M 2D AIThe SynGAP1 missense variant L59M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evaluated predictors lean toward a benign interpretation. Consequently, the variant is most likely benign based on current computational evidence, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.212910 | Structured | 0.484882 | Uncertain | 0.510 | 0.668 | 0.000 | -3.394 | Likely Benign | 0.618 | Likely Pathogenic | Likely Benign | 0.088 | Likely Benign | 0.0772 | 0.3311 | -0.65 | Neutral | 0.824 | Possibly Damaging | 0.910 | Probably Damaging | 3.30 | Benign | 0.00 | Affected | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.175C>G | L59V 2D AIThe SynGAP1 missense variant L59V is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.212910 | Structured | 0.484882 | Uncertain | 0.510 | 0.668 | 0.000 | -4.465 | Likely Benign | 0.588 | Likely Pathogenic | Likely Benign | 0.049 | Likely Benign | 0.1508 | 0.3217 | -1.15 | Neutral | 0.458 | Possibly Damaging | 0.745 | Possibly Damaging | 3.36 | Benign | 0.00 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.176T>A | L59Q 2D AIThe SynGAP1 missense variant L59Q is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools are mixed: benign calls come from SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight this discordance: AlphaMissense‑Optimized predicts a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. No Foldetta stability analysis is available for this residue. Overall, the majority of high‑confidence tools lean toward a pathogenic interpretation, but the presence of several strong benign predictions and the lack of ClinVar evidence suggest uncertainty. The variant is most likely pathogenic based on the prevailing predictions, and this does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.212910 | Structured | 0.484882 | Uncertain | 0.510 | 0.668 | 0.000 | -3.841 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | 0.1103 | 0.0758 | -2.21 | Neutral | 0.943 | Possibly Damaging | 0.944 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||
| c.176T>C | L59P 2D AIThe SynGAP1 missense variant L59P 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 majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict (2 pathogenic vs. 1 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.212910 | Structured | 0.484882 | Uncertain | 0.510 | 0.668 | 0.000 | -7.076 | In-Between | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | 0.3787 | 0.1382 | -2.74 | Deleterious | 0.943 | Possibly Damaging | 0.944 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||
| c.176T>G | L59R 2D AISynGAP1 missense variant L59R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. The predictions are therefore split, with an equal number of benign and pathogenic calls, and the high‑accuracy tools provide contradictory signals. Consequently, the variant is most likely pathogenic based on the presence of multiple pathogenic predictions and the high‑accuracy AlphaMissense‑Optimized result, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.212910 | Structured | 0.484882 | Uncertain | 0.510 | 0.668 | 0.000 | -4.037 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.266 | Likely Benign | 0.1298 | 0.0600 | -2.09 | Neutral | 0.943 | Possibly Damaging | 0.944 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.1051G>A | A351T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A351T missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain predictions come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as inconclusive. Overall, the majority of evidence supports a benign impact for A351T, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -6.863 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.1337 | 0.6713 | 0.22 | Likely Benign | 0.0 | 0.80 | Ambiguous | 0.51 | Ambiguous | 0.49 | Likely Benign | -2.42 | Neutral | 0.524 | Possibly Damaging | 0.138 | Benign | 1.71 | Pathogenic | 0.06 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| 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 | 0.051 | Likely Benign | 0.1862 | 0.5472 | -0.89 | Ambiguous | 0.2 | 6.19 | Destabilizing | 2.65 | Destabilizing | 0.62 | Ambiguous | -3.08 | Deleterious | 0.016 | Benign | 0.007 | Benign | 1.67 | Pathogenic | 0.03 | Affected | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||
| c.1051G>T | A351S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy methods—AlphaMissense‑Optimized, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (integrating FoldX‑MD and Rosetta)—all report benign or likely benign. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely benign; this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -4.823 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.016 | Likely Benign | 0.2558 | 0.5334 | 0.24 | Likely Benign | 0.0 | 0.25 | Likely Benign | 0.25 | Likely Benign | 0.27 | Likely Benign | -1.42 | Neutral | 0.080 | Benign | 0.023 | Benign | 1.88 | Pathogenic | 0.13 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1052C>A | A351D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A351D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and FATHMM; AlphaMissense‑Default and ESM1b are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward pathogenic due to two pathogenic and two uncertain calls. Overall, the majority of tools predict a benign outcome, and this does not contradict the lack of ClinVar annotation. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -7.917 | In-Between | 0.543 | Ambiguous | Likely Benign | 0.114 | Likely Benign | 0.1535 | 0.1386 | -0.02 | Likely Benign | 0.0 | -0.12 | Likely Benign | -0.07 | Likely Benign | 0.49 | Likely Benign | -3.61 | Deleterious | 0.842 | Possibly Damaging | 0.321 | Benign | 1.77 | Pathogenic | 0.11 | Tolerated | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||
| c.1052C>G | A351G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A351G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs two pathogenic), and Foldetta is uncertain. Taken together, the majority of available predictions lean toward a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -4.983 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.2298 | 0.4737 | 0.39 | Likely Benign | 0.0 | 1.04 | Ambiguous | 0.72 | Ambiguous | 0.55 | Ambiguous | -2.53 | Deleterious | 0.688 | Possibly Damaging | 0.138 | Benign | 1.77 | Pathogenic | 0.04 | Affected | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||
| c.1052C>T | A351V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351V is not reported in ClinVar and is absent from gnomAD. Computational predictions cluster into two groups: benign (REVEL, FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen2_HumVar) and pathogenic (PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, FATHMM, SGM‑Consensus). High‑accuracy tools give a mixed signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the balance of evidence leans toward a benign effect, but the presence of several pathogenic predictions introduces uncertainty. The variant is most likely benign based on the current computational data, 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 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -9.002 | Likely Pathogenic | 0.124 | Likely Benign | Likely Benign | 0.052 | Likely Benign | 0.1140 | 0.6565 | 0.09 | Likely Benign | 0.0 | 0.19 | Likely Benign | 0.14 | Likely Benign | 0.29 | Likely Benign | -2.84 | Deleterious | 0.915 | Possibly Damaging | 0.321 | Benign | 1.66 | Pathogenic | 0.03 | Affected | 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 | 0.228 | Likely Benign | 0.2911 | 0.2707 | 0.97 | Ambiguous | 0.0 | 2.51 | Destabilizing | 1.74 | Ambiguous | 0.71 | Ambiguous | -2.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.42 | Tolerated | 3.39 | 32 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||
| c.1435C>T | R479W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R479W is not reported in ClinVar and is present in gnomAD (ID 6‑33438467‑C‑T). Functional prediction tools show a split opinion: benign calls come from REVEL, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic; Foldetta remains inconclusive. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | 6-33438467-C-T | 6 | 3.72e-6 | -11.356 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.249 | Likely Benign | 0.1046 | 0.2933 | 0.60 | Ambiguous | 0.1 | 0.72 | Ambiguous | 0.66 | Ambiguous | 0.42 | Likely Benign | -4.75 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 3.39 | 32 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||
| c.1436G>A | R479Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R479Q is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (variant ID 6‑33438468‑G‑A). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv and HumVar both predict a pathogenic impact. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as likely benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” status; thus the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | Uncertain | 1 | 6-33438468-G-A | 7 | 4.34e-6 | -7.109 | In-Between | 0.259 | Likely Benign | Likely Benign | 0.191 | Likely Benign | 0.2448 | 0.1812 | 0.54 | Ambiguous | 0.1 | 0.57 | Ambiguous | 0.56 | Ambiguous | 0.49 | Likely Benign | -1.16 | Neutral | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.42 | Benign | 0.31 | Tolerated | 3.39 | 32 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||
| c.1436G>C | R479P 2D 3DClick to see structure in 3D Viewer AIClinVar lists the SynGAP1 R479P variant as Uncertain, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. Those that predict a pathogenic effect are FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive are AlphaMissense‑Optimized and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as pathogenic. Overall, the majority of tools and the high‑accuracy methods support a pathogenic classification, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | Uncertain | 1 | -11.795 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.277 | Likely Benign | 0.1993 | 0.3747 | 2.86 | Destabilizing | 0.2 | 3.88 | Destabilizing | 3.37 | Destabilizing | 0.81 | Ambiguous | -3.52 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.41 | Benign | 0.18 | Tolerated | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||
| c.1436G>T | R479L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R479L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM) and pathogenic predictions (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized remains uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No single metric dominates, and the overall evidence is balanced. Therefore, the variant’s pathogenicity is inconclusive; it is not contradicted by ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | -11.118 | Likely Pathogenic | 0.832 | Likely Pathogenic | Ambiguous | 0.265 | Likely Benign | 0.1326 | 0.3624 | 0.45 | Likely Benign | 0.1 | 0.12 | Likely Benign | 0.29 | Likely Benign | 0.39 | Likely Benign | -4.21 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.38 | Benign | 0.15 | Tolerated | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.1438G>A | E480K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480K is catalogued in gnomAD (ID 6‑33438470‑G‑A) but has no entry in ClinVar. Functional prediction tools cluster into two groups: benign predictions come from FoldX and SIFT, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results are reported by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that E480K is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | 6-33438470-G-A | 1 | 6.20e-7 | -14.059 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.768 | Likely Pathogenic | 0.1828 | 0.6813 | 0.40 | Likely Benign | 0.1 | 1.08 | Ambiguous | 0.74 | Ambiguous | 0.83 | Ambiguous | -3.45 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | -1.26 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||
| c.1438G>C | E480Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 E480Q is not reported in ClinVar (no ClinVar ID) and is present in gnomAD (ID 6‑33438470‑G‑C). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and the protein‑folding stability method Foldetta. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized is uncertain and therefore not used as evidence. High‑accuracy assessments show Foldetta predicts benign stability change, SGM Consensus predicts pathogenic, and AlphaMissense‑Optimized is inconclusive. Overall, the predictions are split, but the presence of a benign prediction from a high‑accuracy folding method and the lack of a ClinVar pathogenic claim suggest the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | 6-33438470-G-C | 2 | 1.24e-6 | -12.336 | Likely Pathogenic | 0.845 | Likely Pathogenic | Ambiguous | 0.480 | Likely Benign | 0.0854 | 0.6870 | 0.43 | Likely Benign | 0.0 | -0.01 | Likely Benign | 0.21 | Likely Benign | 0.75 | Ambiguous | -2.29 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | -1.29 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||
| c.1439A>C | E480A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480A is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only SIFT, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the four pathogenic‑predicted tools above) as likely pathogenic, and Foldetta as uncertain. Because most evidence points to a deleterious effect, the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -13.192 | Likely Pathogenic | 0.931 | Likely Pathogenic | Ambiguous | 0.694 | Likely Pathogenic | 0.3468 | 0.6635 | 0.91 | Ambiguous | 0.1 | 1.15 | Ambiguous | 1.03 | Ambiguous | 0.55 | Ambiguous | -5.04 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.09 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1439A>G | E480G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480G missense variant is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in‑silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify it as pathogenic. Predictions that are uncertain—FoldX, premPS, and AlphaMissense‑Optimized—do not provide evidence for benignity. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic, and AlphaMissense‑Optimized remains uncertain. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -11.651 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 0.778 | Likely Pathogenic | 0.2806 | 0.6172 | 1.83 | Ambiguous | 0.1 | 2.34 | Destabilizing | 2.09 | Destabilizing | 0.65 | Ambiguous | -5.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.03 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1439A>T | E480V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only premPS. All other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—classify the variant as pathogenic or likely pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the overwhelming majority of predictions support a pathogenic effect for E480V. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -12.347 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.797 | Likely Pathogenic | 0.0496 | 0.7192 | 0.94 | Ambiguous | 0.1 | 0.74 | Ambiguous | 0.84 | Ambiguous | 0.31 | Likely Benign | -6.07 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | -1.24 | Pathogenic | 0.02 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1440G>C | E480D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, whereas polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. The remaining tools—FoldX, Rosetta, premPS, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority, and Foldetta remains uncertain. Overall, the balance of evidence favors a benign classification for E480D, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -3.001 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.405 | Likely Benign | 0.1526 | 0.4130 | 0.62 | Ambiguous | 0.2 | 1.39 | Ambiguous | 1.01 | Ambiguous | 0.61 | Ambiguous | -0.77 | Neutral | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.1440G>T | E480D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic outcome. The remaining tools—FoldX, Rosetta, premPS, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta providing no definitive stability change. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -3.001 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.405 | Likely Benign | 0.1526 | 0.4130 | 0.62 | Ambiguous | 0.2 | 1.39 | Ambiguous | 1.01 | Ambiguous | 0.61 | Ambiguous | -0.77 | Neutral | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3 | 2 | 0.0 | -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 | 0.672 | Likely Pathogenic | 0.3763 | 0.0571 | 1.94 | Ambiguous | 0.1 | 2.47 | Destabilizing | 2.21 | Destabilizing | 0.51 | Ambiguous | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.00 | Pathogenic | 0.01 | Affected | 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 | 0.672 | Likely Pathogenic | 0.3763 | 0.0571 | 1.94 | Ambiguous | 0.1 | 2.47 | Destabilizing | 2.21 | Destabilizing | 0.51 | Ambiguous | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.00 | Pathogenic | 0.01 | Affected | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||
| c.799T>G | W267G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods corroborate this: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -15.020 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.678 | Likely Pathogenic | 0.4049 | 0.1481 | 4.40 | Destabilizing | 0.2 | 3.99 | Destabilizing | 4.20 | Destabilizing | 1.20 | Destabilizing | -11.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.96 | Pathogenic | 0.03 | Affected | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||
| 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 | 0.593 | Likely Pathogenic | 0.3809 | 0.1415 | 3.42 | Destabilizing | 0.3 | 3.20 | Destabilizing | 3.31 | Destabilizing | 0.87 | Ambiguous | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.03 | Pathogenic | 0.09 | Tolerated | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||
| c.800G>T | W267L 2D AIThe SynGAP1 missense variant W267L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign effect. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS, which are treated as unavailable evidence. High‑accuracy assessments further support a damaging effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” while Foldetta’s stability prediction is uncertain. Overall, the evidence strongly indicates that W267L is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -13.670 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.628 | Likely Pathogenic | 0.2122 | 0.2843 | 1.19 | Ambiguous | 0.7 | 1.31 | Ambiguous | 1.25 | Ambiguous | 0.75 | Ambiguous | -11.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.93 | Pathogenic | 0.01 | Affected | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||
| c.801G>C | W267C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267C is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic based on the consensus of all predictions, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -12.351 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.705 | Likely Pathogenic | 0.3573 | 0.1700 | 2.81 | Destabilizing | 0.2 | 2.20 | Destabilizing | 2.51 | Destabilizing | 1.00 | Destabilizing | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.90 | Pathogenic | 0.01 | Affected | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||
| c.801G>T | W267C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267C is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic based on the consensus of all predictions, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -12.351 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.705 | Likely Pathogenic | 0.3573 | 0.1700 | 2.81 | Destabilizing | 0.2 | 2.20 | Destabilizing | 2.51 | Destabilizing | 1.00 | Destabilizing | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.90 | Pathogenic | 0.01 | Affected | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||
| c.802A>C | I268L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools give uncertain results: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta indicates a benign folding‑stability outcome. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -6.544 | Likely Benign | 0.402 | Ambiguous | Likely Benign | 0.390 | Likely Benign | 0.0635 | 0.3037 | 0.37 | Likely Benign | 0.1 | -0.07 | Likely Benign | 0.15 | Likely Benign | 0.96 | Ambiguous | -1.84 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 1.65 | Pathogenic | 0.03 | Affected | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.802A>G | I268V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign, while Foldetta’s stability analysis is uncertain. Overall, the majority of reliable predictors indicate a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -4.553 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.139 | Likely Benign | 0.0845 | 0.2489 | 1.46 | Ambiguous | 0.0 | 0.95 | Ambiguous | 1.21 | Ambiguous | 0.71 | Ambiguous | -0.56 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 2.15 | Pathogenic | 0.71 | Tolerated | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.802A>T | I268F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; only Rosetta and Foldetta are uncertain. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) remains uncertain. Overall, the consensus of available predictions strongly supports a pathogenic classification for I268F, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -11.426 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.685 | Likely Pathogenic | 0.0427 | 0.2158 | 2.85 | Destabilizing | 0.7 | 0.59 | Ambiguous | 1.72 | Ambiguous | 1.00 | Destabilizing | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.803T>A | I268N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -13.664 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.812 | Likely Pathogenic | 0.0708 | 0.0142 | 3.48 | Destabilizing | 0.1 | 3.17 | Destabilizing | 3.33 | Destabilizing | 2.21 | Destabilizing | -6.26 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.803T>C | I268T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268T is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on pathogenicity include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a destabilizing, pathogenic effect. All available predictions are concordant and point to a deleterious impact. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -10.753 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.828 | Likely Pathogenic | 0.0882 | 0.0638 | 3.44 | Destabilizing | 0.1 | 3.19 | Destabilizing | 3.32 | Destabilizing | 1.93 | Destabilizing | -4.24 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.803T>G | I268S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -13.032 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.841 | Likely Pathogenic | 0.2037 | 0.0530 | 4.93 | Destabilizing | 0.1 | 4.54 | Destabilizing | 4.74 | Destabilizing | 2.10 | Destabilizing | -5.34 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||
| c.804C>G | I268M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I268M missense variant is catalogued in gnomAD (ID 6‑33437709‑C‑G) but has no ClinVar entry. Functional prediction tools largely disagree: benign predictions come from FoldX and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all indicate pathogenicity. Rosetta and Foldetta provide inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the preponderance of evidence from the majority of prediction tools points to a pathogenic effect, which is consistent with the lack of a ClinVar classification but does not contradict any existing ClinVar status (none). Thus, the variant is most likely pathogenic, and this prediction does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | 6-33437709-C-G | 1 | 6.20e-7 | -9.721 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | 0.622 | Likely Pathogenic | 0.0579 | 0.2145 | 0.12 | Likely Benign | 0.2 | 0.95 | Ambiguous | 0.54 | Ambiguous | 1.32 | Destabilizing | -2.58 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.52 | Pathogenic | 0.01 | Affected | 3.38 | 19 | 1 | 2 | -2.6 | 18.03 | ||||||||||||||||||||
| c.805A>C | I269L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I269L missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized all predict benign. Pathogenicity is suggested by polyPhen‑2 (HumDiv and HumVar) and FATHMM, while ESM1b and AlphaMissense‑Default remain uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, Foldetta predicts benign stability, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to an equal split between benign and pathogenic signals. Overall, the balance of evidence favors a benign effect for I269L, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -7.588 | In-Between | 0.470 | Ambiguous | Likely Benign | 0.348 | Likely Benign | 0.0662 | 0.2817 | 0.00 | Likely Benign | 0.0 | 0.19 | Likely Benign | 0.10 | Likely Benign | 0.47 | Likely Benign | -1.47 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 1.88 | Pathogenic | 0.28 | Tolerated | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.805A>G | I269V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I269V missense variant has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that are uncertain or inconclusive are FoldX, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools lean toward a benign interpretation, but the high‑accuracy consensus indicates a pathogenic signal, leaving the variant’s clinical significance uncertain. This assessment does not contradict any existing ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -8.748 | Likely Pathogenic | 0.344 | Ambiguous | Likely Benign | 0.393 | Likely Benign | 0.0844 | 0.2859 | 0.95 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.72 | Ambiguous | 0.71 | Ambiguous | -0.72 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 1.87 | Pathogenic | 0.10 | Tolerated | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||
| c.805A>T | I269L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: eight tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Optimized) predict a benign effect, while three tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM) predict pathogenicity. Two tools (ESM1b, AlphaMissense‑Default) return uncertain results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized classifies the variant as benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign impact. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields no clear majority and is therefore unavailable as evidence. Overall, the preponderance of evidence supports a benign classification, which is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -7.588 | In-Between | 0.470 | Ambiguous | Likely Benign | 0.348 | Likely Benign | 0.0662 | 0.2817 | 0.00 | Likely Benign | 0.0 | 0.19 | Likely Benign | 0.10 | Likely Benign | 0.47 | Likely Benign | -1.47 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 1.88 | Pathogenic | 0.28 | Tolerated | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.806T>A | I269K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT is the sole benign predictor, whereas the remaining methods—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. FoldX and Rosetta individually report uncertain effects, and Foldetta remains unavailable. Overall, the consensus of the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -14.609 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.763 | Likely Pathogenic | 0.0878 | 0.0713 | 1.45 | Ambiguous | 0.1 | 1.86 | Ambiguous | 1.66 | Ambiguous | 1.55 | Destabilizing | -5.10 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.76 | Pathogenic | 0.06 | Tolerated | -2 | -3 | -8.4 | 15.01 | |||||||||||||||||||||||||
| c.806T>C | I269T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269T is not reported in ClinVar (no ClinVar entry) but is present in gnomAD (variant ID 6‑33437711‑T‑C). Among general in‑silico predictors, only SIFT classifies the change as benign, whereas the remaining tools that provide a definitive call (REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. High‑accuracy assessments give a more nuanced view: AlphaMissense‑Optimized is uncertain; 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. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | 6-33437711-T-C | 2 | 1.24e-6 | -9.376 | Likely Pathogenic | 0.887 | Likely Pathogenic | Ambiguous | 0.727 | Likely Pathogenic | 0.0833 | 0.0808 | 1.97 | Ambiguous | 0.1 | 2.10 | Destabilizing | 2.04 | Destabilizing | 1.38 | Destabilizing | -3.70 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.72 | Pathogenic | 0.09 | Tolerated | 3.38 | 19 | -1 | 0 | -5.2 | -12.05 | ||||||||||||||||||||
| c.806T>G | I269R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: the benign group contains only SIFT, whereas the pathogenic group includes SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta give uncertain results, and Foldetta is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as unavailable. Based on the preponderance of pathogenic predictions, 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 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -14.567 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.765 | Likely Pathogenic | 0.1108 | 0.0870 | 1.34 | Ambiguous | 0.1 | 1.99 | Ambiguous | 1.67 | Ambiguous | 1.50 | Destabilizing | -5.23 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.69 | Pathogenic | 0.07 | Tolerated | -2 | -3 | -9.0 | 43.03 | |||||||||||||||||||||||||
| c.807A>G | I269M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269M is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include PROVEAN and AlphaMissense‑Optimized, whereas REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default predict it to be pathogenic. Five tools (FoldX, Rosetta, Foldetta, premPS, and ESM1b) give uncertain results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized reports a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta remains uncertain. Overall, the majority of predictions support a pathogenic impact, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -7.863 | In-Between | 0.715 | Likely Pathogenic | Likely Benign | 0.507 | Likely Pathogenic | 0.0580 | 0.2283 | 0.91 | Ambiguous | 0.1 | 1.66 | Ambiguous | 1.29 | Ambiguous | 0.94 | Ambiguous | -2.19 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.75 | Pathogenic | 0.05 | Affected | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||
| c.1066C>A | R356S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R356S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and SIFT, whereas the remaining tools—premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized—predict it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for R356S, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | -13.059 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.292 | Likely Benign | 0.2891 | 0.4491 | 1.00 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.90 | Ambiguous | 1.04 | Destabilizing | -5.28 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 1.84 | Pathogenic | 0.07 | Tolerated | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||
| c.1066C>G | R356G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R356G missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and SIFT, while the majority of tools predict a pathogenic outcome: SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are uncertain and therefore treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the preponderance of pathogenic predictions indicates that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which contains no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | -12.305 | Likely Pathogenic | 0.883 | Likely Pathogenic | Ambiguous | 0.271 | Likely Benign | 0.3505 | 0.3793 | 1.02 | Ambiguous | 0.0 | 1.80 | Ambiguous | 1.41 | Ambiguous | 1.06 | Destabilizing | -6.20 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 1.95 | Pathogenic | 0.08 | Tolerated | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.1066C>T | R356C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R356C is listed in ClinVar as Benign (ClinVar ID 469145.0) and is present in gnomAD (ID 6‑33437971‑C‑T). Functional prediction tools cluster into two groups: benign predictions from REVEL and AlphaMissense‑Optimized, and pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic effect, contradicting the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | Likely Benign | 1 | 6-33437971-C-T | 5 | 3.10e-6 | -11.827 | Likely Pathogenic | 0.774 | Likely Pathogenic | Likely Benign | 0.312 | Likely Benign | 0.3238 | 0.3618 | 0.76 | Ambiguous | 0.0 | 1.19 | Ambiguous | 0.98 | Ambiguous | 0.84 | Ambiguous | -7.12 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 1.67 | Pathogenic | 0.00 | Affected | 3.39 | 22 | -4 | -3 | 7.0 | -53.05 | 212.3 | 91.0 | -0.1 | 0.3 | -0.3 | 0.1 | X | Potentially Pathogenic | Arg356 is located in a loop that includes a short helical section and connects two anti-parallel β sheet strands (res. Gly341-Pro349, res. Thr359-Pro364). In the WT simulations, the guanidinium group of Arg356 alternately forms salt bridges with the carboxylate groups of the GAP domain residues, Glu446 and Glu698. Arg356 also forms hydrogen bonds with the hydroxyl group of the GAP domain residue Thr691 and interacts with Met409 at the C2-GAP interface.In the variant simulations, the Cys356 mutation fails to maintain any of the Arg356 interactions and only occasionally forms weak hydrogen bonds with nearby C2 domain residues (e.g., Gln407). Although no negative structural effects are observed during the simulations, Arg356 is located at the C2 and GAP domain interface, making the residue swap potentially detrimental to the tertiary structure assembly. | |||||||||
| c.1067G>A | R356H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R356H is recorded in ClinVar as benign (ClinVar ID 2984966.0) and is present in the gnomAD database (6‑33437972‑G‑A). Prediction tools that indicate a benign effect include REVEL, Rosetta, Foldetta, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default, with the SGM‑Consensus also labeling it likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions support a pathogenic impact, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | Likely Benign | 1 | 6-33437972-G-A | 9 | 5.66e-6 | -11.453 | Likely Pathogenic | 0.614 | Likely Pathogenic | Likely Benign | 0.314 | Likely Benign | 0.3493 | 0.2206 | 0.59 | Ambiguous | 0.1 | -0.27 | Likely Benign | 0.16 | Likely Benign | 1.17 | Destabilizing | -4.43 | Deleterious | 0.999 | Probably Damaging | 0.987 | Probably Damaging | 1.70 | Pathogenic | 0.01 | Affected | 3.39 | 22 | 0 | 2 | 1.3 | -19.05 | ||||||||||||||||||
| c.1067G>C | R356P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R356P missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FoldX, whereas a majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive are AlphaMissense‑Optimized, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R356P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | -12.956 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 0.451 | Likely Benign | 0.2213 | 0.5033 | 0.48 | Likely Benign | 0.1 | 0.72 | Ambiguous | 0.60 | Ambiguous | 1.05 | Destabilizing | -6.23 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 1.72 | Pathogenic | 0.02 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.1067G>T | R356L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R356L is not reported in ClinVar and is present in gnomAD (ID 6‑33437972‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, and Foldetta, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are AlphaMissense‑Optimized, Rosetta, 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 outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for R356L, and this conclusion does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | 6-33437972-G-T | -13.957 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.412 | Likely Benign | 0.2110 | 0.5242 | -0.04 | Likely Benign | 0.1 | -0.57 | Ambiguous | -0.31 | Likely Benign | 0.68 | Ambiguous | -6.20 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 3.39 | 22 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||
| 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 | 0.860 | Likely Pathogenic | 0.1940 | 0.3806 | 0.43 | Likely Benign | 0.2 | 4.81 | Destabilizing | 2.62 | Destabilizing | 0.82 | Ambiguous | -5.51 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.39 | Pathogenic | 0.09 | Tolerated | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||
| c.1855A>G | T619A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T619A missense variant is not reported in ClinVar and has no gnomAD entry. Consensus prediction tools cluster into two groups: benign predictions come from SIFT, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized classifying the change as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely pathogenic; Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -6.341 | Likely Benign | 0.672 | Likely Pathogenic | Likely Benign | 0.613 | Likely Pathogenic | 0.3915 | 0.3109 | 0.59 | Ambiguous | 0.1 | 0.62 | Ambiguous | 0.61 | Ambiguous | 0.53 | Ambiguous | -4.21 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | -1.27 | Pathogenic | 0.17 | Tolerated | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||
| c.1855A>T | T619S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T619S is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports a benign outcome, whereas the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, yields an uncertain result. Overall, the majority of evidence points to a pathogenic effect for T619S, and this conclusion does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | Uncertain | 1 | -8.608 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.602 | Likely Pathogenic | 0.3255 | 0.2860 | 1.09 | Ambiguous | 0.2 | 1.35 | Ambiguous | 1.22 | Ambiguous | 0.85 | Ambiguous | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.30 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||
| c.1856C>A | T619N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T619N has no ClinVar entry and is not reported in gnomAD. Prediction tools that assess pathogenicity all lean toward a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -11.796 | Likely Pathogenic | 0.900 | Likely Pathogenic | Ambiguous | 0.715 | Likely Pathogenic | 0.0998 | 0.2690 | 0.61 | Ambiguous | 0.1 | 0.96 | Ambiguous | 0.79 | Ambiguous | 1.23 | Destabilizing | -4.61 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.38 | Pathogenic | 0.05 | Affected | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||
| c.1856C>G | T619S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T619S missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) uniformly predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized remains benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -8.608 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.523 | Likely Pathogenic | 0.3255 | 0.2860 | 1.09 | Ambiguous | 0.2 | 1.35 | Ambiguous | 1.22 | Ambiguous | 0.85 | Ambiguous | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.30 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||
| c.1856C>T | T619I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T619I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity unanimously classify the variant as pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the remaining tools (FoldX, Rosetta, Foldetta, premPS) return uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Based on the consensus of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -11.760 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.735 | Likely Pathogenic | 0.0869 | 0.4377 | -1.06 | Ambiguous | 0.1 | -1.35 | Ambiguous | -1.21 | Ambiguous | 0.58 | Ambiguous | -5.54 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.40 | Pathogenic | 0.03 | Affected | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||
| c.658T>A | F220I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yielding 3 pathogenic versus 1 benign calls, thus supporting a pathogenic classification. High‑accuracy tools specifically report pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -12.041 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.921 | Likely Pathogenic | 0.2292 | 0.3127 | 3.11 | Destabilizing | 0.1 | 2.35 | Destabilizing | 2.73 | Destabilizing | 1.03 | Destabilizing | -4.98 | Deleterious | 0.300 | Benign | 0.098 | Benign | 4.06 | Benign | 0.01 | Affected | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||
| c.658T>C | F220L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -9.601 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.850 | Likely Pathogenic | 0.2589 | 0.4108 | 2.08 | Destabilizing | 0.1 | 2.24 | Destabilizing | 2.16 | Destabilizing | 1.33 | Destabilizing | -4.95 | Deleterious | 0.003 | Benign | 0.005 | Benign | 4.24 | Benign | 0.02 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.658T>G | F220V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220V is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -11.599 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.911 | Likely Pathogenic | 0.2351 | 0.3315 | 3.83 | Destabilizing | 0.1 | 4.11 | Destabilizing | 3.97 | Destabilizing | 1.56 | Destabilizing | -5.81 | Deleterious | 0.075 | Benign | 0.015 | Benign | 4.04 | Benign | 0.01 | Affected | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||
| c.659T>A | F220Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, FATHMM, and polyPhen‑2 HumVar. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is classified as pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain and therefore not considered evidence. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that F220Y is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -12.541 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.879 | Likely Pathogenic | 0.1479 | 0.2661 | 2.25 | Destabilizing | 0.1 | 0.35 | Likely Benign | 1.30 | Ambiguous | 1.14 | Destabilizing | -2.54 | Deleterious | 0.928 | Possibly Damaging | 0.395 | Benign | 4.07 | Benign | 0.00 | Affected | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||
| c.659T>C | F220S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all available scores (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default) indicate pathogenicity, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -15.258 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.954 | Likely Pathogenic | 0.3813 | 0.1143 | 4.06 | Destabilizing | 0.1 | 4.67 | Destabilizing | 4.37 | Destabilizing | 1.44 | Destabilizing | -6.67 | Deleterious | 0.928 | Possibly Damaging | 0.477 | Possibly Damaging | 4.03 | Benign | 0.01 | Affected | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||
| c.659T>G | F220C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220C is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -12.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.941 | Likely Pathogenic | 0.2264 | 0.2012 | 3.67 | Destabilizing | 0.0 | 5.03 | Destabilizing | 4.35 | Destabilizing | 2.22 | Destabilizing | -6.72 | Deleterious | 0.994 | Probably Damaging | 0.753 | Possibly Damaging | 4.03 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||
| c.660T>A | F220L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -9.601 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.752 | Likely Pathogenic | 0.2589 | 0.4108 | 2.08 | Destabilizing | 0.1 | 2.24 | Destabilizing | 2.16 | Destabilizing | 1.33 | Destabilizing | -4.95 | Deleterious | 0.003 | Benign | 0.005 | Benign | 4.24 | Benign | 0.02 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.660T>G | F220L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -9.601 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.752 | Likely Pathogenic | 0.2589 | 0.4108 | 2.08 | Destabilizing | 0.1 | 2.24 | Destabilizing | 2.16 | Destabilizing | 1.33 | Destabilizing | -4.95 | Deleterious | 0.003 | Benign | 0.005 | Benign | 4.24 | Benign | 0.02 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.1072T>A | F358I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F358I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports an uncertain impact. Overall, the preponderance of evidence points to a pathogenic effect for F358I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -10.636 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.393 | Likely Benign | 0.2331 | 0.2821 | 0.93 | Ambiguous | 0.2 | 1.66 | Ambiguous | 1.30 | Ambiguous | 0.95 | Ambiguous | -4.45 | Deleterious | 0.993 | Probably Damaging | 0.977 | Probably Damaging | 4.07 | Benign | 0.13 | Tolerated | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||
| c.1072T>C | F358L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results are reported for Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta’s stability prediction is unavailable due to inconclusiveness. Overall, the majority of available evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -7.865 | In-Between | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.290 | Likely Benign | 0.2555 | 0.3602 | 0.18 | Likely Benign | 0.1 | 1.62 | Ambiguous | 0.90 | Ambiguous | 0.97 | Ambiguous | -4.21 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 4.12 | Benign | 0.22 | Tolerated | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||
| c.1072T>G | F358V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F358V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for F358V, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -9.021 | Likely Pathogenic | 0.847 | Likely Pathogenic | Ambiguous | 0.408 | Likely Benign | 0.2222 | 0.2978 | 1.42 | Ambiguous | 0.2 | 1.68 | Ambiguous | 1.55 | Ambiguous | 0.93 | Ambiguous | -5.32 | Deleterious | 0.993 | Probably Damaging | 0.968 | Probably Damaging | 4.09 | Benign | 0.18 | Tolerated | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||
| c.1073T>A | F358Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F358Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, ESM1b, FATHMM, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a Likely Benign result (3 benign vs. 1 pathogenic), and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign effect. premPS is uncertain and is treated as unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -6.458 | Likely Benign | 0.606 | Likely Pathogenic | Likely Benign | 0.231 | Likely Benign | 0.1467 | 0.2697 | 0.42 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.32 | Likely Benign | 0.84 | Ambiguous | -2.17 | Neutral | 0.993 | Probably Damaging | 0.952 | Probably Damaging | 4.05 | Benign | 0.36 | Tolerated | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||
| c.1073T>C | F358S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358S variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of algorithms predict a pathogenic outcome: FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Rosetta’s assessment is uncertain and is not taken as evidence. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of pathogenic predictions and the agreement of the high‑accuracy tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -9.316 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.493 | Likely Benign | 0.3891 | 0.1333 | 2.32 | Destabilizing | 0.2 | 1.97 | Ambiguous | 2.15 | Destabilizing | 1.14 | Destabilizing | -6.48 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 4.07 | Benign | 0.20 | Tolerated | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||
| c.1073T>G | F358C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F358C is not reported in ClinVar and is absent from gnomAD. Consensus from standard in‑silico predictors shows a split: benign calls come from REVEL, SIFT, and FATHMM, whereas pathogenic calls arise from Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is inconclusive, Foldetta is inconclusive, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward pathogenic. Because the majority of available predictions favor a damaging effect, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -7.966 | In-Between | 0.927 | Likely Pathogenic | Ambiguous | 0.460 | Likely Benign | 0.2364 | 0.1800 | 1.68 | Ambiguous | 0.1 | 2.19 | Destabilizing | 1.94 | Ambiguous | 1.18 | Destabilizing | -6.36 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 4.02 | Benign | 0.06 | Tolerated | -4 | -2 | -0.3 | -44.04 | ||||||||||||||||||||||||||
| c.1074C>A | F358L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results are reported for Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta’s stability prediction is unavailable due to inconclusiveness. Overall, the majority of available evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -7.865 | In-Between | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.215 | Likely Benign | 0.2555 | 0.3602 | 0.18 | Likely Benign | 0.1 | 1.62 | Ambiguous | 0.90 | Ambiguous | 0.97 | Ambiguous | -4.21 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 4.12 | Benign | 0.22 | Tolerated | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||
| c.1074C>G | F358L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta’s stability prediction is unavailable. Overall, the majority of reliable tools predict a pathogenic impact for F358L. This conclusion does not contradict ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -7.865 | In-Between | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.215 | Likely Benign | 0.2555 | 0.3602 | 0.18 | Likely Benign | 0.1 | 1.62 | Ambiguous | 0.90 | Ambiguous | 0.97 | Ambiguous | -4.21 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 4.12 | Benign | 0.22 | Tolerated | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||
| c.1315C>A | L439M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L439M is reported in gnomAD (variant ID 6‑33438220‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on benign impact include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from premPS, polyPhen‑2 (HumDiv and HumVar) and SIFT. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as inconclusive. Overall, the majority of evidence points to a benign effect; there is no ClinVar classification to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | 6-33438220-C-A | 1 | 6.20e-7 | -5.840 | Likely Benign | 0.363 | Ambiguous | Likely Benign | 0.187 | Likely Benign | 0.0720 | 0.2753 | -0.33 | Likely Benign | 0.1 | 1.34 | Ambiguous | 0.51 | Ambiguous | 1.01 | Destabilizing | -1.43 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 3.38 | 25 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||
| 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 | 0.121 | Likely Benign | 0.1272 | 0.2628 | 2.34 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.37 | Destabilizing | 0.91 | Ambiguous | -1.13 | Neutral | 0.976 | Probably Damaging | 0.941 | Probably Damaging | 3.36 | Benign | 0.12 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1316T>A | L439Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L439Q is 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 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 | -11.162 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.575 | Likely Pathogenic | 0.1065 | 0.0488 | 2.50 | Destabilizing | 0.1 | 2.06 | Destabilizing | 2.28 | Destabilizing | 1.35 | Destabilizing | -5.15 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.01 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| 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 | 0.539 | Likely Pathogenic | 0.3426 | 0.1192 | 6.30 | Destabilizing | 0.2 | 7.62 | Destabilizing | 6.96 | Destabilizing | 1.28 | Destabilizing | -5.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.02 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| 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 | 0.554 | Likely Pathogenic | 0.1217 | 0.0488 | 1.90 | Ambiguous | 0.5 | 2.62 | Destabilizing | 2.26 | Destabilizing | 1.40 | Destabilizing | -5.25 | Deleterious | 0.996 | Probably Damaging | 0.983 | Probably Damaging | 3.22 | Benign | 0.01 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1861C>G | R621G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R621G is reported in gnomAD (ID 6‑33440913‑C‑G) but has no ClinVar entry. In silico predictors largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only benign prediction is from FATHMM; FoldX and Foldetta give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar data. 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 | 6-33440913-C-G | 1 | 6.20e-7 | -16.611 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.558 | Likely Pathogenic | 0.3109 | 0.2651 | 1.18 | Ambiguous | 0.3 | 2.07 | Destabilizing | 1.63 | Ambiguous | 1.17 | Destabilizing | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.84 | Benign | 0.01 | Affected | 3.37 | 35 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||
| c.1862G>A | R621Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R621Q is listed in ClinVar (ID 578137.0) as benign and is present in gnomAD (variant ID 6‑33440914‑G‑A). Functional prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX, Rosetta, or Foldetta supports a benign outcome. Overall, the preponderance of predictions indicates a likely pathogenic effect, which contradicts the benign classification reported in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | Likely Benign | 1 | 6-33440914-G-A | 19 | 1.18e-5 | -14.682 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.621 | Likely Pathogenic | 0.2590 | 0.1963 | 0.81 | Ambiguous | 0.1 | 1.13 | Ambiguous | 0.97 | Ambiguous | 1.35 | Destabilizing | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.82 | Benign | 0.01 | Affected | 3.37 | 35 | 1 | 1 | 1.0 | -28.06 | 243.7 | 54.3 | 0.0 | 0.0 | -0.4 | 0.2 | X | X | Potentially Pathogenic | The guanidinium group of Arg621, located in an α helix (res. Glu617-Asn635), forms a salt bridge with Glu525 in a nearby loop and stacks with Leu635. In the variant simulations, the carboxamide side chain of Gln621, which can act as both a hydrogen bond acceptor and donor, also stacks with Leu635 but can only sporadically hydrogen bond with Glu525.Accordingly, the residue swap could affect the tertiary structure integrity by disrupting the salt bridge formation. Additionally, due to its location at the GAP-Ras interface, the residue swap could impact the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations. | ||||||||
| c.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 | 0.745 | Likely Pathogenic | 0.2143 | 0.3692 | 4.94 | Destabilizing | 0.4 | 9.39 | Destabilizing | 7.17 | Destabilizing | 0.96 | Ambiguous | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.81 | Benign | 0.01 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.1862G>T | R621L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R621L has no ClinVar entry and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, premPS, and FATHMM, whereas the majority—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label it pathogenic or likely pathogenic. FoldX and Foldetta return uncertain results and are not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, and Foldetta remains inconclusive. Overall, the consensus of the available predictions points to a pathogenic effect for R621L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | -16.055 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.718 | Likely Pathogenic | 0.1424 | 0.3568 | 1.70 | Ambiguous | 0.3 | -0.22 | Likely Benign | 0.74 | Ambiguous | 0.34 | Likely Benign | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.83 | Benign | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.2035T>A | F679I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM. In contrast, a majority of predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently classify the substitution as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as Likely Pathogenic. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain, and the SGM Consensus remains pathogenic. Because the uncertain results are treated as unavailable, the clear majority of predictions support pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no entry for F679I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -12.620 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 0.498 | Likely Benign | 0.1725 | 0.2322 | 1.62 | Ambiguous | 0.4 | -0.27 | Likely Benign | 0.68 | Ambiguous | 0.88 | Ambiguous | -5.91 | Deleterious | 0.993 | Probably Damaging | 0.977 | Probably Damaging | 3.59 | Benign | 0.01 | Affected | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||
| c.2035T>C | F679L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679L 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 Rosetta, Foldetta, and FATHMM, while the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (FoldX and premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for F679L, 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 | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -11.395 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.506 | Likely Pathogenic | 0.1918 | 0.3493 | 1.07 | Ambiguous | 0.0 | -0.36 | Likely Benign | 0.36 | Likely Benign | 0.82 | Ambiguous | -5.91 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 3.54 | Benign | 0.03 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.2035T>G | F679V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta provide inconclusive results and are treated as unavailable. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -11.868 | Likely Pathogenic | 0.900 | Likely Pathogenic | Ambiguous | 0.497 | Likely Benign | 0.1830 | 0.2349 | 1.92 | Ambiguous | 0.5 | 0.29 | Likely Benign | 1.11 | Ambiguous | 0.89 | Ambiguous | -6.86 | Deleterious | 0.993 | Probably Damaging | 0.968 | Probably Damaging | 3.50 | Benign | 0.01 | Affected | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||
| c.2036T>A | F679Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Two tools give uncertain results: premPS and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves to benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Overall, the majority of evidence indicates that F679Y is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -5.842 | Likely Benign | 0.462 | Ambiguous | Likely Benign | 0.315 | Likely Benign | 0.1306 | 0.1954 | 0.48 | Likely Benign | 0.2 | 0.13 | Likely Benign | 0.31 | Likely Benign | 0.71 | Ambiguous | -2.71 | Deleterious | 0.993 | Probably Damaging | 0.952 | Probably Damaging | 3.47 | Benign | 0.14 | Tolerated | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||
| c.2036T>C | F679S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679S 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 12 tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as pathogenic. FoldX reports an uncertain outcome and is therefore not counted as evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Based on the preponderance of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -12.159 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.575 | Likely Pathogenic | 0.4276 | 0.0200 | 1.86 | Ambiguous | 0.4 | 2.20 | Destabilizing | 2.03 | Destabilizing | 1.28 | Destabilizing | -7.86 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 3.50 | Benign | 0.04 | Affected | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||
| c.2036T>G | F679C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679C has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. FoldX and Foldetta are uncertain and are treated as unavailable evidence. 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 remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for F679C. This prediction is not contradicted by ClinVar status, which currently lacks any classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -10.269 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.532 | Likely Pathogenic | 0.2344 | 0.0949 | 1.65 | Ambiguous | 0.3 | 2.02 | Destabilizing | 1.84 | Ambiguous | 1.17 | Destabilizing | -7.86 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.40 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||
| c.2037T>A | F679L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F679L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, FATHMM, and Foldetta, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results from FoldX and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. The majority of evidence points toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -11.395 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | 0.1918 | 0.3493 | 1.07 | Ambiguous | 0.0 | -0.36 | Likely Benign | 0.36 | Likely Benign | 0.82 | Ambiguous | -5.91 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 3.54 | Benign | 0.03 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.2037T>G | F679L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX and premPS are inconclusive. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any ClinVar annotation because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -11.395 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | 0.1918 | 0.3493 | 1.07 | Ambiguous | 0.0 | -0.36 | Likely Benign | 0.36 | Likely Benign | 0.82 | Ambiguous | -5.91 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 3.54 | Benign | 0.03 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.775C>G | R259G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas the remaining 13 tools—including SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The high‑accuracy subset reinforces this assessment: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. Rosetta alone is uncertain and is treated as unavailable. Overall, the consensus of available predictions indicates that R259G is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.338208 | Uncertain | 0.885 | 0.255 | 0.250 | -15.389 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.762 | Likely Pathogenic | 0.3342 | 0.4139 | 3.17 | Destabilizing | 0.6 | 1.53 | Ambiguous | 2.35 | Destabilizing | 1.14 | Destabilizing | -6.43 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 5.78 | Benign | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.775C>T | R259W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R259W is listed in ClinVar with an uncertain significance (ClinVar ID 2014570.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains inconclusive. Overall, the preponderance of evidence indicates that R259W is most likely pathogenic, a conclusion that does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.338208 | Uncertain | 0.885 | 0.255 | 0.250 | Uncertain | 1 | -12.186 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.691 | Likely Pathogenic | 0.1221 | 0.4269 | 1.95 | Ambiguous | 0.8 | 0.51 | Ambiguous | 1.23 | Ambiguous | 0.51 | Ambiguous | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 3.39 | 15 | 2 | -3 | 3.6 | 30.03 | 254.0 | 40.0 | 0.2 | 0.2 | 0.2 | 0.4 | X | X | X | Potentially Pathogenic | The guanidinium group of Arg259, located at the beginning of an anti-parallel β sheet strand (res. Arg259-Arg272), forms salt bridges with the carboxylate groups of Asp684 at the end of an α helix (res. Ile683-Gln702, GAP domain) and Asp261 on the same β strand. The Arg259 side chain also frequently forms hydrogen bonds with the backbone carbonyl groups of Ser257, Asn256, and Asp255. In the variant simulations, the indole ring of the Trp259 side chain cannot form salt bridges or maintain hydrogen bonding with the carboxylate group of Asp684 or other nearby residues. Notably, the amino group of the Lys254 side chain maintains a salt bridge with Asp684 and Glu244 throughout the variant simulations, while it forms a cation-π bond with the indole ring of Trp259 in the variant. This salt bridge is not maintained in the WT simulations. Additionally, the partially or loosely α helical conformation of a lysine-containing loop (res. Lys251-Ser257), which extends to a nearby α helix (res. Met414-Asn426), could be stabilized due to the residue swap. Moreover, the bulky size of the Trp259 side chain requires nearby residues to adjust their positioning to accommodate the introduced residue, weakening the tertiary structure assembly between the C2, PH, and GAP domains. The residue swap potentially causes more severe effects during protein folding or for the SynGAP-membrane interaction than the solvent-only simulations imply. | ||||||||||
| c.776G>A | R259Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259Q is catalogued in gnomAD (6‑33437681‑G‑A) but has no entry in ClinVar. In silico assessment shows a consensus of pathogenicity: 9 of 11 evaluated tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a deleterious effect, while only FATHMM indicates a benign outcome. Predictions of protein‑stability change are inconclusive, with FoldX, Rosetta and the combined Foldetta method returning uncertain results. High‑accuracy predictors reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies the variant as likely pathogenic; Foldetta remains uncertain. Overall, the computational evidence strongly favors a pathogenic interpretation, and this is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.338208 | Uncertain | 0.885 | 0.255 | 0.250 | 6-33437681-G-A | 1 | 6.20e-7 | -12.598 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.851 | Likely Pathogenic | 0.3329 | 0.2703 | 1.19 | Ambiguous | 0.3 | 1.30 | Ambiguous | 1.25 | Ambiguous | 1.40 | Destabilizing | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.978 | Probably Damaging | 5.81 | Benign | 0.01 | Affected | 3.39 | 15 | 1 | 1 | 1.0 | -28.06 | 258.7 | 52.8 | 0.1 | 0.1 | -0.3 | 0.4 | X | X | Potentially Pathogenic | The guanidinium group of Arg259, located at the beginning of an anti-parallel β sheet strand (res. Arg259-Arg272), forms salt bridges with the carboxylate groups of Asp684 at the end of an α helix (res. Ile683-Gln702, GAP domain) and Asp261 on the same β strand. The Arg259 side chain also frequently forms hydrogen bonds with the backbone carbonyl groups of Ser257, Asn256, and Asp255. In the variant simulations, the carboxamide group of the Gln259 side chain cannot form salt bridges or maintain hydrogen bonding with the carboxylate group of Asp684, which could affect the tertiary structure assembly between the C2 and GAP domains. Notably, the amino group of the Lys254 side chain maintains a salt bridge with Asp684 and Glu244 throughout the variant simulations, but this interaction is not maintained in the WT simulations. Thus, the partially or loosely α helical conformation of a lysine-containing loop (res. Lys251-Ser257), which extends to a nearby α helix (res. Met414-Asn426), could be stabilized due to the residue swap. | ||||||||||
| c.776G>C | R259P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods further support this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.338208 | Uncertain | 0.885 | 0.255 | 0.250 | -14.876 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.902 | Likely Pathogenic | 0.2051 | 0.5249 | 6.34 | Destabilizing | 1.6 | 3.78 | Destabilizing | 5.06 | Destabilizing | 1.16 | Destabilizing | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.84 | Benign | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.776G>T | R259L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259L is not reported in ClinVar and is absent from gnomAD. Among the available in‑silico predictors, the benign‑predicted tools are Rosetta and FATHMM, while the pathogenic‑predicted tools include SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Foldetta and premPS are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of predictions support a pathogenic effect, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.338208 | Uncertain | 0.885 | 0.255 | 0.250 | -14.185 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.894 | Likely Pathogenic | 0.1934 | 0.5499 | 2.84 | Destabilizing | 1.1 | 0.16 | Likely Benign | 1.50 | Ambiguous | 0.64 | Ambiguous | -6.43 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 5.87 | Benign | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.928G>A | E310K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310K 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 (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenic or likely pathogenic. 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, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic based on the available predictions, 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 | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | Conflicting | 4 | -14.601 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.764 | Likely Pathogenic | 0.2496 | 0.8453 | 1.97 | Ambiguous | 1.2 | 3.66 | Destabilizing | 2.82 | Destabilizing | 1.02 | Destabilizing | -3.68 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 1.19 | Pathogenic | 0.01 | Affected | 3.38 | 19 | 0 | 1 | -0.4 | -0.94 | 213.4 | 58.0 | 0.1 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the side chain hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand (res. Met289-Arg299). Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the amino group of the Lys310 side chain hydrogen bonds with the GAP domain residues and forms a salt bridge with Glu613. Although no apparent negative effects are seen due to the residue swap, it is possible that the loss of hydrogen bonding with the hydroxyl group of the Thr295 side chain causes problems during folding, potentially compromising the twisting of the β sheet. | ||||||||||||
| c.928G>C | E310Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign are Rosetta and Foldetta, whereas the remaining tools—REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict pathogenicity. FoldX and premPS give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Pathogenic; Foldetta, a protein‑folding stability approach combining FoldX‑MD and Rosetta, predicts a benign outcome. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | -11.093 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.688 | Likely Pathogenic | 0.1334 | 0.8341 | 1.16 | Ambiguous | 0.5 | -0.38 | Likely Benign | 0.39 | Likely Benign | 0.85 | Ambiguous | -2.76 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.24 | Pathogenic | 0.01 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.929A>C | E310A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E310A missense variant is not reported in ClinVar or gnomAD. Prediction tools largely converge on a pathogenic effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while premPS is the sole benign predictor. Uncertain calls come from FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus labels it likely pathogenic, and Foldetta remains inconclusive. With the overwhelming majority of evidence pointing to deleterious impact and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | -13.878 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.850 | Likely Pathogenic | 0.3980 | 0.8097 | 1.65 | Ambiguous | 0.6 | 1.65 | Ambiguous | 1.65 | Ambiguous | 0.50 | Likely Benign | -5.52 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.16 | Pathogenic | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.929A>G | E310G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310G is listed in ClinVar as Pathogenic (ClinVar ID 2732842.0) and is not reported in gnomAD. Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only premPS predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and this prediction is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | Pathogenic | 1 | -14.132 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.848 | Likely Pathogenic | 0.2736 | 0.6932 | 2.38 | Destabilizing | 0.7 | 3.56 | Destabilizing | 2.97 | Destabilizing | 0.36 | Likely Benign | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.12 | Pathogenic | 0.00 | Affected | 3.38 | 19 | -2 | 0 | 3.1 | -72.06 | |||||||||||||||||||||
| c.929A>T | E310V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E310V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are Rosetta and premPS, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. FoldX and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that E310V is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | -15.494 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.871 | Likely Pathogenic | 0.0849 | 0.8729 | 1.08 | Ambiguous | 0.9 | 0.06 | Likely Benign | 0.57 | Ambiguous | 0.14 | Likely Benign | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.12 | Pathogenic | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| 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 | 0.666 | Likely Pathogenic | 0.1981 | 0.5222 | 1.87 | Ambiguous | 0.5 | 2.39 | Destabilizing | 2.13 | Destabilizing | 1.04 | Destabilizing | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.19 | Pathogenic | 0.02 | Affected | 3.38 | 19 | 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 | 0.666 | Likely Pathogenic | 0.1981 | 0.5222 | 1.87 | Ambiguous | 0.5 | 2.39 | Destabilizing | 2.13 | Destabilizing | 1.04 | Destabilizing | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.19 | Pathogenic | 0.02 | Affected | 3.38 | 19 | 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.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 | 0.558 | Likely Pathogenic | 0.1187 | 0.5050 | 3.06 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.73 | Destabilizing | 0.63 | Ambiguous | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.1342G>C | A448P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a likely pathogenic result; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -13.706 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.650 | Likely Pathogenic | 0.1758 | 0.3626 | 5.42 | Destabilizing | 0.0 | 8.74 | Destabilizing | 7.08 | Destabilizing | 1.16 | Destabilizing | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.01 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1342G>T | A448S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A448S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because none exists. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.213 | Likely Pathogenic | 0.590 | Likely Pathogenic | Likely Benign | 0.310 | Likely Benign | 0.2420 | 0.3471 | 1.18 | Ambiguous | 0.1 | 1.97 | Ambiguous | 1.58 | Ambiguous | 0.55 | Ambiguous | -2.96 | Deleterious | 0.965 | Probably Damaging | 0.972 | Probably Damaging | 3.27 | Benign | 0.06 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1343C>A | A448D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448D is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or folding result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -17.290 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.662 | Likely Pathogenic | 0.1541 | 0.1741 | 8.13 | Destabilizing | 0.2 | 4.35 | Destabilizing | 6.24 | Destabilizing | 1.40 | Destabilizing | -5.93 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||
| c.1343C>G | A448G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448G resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; FoldX is inconclusive. High‑accuracy assessments further clarify the impact: AlphaMissense‑Optimized reports a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.984 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 0.378 | Likely Benign | 0.2135 | 0.2936 | 1.76 | Ambiguous | 0.0 | 2.45 | Destabilizing | 2.11 | Destabilizing | 1.00 | Destabilizing | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.15 | Benign | 0.06 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1343C>T | A448V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools (Rosetta and premPS) yield uncertain results. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates that A448V is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -10.372 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.487 | Likely Benign | 0.0950 | 0.4955 | 3.31 | Destabilizing | 0.2 | 1.80 | Ambiguous | 2.56 | Destabilizing | 0.66 | Ambiguous | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.955 | Probably Damaging | 3.26 | Benign | 0.02 | Affected | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.1582C>A | P528T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528T is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tools predict a benign outcome. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic. This conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -13.782 | Likely Pathogenic | 0.798 | Likely Pathogenic | Ambiguous | 0.673 | Likely Pathogenic | 0.1367 | 0.4360 | 2.05 | Destabilizing | 0.3 | 1.01 | Ambiguous | 1.53 | Ambiguous | 0.66 | Ambiguous | -7.69 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||
| c.1582C>G | P528A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized, while the remaining pathogenic‑predicting tools are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the remaining tools (FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy methods give AlphaMissense‑Optimized a benign score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) a pathogenic prediction, and Foldetta an uncertain result. Overall, the majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -11.562 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 0.548 | Likely Pathogenic | 0.3146 | 0.3914 | 1.57 | Ambiguous | 0.1 | 1.49 | Ambiguous | 1.53 | Ambiguous | 0.69 | Ambiguous | -7.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||
| c.1582C>T | P528S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528S missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Only FATHMM predicts a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is inconclusive. No folding‑stability metrics (FoldX, Rosetta, premPS) provide definitive evidence. Overall, the preponderance of pathogenic predictions suggests the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -11.729 | Likely Pathogenic | 0.819 | Likely Pathogenic | Ambiguous | 0.617 | Likely Pathogenic | 0.3115 | 0.3982 | 1.88 | Ambiguous | 0.1 | 1.28 | Ambiguous | 1.58 | Ambiguous | 0.80 | Ambiguous | -7.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||
| c.1583C>A | P528H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the change as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely pathogenic. No tool predicts a benign outcome; the remaining predictions (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain or inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence supports a pathogenic interpretation, and this is consistent with the absence of a ClinVar entry; there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -15.365 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | 0.565 | Likely Pathogenic | 0.1434 | 0.3523 | 1.93 | Ambiguous | 0.1 | 0.74 | Ambiguous | 1.34 | Ambiguous | 0.61 | Ambiguous | -8.61 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.47 | Pathogenic | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||
| c.1583C>G | P528R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528R missense variant is not reported in ClinVar and is absent from gnomAD. No in silico predictor classifies it as benign; the following tools predict pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions that are uncertain or inconclusive (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -16.367 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.615 | Likely Pathogenic | 0.1261 | 0.2543 | 0.76 | Ambiguous | 0.4 | 0.67 | Ambiguous | 0.72 | Ambiguous | 0.73 | Ambiguous | -8.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||
| c.1583C>T | P528L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only premPS, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Because the majority of evidence points to a deleterious effect and no ClinVar annotation exists to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -13.752 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 0.555 | Likely Pathogenic | 0.1975 | 0.5574 | 1.31 | Ambiguous | 0.1 | 0.61 | Ambiguous | 0.96 | Ambiguous | 0.19 | Likely Benign | -9.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| 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 | 0.872 | Likely Pathogenic | 0.1997 | 0.2842 | 2.09 | Destabilizing | 0.3 | 3.10 | Destabilizing | 2.60 | Destabilizing | 1.72 | Destabilizing | -5.52 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.23 | Pathogenic | 0.01 | Affected | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||
| c.934T>C | F312L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” The only tool with an inconclusive result is FoldX, which is listed as “Uncertain.” No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -9.891 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.852 | Likely Pathogenic | 0.2149 | 0.3813 | 1.16 | Ambiguous | 0.3 | 2.91 | Destabilizing | 2.04 | Destabilizing | 1.27 | Destabilizing | -5.52 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.32 | Pathogenic | 0.05 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.934T>G | F312V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312V is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the change as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -12.206 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.877 | Likely Pathogenic | 0.1998 | 0.2810 | 2.13 | Destabilizing | 0.1 | 3.46 | Destabilizing | 2.80 | Destabilizing | 1.80 | Destabilizing | -6.43 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.25 | Pathogenic | 0.00 | Affected | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||
| c.935T>A | F312Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a deleterious effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default, all of which classify the change as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta provide uncertain results. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -7.571 | In-Between | 0.949 | Likely Pathogenic | Ambiguous | 0.744 | Likely Pathogenic | 0.1443 | 0.2728 | 1.04 | Ambiguous | 0.1 | 0.89 | Ambiguous | 0.97 | Ambiguous | 0.99 | Ambiguous | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 1.21 | Pathogenic | 0.02 | Affected | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||
| c.935T>C | F312S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All available in‑silico predictors classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, with no contradiction to ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -14.075 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.880 | Likely Pathogenic | 0.3563 | 0.1578 | 3.74 | Destabilizing | 0.3 | 5.64 | Destabilizing | 4.69 | Destabilizing | 2.70 | Destabilizing | -7.35 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.17 | Pathogenic | 0.00 | Affected | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||
| c.935T>G | F312C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Based on the unanimous pathogenic predictions and the absence of benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -11.991 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.870 | Likely Pathogenic | 0.2293 | 0.2010 | 2.98 | Destabilizing | 0.3 | 4.97 | Destabilizing | 3.98 | Destabilizing | 1.46 | Destabilizing | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.16 | Pathogenic | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||
| c.936C>A | F312L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” The only tool with an inconclusive result is FoldX, which is listed as “Uncertain.” No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -9.891 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.615 | Likely Pathogenic | 0.2149 | 0.3813 | 1.16 | Ambiguous | 0.3 | 2.91 | Destabilizing | 2.04 | Destabilizing | 1.27 | Destabilizing | -5.52 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.32 | Pathogenic | 0.05 | Affected | 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 | 0.615 | Likely Pathogenic | 0.2149 | 0.3813 | 1.16 | Ambiguous | 0.3 | 2.91 | Destabilizing | 2.04 | Destabilizing | 1.27 | Destabilizing | -5.52 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.32 | Pathogenic | 0.05 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.1303T>A | L435M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L435M missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -4.705 | Likely Benign | 0.534 | Ambiguous | Likely Benign | 0.233 | Likely Benign | 0.0675 | 0.2753 | 0.24 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.63 | Ambiguous | 1.05 | Destabilizing | -1.74 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.17 | Benign | 0.01 | Affected | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||
| c.1303T>G | L435V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435V has no ClinVar assertion and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Default. ESM1b is uncertain. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—favors pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. With the preponderance of pathogenic calls from both general and high‑accuracy tools, 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 | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -7.134 | In-Between | 0.571 | Likely Pathogenic | Likely Benign | 0.217 | Likely Benign | 0.1216 | 0.2628 | 2.97 | Destabilizing | 0.1 | 2.33 | Destabilizing | 2.65 | Destabilizing | 1.36 | Destabilizing | -2.80 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.23 | Benign | 0.06 | Tolerated | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||
| 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 | 0.596 | Likely Pathogenic | 0.2705 | 0.0505 | 4.18 | Destabilizing | 0.0 | 4.09 | Destabilizing | 4.14 | Destabilizing | 1.83 | Destabilizing | -5.63 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.18 | Benign | 0.01 | Affected | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||
| c.1304T>G | L435W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L435W 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. The majority of other in silico predictors (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic, and the SGM‑Consensus score is “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) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the computational evidence strongly favors a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | Uncertain | 1 | -14.889 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.572 | Likely Pathogenic | 0.0536 | 0.2496 | 2.11 | Destabilizing | 0.1 | 0.69 | Ambiguous | 1.40 | Ambiguous | 1.66 | Destabilizing | -5.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 3.37 | 29 | -2 | -2 | -4.7 | 73.05 | 242.2 | -25.2 | 0.0 | 0.0 | 0.3 | 0.1 | X | Potentially Pathogenic | The iso-butyl side chain of Leu435, located in an α helix (res. Met414-Glu436), packs against other hydrophobic residues in an interhelix space (e.g., Val699, Val447, Leu489, Leu439) in the WT simulations. In the variant simulations, the indole ring of Trp435 fits into the same niche despite its considerably bulkier size. Additionally, the side chain forms an H-bond with the backbone carbonyl of Leu696 in an α helix (res. Asp684-Gln702). Although no apparent negative changes are observed during the variant simulation, the size difference between the swapped residues could affect the protein folding process. | ||||||||||||
| c.1305G>C | L435F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, providing no definitive evidence for either outcome. Given the preponderance of pathogenic predictions and the lack of any ClinVar annotation to contradict this assessment, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -11.871 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | 0.0587 | 0.2723 | 0.51 | Ambiguous | 0.1 | 0.95 | Ambiguous | 0.73 | Ambiguous | 0.69 | Ambiguous | -3.75 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1305G>T | L435F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (Likely Pathogenic). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, providing no definitive evidence for either outcome. Given the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -11.871 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | 0.0587 | 0.2723 | 0.51 | Ambiguous | 0.1 | 0.95 | Ambiguous | 0.73 | Ambiguous | 0.69 | Ambiguous | -3.75 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1873C>A | L625I 2D AIThe SynGAP1 missense variant L625I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas a majority of tools (premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Tools with uncertain or inconclusive results—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, the overall evidence leans toward pathogenicity, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -11.713 | Likely Pathogenic | 0.866 | Likely Pathogenic | Ambiguous | 0.412 | Likely Benign | 0.0864 | 0.3588 | 0.75 | Ambiguous | 0.6 | 0.72 | Ambiguous | 0.74 | Ambiguous | 1.09 | Destabilizing | -1.96 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.06 | Benign | 0.01 | Affected | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1873C>G | L625V 2D AISynGAP1 missense variant L625V is listed in ClinVar with an uncertain significance (ClinVar ID 3392716.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | Uncertain | 1 | -11.319 | Likely Pathogenic | 0.833 | Likely Pathogenic | Ambiguous | 0.480 | Likely Benign | 0.1306 | 0.3427 | 1.80 | Ambiguous | 0.7 | 1.69 | Ambiguous | 1.75 | Ambiguous | 1.42 | Destabilizing | -2.96 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||
| c.1873C>T | L625F 2D AIThe SynGAP1 missense variant L625F is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that predict a pathogenic effect include SGM‑Consensus (Likely Pathogenic), Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain or inconclusive are FoldX, premPS, and Foldetta. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is Uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -12.989 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.479 | Likely Benign | 0.0586 | 0.2998 | 1.70 | Ambiguous | 1.3 | 2.26 | Destabilizing | 1.98 | Ambiguous | 0.74 | Ambiguous | -3.82 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.01 | Benign | 0.01 | Affected | 2 | 0 | -1.0 | 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 | 0.738 | Likely Pathogenic | 0.0954 | 0.0541 | 2.85 | Destabilizing | 0.3 | 2.96 | Destabilizing | 2.91 | Destabilizing | 2.02 | Destabilizing | -6.87 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||
| 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 | 0.746 | Likely Pathogenic | 0.3294 | 0.1313 | 5.47 | Destabilizing | 0.6 | 12.49 | Destabilizing | 8.98 | Destabilizing | 1.98 | Destabilizing | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| 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 | 0.733 | Likely Pathogenic | 0.1091 | 0.0615 | 2.31 | Destabilizing | 0.7 | 4.21 | Destabilizing | 3.26 | Destabilizing | 1.88 | Destabilizing | -5.93 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.99 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.931C>A | H311N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of evaluated tools predict pathogenicity, suggesting that H311N is most likely pathogenic. This prediction does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -9.545 | Likely Pathogenic | 0.661 | Likely Pathogenic | Likely Benign | 0.475 | Likely Benign | 0.1566 | 0.2380 | 0.82 | Ambiguous | 0.1 | 1.12 | Ambiguous | 0.97 | Ambiguous | 0.72 | Ambiguous | -5.35 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.89 | Pathogenic | 0.06 | Tolerated | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||
| c.931C>G | H311D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess evolutionary conservation and protein function uniformly indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. The majority‑vote consensus (SGM‑Consensus) also reports it as likely pathogenic. Tools that evaluate structural stability give inconclusive results: FoldX, Rosetta, Foldetta, and premPS are listed as uncertain. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (derived from the same set of predictors) reports likely pathogenic, while Foldetta’s combined FoldX‑MD/Rosetta stability analysis remains uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect, which is consistent with the absence of a benign ClinVar annotation and the lack of population frequency data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -13.513 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.633 | Likely Pathogenic | 0.2301 | 0.2008 | 1.27 | Ambiguous | 0.0 | 1.83 | Ambiguous | 1.55 | Ambiguous | 0.89 | Ambiguous | -6.94 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.94 | Pathogenic | 0.02 | Affected | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||
| c.931C>T | H311Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools with uncertain or inconclusive results—Rosetta, Foldetta, and AlphaMissense‑Default—are treated as unavailable for pathogenicity assessment. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the predictions are split, with five tools favoring benign, five favoring pathogenic, and three inconclusive. Based on the available evidence, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -4.513 | Likely Benign | 0.342 | Ambiguous | Likely Benign | 0.456 | Likely Benign | 0.0965 | 0.4180 | -0.06 | Likely Benign | 0.2 | -1.58 | Ambiguous | -0.82 | Ambiguous | 0.18 | Likely Benign | -3.80 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.86 | Pathogenic | 0.02 | Affected | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||
| c.932A>C | H311P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign outcome; the remaining predictions are uncertain (FoldX, Foldetta, premPS, AlphaMissense‑Optimized). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the majority of evidence points to a deleterious impact on protein function. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for H311P. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -10.454 | Likely Pathogenic | 0.869 | Likely Pathogenic | Ambiguous | 0.724 | Likely Pathogenic | 0.2173 | 0.4172 | 1.57 | Ambiguous | 0.6 | 2.39 | Destabilizing | 1.98 | Ambiguous | 0.74 | Ambiguous | -7.76 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.87 | Pathogenic | 0.01 | Affected | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||
| c.932A>G | H311R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -9.825 | Likely Pathogenic | 0.719 | Likely Pathogenic | Likely Benign | 0.532 | Likely Pathogenic | 0.1931 | 0.2490 | 0.43 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.64 | Ambiguous | 0.70 | Ambiguous | -5.72 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.94 | Pathogenic | 0.14 | Tolerated | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||
| c.932A>T | H311L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311L missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta. Tools that predict a pathogenic outcome are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign effect. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -10.119 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | 0.663 | Likely Pathogenic | 0.0961 | 0.5292 | -0.53 | Ambiguous | 0.0 | -0.04 | Likely Benign | -0.29 | Likely Benign | 0.43 | Likely Benign | -7.99 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.87 | Pathogenic | 0.02 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||
| c.933C>A | H311Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. The high‑accuracy consensus methods give mixed signals: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, more tools (seven) predict pathogenicity than benign (four), and the SGM Consensus supports a pathogenic classification, while Foldetta offers a contrary benign prediction. The variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict the absence of a ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -8.656 | Likely Pathogenic | 0.792 | Likely Pathogenic | Ambiguous | 0.414 | Likely Benign | 0.1490 | 0.3775 | 0.15 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.27 | Likely Benign | 0.92 | Ambiguous | -5.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.94 | Pathogenic | 0.03 | Affected | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| c.933C>G | H311Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311Q missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. With seven pathogenic versus four benign predictions, the overall consensus leans toward pathogenicity. This conclusion does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -8.656 | Likely Pathogenic | 0.792 | Likely Pathogenic | Ambiguous | 0.414 | Likely Benign | 0.1490 | 0.3775 | 0.15 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.27 | Likely Benign | 0.92 | Ambiguous | -5.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.94 | Pathogenic | 0.03 | Affected | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| c.1210G>A | A404T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: SGM‑Consensus (Likely Benign), REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FoldX and premPS are inconclusive, so they are treated as unavailable. High‑accuracy methods corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta) is benign. Overall, the evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -6.674 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.1710 | 0.7367 | 0.74 | Ambiguous | 0.1 | -0.01 | Likely Benign | 0.37 | Likely Benign | 0.56 | Ambiguous | -1.74 | Neutral | 0.049 | Benign | 0.011 | Benign | 4.12 | Benign | 0.09 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.1210G>C | A404P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A404P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, both polyPhen‑2 versions, and FATHMM, while pathogenic calls arise from FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not 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 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -11.819 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.227 | Likely Benign | 0.2271 | 0.6366 | 3.03 | Destabilizing | 0.1 | 0.24 | Likely Benign | 1.64 | Ambiguous | 1.17 | Destabilizing | -3.16 | Deleterious | 0.433 | Benign | 0.080 | Benign | 4.02 | Benign | 0.03 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1210G>T | A404S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a benign effect. No inconclusive or missing predictions are present. Based on the unanimous benign predictions and the lack of ClinVar evidence, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -1.937 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 0.078 | Likely Benign | 0.2970 | 0.6178 | 0.13 | Likely Benign | 0.0 | 0.83 | Ambiguous | 0.48 | Likely Benign | 0.28 | Likely Benign | -0.07 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.18 | Benign | 0.22 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| 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 | 0.163 | Likely Benign | 0.1423 | 0.2383 | 2.16 | Destabilizing | 0.1 | 3.04 | Destabilizing | 2.60 | Destabilizing | 1.51 | Destabilizing | -2.77 | Deleterious | 0.179 | Benign | 0.033 | Benign | 4.02 | Benign | 0.02 | Affected | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||
| c.1211C>G | A404G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS and SIFT. FoldX, Rosetta, and Foldetta give uncertain or inconclusive results and are treated as unavailable. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points to a benign impact for A404G, 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 Benign | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -5.277 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.2370 | 0.5054 | 0.92 | Ambiguous | 0.0 | 1.88 | Ambiguous | 1.40 | Ambiguous | 1.18 | Destabilizing | -2.34 | Neutral | 0.045 | Benign | 0.013 | Benign | 4.03 | Benign | 0.00 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1211C>T | A404V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A404V missense variant is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438116‑C‑T). Prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and ESM1b. Four tools (FoldX, Rosetta, AlphaMissense‑Default, Foldetta) give uncertain or inconclusive results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of predictions lean toward a benign impact, though a key consensus method suggests pathogenicity, leaving the variant’s effect unresolved. **The variant is most likely benign based on the prevailing predictions, 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. | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | 6-33438116-C-T | 1 | 6.20e-7 | -8.219 | Likely Pathogenic | 0.343 | Ambiguous | Likely Benign | 0.118 | Likely Benign | 0.1288 | 0.6842 | 0.56 | Ambiguous | 0.3 | -1.55 | Ambiguous | -0.50 | Ambiguous | -0.05 | Likely Benign | -2.96 | Deleterious | 0.345 | Benign | 0.018 | Benign | 4.20 | Benign | 0.47 | Tolerated | 3.38 | 28 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||
| c.796C>A | L266M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools remain uncertain: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of tools (six benign vs. four pathogenic, with two uncertain) lean toward a benign classification, and this conclusion is not contradicted by ClinVar status. Thus, the variant is most likely benign based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -9.740 | Likely Pathogenic | 0.362 | Ambiguous | Likely Benign | 0.288 | Likely Benign | 0.0581 | 0.2853 | 0.07 | Likely Benign | 0.1 | -0.47 | Likely Benign | -0.20 | Likely Benign | 0.95 | Ambiguous | -1.66 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.55 | Pathogenic | 0.07 | Tolerated | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||
| c.796C>G | L266V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L266V 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta give uncertain results and are therefore considered unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta is also inconclusive. Consequently, the variant is most likely benign based on the current predictions, and this assessment does not contradict ClinVar, which has no reported status for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -8.586 | Likely Pathogenic | 0.153 | Likely Benign | Likely Benign | 0.193 | Likely Benign | 0.1152 | 0.2456 | 1.71 | Ambiguous | 0.1 | 0.97 | Ambiguous | 1.34 | Ambiguous | 1.32 | Destabilizing | -2.20 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.37 | Pathogenic | 0.11 | Tolerated | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||
| c.797T>A | L266Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L266Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect: none. Tools that agree on a pathogenic effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The only tool with an uncertain outcome is Rosetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -16.672 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.563 | Likely Pathogenic | 0.0815 | 0.0558 | 2.92 | Destabilizing | 0.1 | 1.49 | Ambiguous | 2.21 | Destabilizing | 2.21 | Destabilizing | -5.25 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | -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 | 0.654 | Likely Pathogenic | 0.3158 | 0.1021 | 7.08 | Destabilizing | 0.1 | 4.02 | Destabilizing | 5.55 | Destabilizing | 2.31 | Destabilizing | -6.06 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.797T>G | L266R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -17.131 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.574 | Likely Pathogenic | 0.1059 | 0.0558 | 3.97 | Destabilizing | 0.2 | 2.76 | Destabilizing | 3.37 | Destabilizing | 2.04 | Destabilizing | -5.32 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1603A>C | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R is not reported in ClinVar and is present in gnomAD (ID 6‑33438846‑A‑C). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized, Foldetta, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the balance of evidence, especially the SGM Consensus, points to a pathogenic interpretation. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | 6-33438846-A-C | 3 | 1.86e-6 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.390 | Likely Benign | 0.1086 | 0.3743 | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||
| c.1603A>G | S535G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for S535G, and this conclusion does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -4.619 | Likely Benign | 0.143 | Likely Benign | Likely Benign | 0.247 | Likely Benign | 0.2858 | 0.4644 | 0.19 | Likely Benign | 0.0 | 0.93 | Ambiguous | 0.56 | Ambiguous | 0.64 | Ambiguous | -1.75 | Neutral | 0.606 | Possibly Damaging | 0.114 | Benign | -1.30 | Pathogenic | 0.19 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||
| c.1603A>T | S535C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. Two tools, FoldX and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -7.526 | In-Between | 0.165 | Likely Benign | Likely Benign | 0.500 | Likely Pathogenic | 0.1139 | 0.5633 | 0.57 | Ambiguous | 0.1 | 0.25 | Likely Benign | 0.41 | Likely Benign | 0.47 | Likely Benign | -2.96 | Deleterious | 0.933 | Possibly Damaging | 0.419 | Benign | -1.33 | Pathogenic | 0.02 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||
| c.1604G>A | S535N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Across the broad panel of in‑silico predictors, 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign”) uniformly predict a benign effect, whereas only FATHMM assigns a pathogenic label. High‑accuracy assessments corroborate the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Thus, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -4.957 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.176 | Likely Benign | 0.1390 | 0.4784 | -0.46 | Likely Benign | 0.2 | -0.26 | Likely Benign | -0.36 | Likely Benign | 0.18 | Likely Benign | -0.05 | Neutral | 0.070 | Benign | 0.032 | Benign | -1.25 | Pathogenic | 0.29 | Tolerated | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||
| c.1604G>C | S535T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535T is catalogued in ClinVar as benign (ClinVar ID 537005.0) and is observed in gnomAD (variant ID 6‑33438847‑G‑C). In silico prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. Only FATHMM predicts a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM Consensus is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the consensus of predictive tools and high‑accuracy methods indicates that the variant is most likely benign, consistent with its ClinVar classification and presence in gnomAD. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | Benign | 1 | 6-33438847-G-C | 14 | 8.67e-6 | -3.886 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.177 | Likely Benign | 0.1456 | 0.6291 | 0.45 | Likely Benign | 0.1 | -0.27 | Likely Benign | 0.09 | Likely Benign | 0.17 | Likely Benign | -0.81 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.25 | Pathogenic | 0.25 | Tolerated | 3.37 | 35 | 1 | 1 | 0.1 | 14.03 | 201.3 | -17.3 | -0.1 | 0.7 | -0.2 | 0.1 | X | Potentially Benign | Ser535 is located near the terminal end of an α-helix (res. Ala533-Val560) close to the membrane interface. In the WT simulations, the hydroxyl side chain of Ser535 forms hydrogen bonds with nearby residues (e.g., His539, Glu538) without any specific interactions. These hydrogen bonds disrupt the structure of the terminal end of the α-helix (Ala533-Ser535), causing it to weaken or unfold during the WT simulations. In the variant simulations, Thr535, a hydrophilic residue with a hydroxyl group of almost the same size as Ser, interacts more frequently with the preceding loop residues (e.g., Thr532, Cys531) due to its longer side chain. Regardless, the residue swap is tolerated in the simulations with no negative effects. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | 10.1016/j.ajhg.2020.11.011 | ||||||||
| c.1604G>T | S535I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the preponderance of evidence points to a benign impact for S535I, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -8.073 | Likely Pathogenic | 0.330 | Likely Benign | Likely Benign | 0.246 | Likely Benign | 0.1123 | 0.5571 | 0.50 | Ambiguous | 0.0 | -0.42 | Likely Benign | 0.04 | Likely Benign | 0.14 | Likely Benign | -2.49 | Neutral | 0.004 | Benign | 0.004 | Benign | -1.25 | Pathogenic | 0.07 | Tolerated | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||
| c.1605T>A | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls come from polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is also inconclusive. Overall, the balance of evidence, particularly the SGM Consensus, points to a pathogenic effect. This conclusion does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.432 | Likely Benign | 0.1086 | 0.3743 | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||
| c.1605T>G | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls come from polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is also inconclusive. Overall, the balance of evidence, particularly the SGM Consensus, points to a pathogenic effect. This conclusion does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.432 | Likely Benign | 0.1086 | 0.3743 | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||
| c.1831A>C | M611L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome, while Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -6.721 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.229 | Likely Benign | 0.1130 | 0.3547 | 0.39 | Likely Benign | 0.1 | 0.65 | Ambiguous | 0.52 | Ambiguous | 0.56 | Ambiguous | -1.29 | Neutral | 0.059 | Benign | 0.017 | Benign | -1.07 | Pathogenic | 0.76 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1831A>G | M611V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields an inconclusive result (two benign, two pathogenic). Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports an uncertain effect, so its result is treated as unavailable. Overall, the balance of evidence leans toward a benign impact, 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. | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -8.057 | Likely Pathogenic | 0.176 | Likely Benign | Likely Benign | 0.315 | Likely Benign | 0.2324 | 0.2721 | 1.42 | Ambiguous | 0.4 | 1.56 | Ambiguous | 1.49 | Ambiguous | 0.66 | Ambiguous | -2.06 | Neutral | 0.960 | Probably Damaging | 0.474 | Possibly Damaging | -1.04 | Pathogenic | 0.49 | Tolerated | 2 | 1 | 2.3 | -32.06 | ||||||||||||||||||||||||||
| c.1831A>T | M611L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while Rosetta, Foldetta, and premPS are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the preponderance of evidence points to a benign impact for M611L, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -6.721 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.229 | Likely Benign | 0.1130 | 0.3547 | 0.39 | Likely Benign | 0.1 | 0.65 | Ambiguous | 0.52 | Ambiguous | 0.56 | Ambiguous | -1.29 | Neutral | 0.059 | Benign | 0.017 | Benign | -1.07 | Pathogenic | 0.76 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| 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 | 0.665 | Likely Pathogenic | 0.1193 | 0.0688 | 1.86 | Ambiguous | 0.6 | 2.65 | Destabilizing | 2.26 | Destabilizing | 1.65 | Destabilizing | -4.10 | Deleterious | 0.250 | Benign | 0.120 | Benign | -1.26 | Pathogenic | 0.03 | Affected | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||
| c.1832T>C | M611T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33440884‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | Uncertain | 1 | 6-33440884-T-C | 1 | 6.19e-7 | -5.696 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.240 | Likely Benign | 0.1635 | 0.1415 | 1.98 | Ambiguous | 0.2 | 0.94 | Ambiguous | 1.46 | Ambiguous | 0.87 | Ambiguous | -2.40 | Neutral | 0.034 | Benign | 0.038 | Benign | -1.19 | Pathogenic | 0.29 | Tolerated | 3.37 | 35 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||
| c.1832T>G | M611R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611R 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 AlphaMissense‑Optimized, polyPhen2_HumVar, and SIFT. Tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen2_HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is reported as uncertain. No prediction or folding result is missing; all available data are considered. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. 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 | -11.050 | Likely Pathogenic | 0.642 | Likely Pathogenic | Likely Benign | 0.644 | Likely Pathogenic | 0.1399 | 0.0837 | 1.80 | Ambiguous | 0.8 | 2.00 | Destabilizing | 1.90 | Ambiguous | 1.58 | Destabilizing | -4.10 | Deleterious | 0.779 | Possibly Damaging | 0.159 | Benign | -1.21 | Pathogenic | 0.21 | Tolerated | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||
| c.1833G>A | M611I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M611I is reported in gnomAD (ID 6‑33440885‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further clarify the variant’s likely effect: AlphaMissense‑Optimized classifies it as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain stability change. No folding‑stability method provides definitive evidence. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not conflict with ClinVar status, which lacks an entry for the variant. 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 | 6-33440885-G-A | 1 | 6.19e-7 | -8.552 | Likely Pathogenic | 0.736 | Likely Pathogenic | Likely Benign | 0.292 | Likely Benign | 0.1009 | 0.2302 | 1.45 | Ambiguous | 0.4 | 1.36 | Ambiguous | 1.41 | Ambiguous | 0.72 | Ambiguous | -2.10 | Neutral | 0.250 | Benign | 0.091 | Benign | -1.14 | Pathogenic | 0.38 | Tolerated | 3.37 | 35 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||
| c.1833G>C | M611I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M611I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are SGM‑Consensus, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of evidence points toward a pathogenic classification, 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 | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -8.552 | Likely Pathogenic | 0.736 | Likely Pathogenic | Likely Benign | 0.292 | Likely Benign | 0.1009 | 0.2302 | 1.45 | Ambiguous | 0.4 | 1.36 | Ambiguous | 1.41 | Ambiguous | 0.72 | Ambiguous | -2.10 | Neutral | 0.250 | Benign | 0.091 | Benign | -1.14 | Pathogenic | 0.38 | Tolerated | 3.37 | 35 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||
| c.1833G>T | M611I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M611I is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Predictors that classify it as pathogenic are SGM‑Consensus, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, premPS, and Foldetta) provide uncertain or unavailable results. High‑accuracy assessment shows AlphaMissense‑Optimized predicts benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic; Foldetta’s stability output is unavailable. Overall, the majority of predictions lean toward a benign effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -8.552 | Likely Pathogenic | 0.736 | Likely Pathogenic | Likely Benign | 0.292 | Likely Benign | 0.1009 | 0.2302 | 1.45 | Ambiguous | 0.4 | 1.36 | Ambiguous | 1.41 | Ambiguous | 0.72 | Ambiguous | -2.10 | Neutral | 0.250 | Benign | 0.091 | Benign | -1.14 | Pathogenic | 0.38 | Tolerated | 3.37 | 35 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||
| c.1843C>A | P615T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615T is not reported in ClinVar and is absent from gnomAD. Among the evaluated in‑silico predictors, SIFT is the sole tool that predicts a benign effect, whereas the remaining majority—including REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. Predictions from Rosetta, Foldetta, and premPS are uncertain and do not provide definitive evidence. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates it is likely pathogenic, while Foldetta’s stability analysis remains inconclusive. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. 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 | -13.764 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.823 | Likely Pathogenic | 0.1602 | 0.3806 | 3.02 | Destabilizing | 0.3 | 0.95 | Ambiguous | 1.99 | Ambiguous | 0.75 | Ambiguous | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.26 | Pathogenic | 0.06 | Tolerated | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||
| c.1843C>G | P615A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P615A variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include SIFT and Rosetta, whereas the majority of predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) all suggest a pathogenic impact. Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for P615A, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -12.156 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.693 | Likely Pathogenic | 0.3169 | 0.3214 | 1.73 | Ambiguous | 0.3 | 0.35 | Likely Benign | 1.04 | Ambiguous | 0.85 | Ambiguous | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.25 | Pathogenic | 0.10 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||
| c.1843C>T | P615S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615S is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a pathogenic effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM Consensus also indicates a likely pathogenic outcome. No tools predict a benign effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, while Foldetta’s stability prediction is uncertain and therefore not taken as evidence. Overall, the preponderance of evidence points to the variant being most likely pathogenic, with no contradiction to the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -12.566 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.780 | Likely Pathogenic | 0.3191 | 0.3310 | 2.46 | Destabilizing | 0.3 | 1.28 | Ambiguous | 1.87 | Ambiguous | 0.98 | Ambiguous | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.19 | Pathogenic | 0.04 | Affected | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||
| c.1844C>A | P615Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change P615Q is not listed in ClinVar and has no allele record in gnomAD. Functional prediction tools that assess sequence conservation and structural impact uniformly classify the variant as pathogenic: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only Rosetta and the combined Foldetta stability assessment are inconclusive. Grouping the predictions, the benign category contains no tools, while the pathogenic category includes all the above. 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 remains uncertain. 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 | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -13.247 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.742 | Likely Pathogenic | 0.1395 | 0.3445 | 2.16 | Destabilizing | 0.3 | 1.28 | Ambiguous | 1.72 | Ambiguous | 1.33 | Destabilizing | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.28 | Pathogenic | 0.01 | Affected | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||
| 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 | 0.871 | Likely Pathogenic | 0.1463 | 0.2603 | 2.62 | Destabilizing | 0.5 | 2.69 | Destabilizing | 2.66 | Destabilizing | 1.14 | Destabilizing | -8.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||
| c.1844C>T | P615L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615L is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS and Rosetta, whereas the remaining tools—REVEL, FoldX, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, PROVEAN, and the SGM Consensus—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity, and Foldetta yields an uncertain result. Taken together, the overwhelming majority of computational evidence indicates that P615L is likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -11.884 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.699 | Likely Pathogenic | 0.1949 | 0.4692 | 2.03 | Destabilizing | 0.4 | -0.01 | Likely Benign | 1.01 | Ambiguous | 0.50 | Likely Benign | -9.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.13 | Pathogenic | 0.04 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| 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 | 0.829 | Likely Pathogenic | 0.2332 | 0.5995 | 0.56 | Ambiguous | 0.1 | 2.86 | Destabilizing | 1.71 | Ambiguous | 0.82 | Ambiguous | -3.77 | Deleterious | 0.994 | Probably Damaging | 0.951 | Probably Damaging | 4.71 | Benign | 0.02 | Affected | 3.37 | 29 | 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.1306G>C | E436Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E436Q is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include premPS and FATHMM, while the majority of tools predict a pathogenic outcome: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the consensus of pathogenic predictions outweighs benign ones, and the high‑accuracy tools reinforce a pathogenic classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -12.413 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.607 | Likely Pathogenic | 0.1237 | 0.5809 | 0.51 | Ambiguous | 0.1 | 1.58 | Ambiguous | 1.05 | Ambiguous | 0.50 | Likely Benign | -2.76 | Deleterious | 0.992 | Probably Damaging | 0.946 | Probably Damaging | 4.64 | Benign | 0.01 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1307A>C | E436A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E436A is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include Foldetta, premPS, and FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. Two high‑accuracy predictors give concordant results: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. No prediction is missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for E436A, 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 | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -12.678 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.825 | Likely Pathogenic | 0.3901 | 0.5116 | 1.03 | Ambiguous | 0.0 | -0.88 | Ambiguous | 0.08 | Likely Benign | 0.23 | Likely Benign | -5.68 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 4.65 | Benign | 0.05 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1307A>G | E436G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of algorithms (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, premPS, and Foldetta are inconclusive. 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’s stability prediction is uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -12.355 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.802 | Likely Pathogenic | 0.2910 | 0.4841 | 1.50 | Ambiguous | 0.1 | 2.02 | Destabilizing | 1.76 | Ambiguous | 0.58 | Ambiguous | -6.63 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 4.61 | Benign | 0.03 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1307A>T | E436V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436V variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, while the remaining evaluated algorithms (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Based on the preponderance of pathogenic predictions and the high‑accuracy tools’ results, 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 | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -13.364 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.875 | Likely Pathogenic | 0.0727 | 0.5952 | 1.45 | Ambiguous | 0.0 | 1.62 | Ambiguous | 1.54 | Ambiguous | 0.30 | Likely Benign | -6.63 | Deleterious | 0.995 | Probably Damaging | 0.967 | Probably Damaging | 4.64 | Benign | 0.03 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1308G>C | E436D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions are limited to FATHMM, while the remaining nine tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic (3 pathogenic vs. 1 benign). Foldetta’s stability prediction is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -10.355 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.554 | Likely Pathogenic | 0.1938 | 0.3553 | 0.55 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.63 | Ambiguous | 0.73 | Ambiguous | -2.85 | Deleterious | 0.986 | Probably Damaging | 0.921 | Probably Damaging | 4.61 | Benign | 0.01 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1308G>T | E436D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions are limited to FATHMM, while the remaining nine tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic (3 pathogenic vs. 1 benign). Foldetta’s stability prediction is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -10.355 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.554 | Likely Pathogenic | 0.1938 | 0.3553 | 0.55 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.63 | Ambiguous | 0.73 | Ambiguous | -2.85 | Deleterious | 0.986 | Probably Damaging | 0.921 | Probably Damaging | 4.61 | Benign | 0.01 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.2149C>A | L717I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only two tools—polyPhen‑2 HumDiv and HumVar—predict a pathogenic outcome, while premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -4.836 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.182 | Likely Benign | 0.0712 | 0.2570 | 0.27 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.30 | Likely Benign | -0.73 | Ambiguous | 0.60 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 3.43 | Benign | 1.00 | Tolerated | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||
| c.2149C>G | L717V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Two tools predict a damaging effect: polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Stability‑based methods (FoldX, Rosetta, Foldetta) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as inconclusive. Taken together, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar assertion, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -6.164 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 0.119 | Likely Benign | 0.1226 | 0.2489 | 1.53 | Ambiguous | 0.0 | 1.25 | Ambiguous | 1.39 | Ambiguous | 0.09 | Likely Benign | -0.25 | Neutral | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.38 | Benign | 0.51 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.2149C>T | L717F 2D AIThe SynGAP1 missense variant L717F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. No folding‑stability metrics (FoldX, Rosetta, premPS) provide decisive evidence. Overall, the majority of predictions lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -10.917 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | 0.0444 | 0.2207 | 0.74 | Ambiguous | 0.6 | 0.59 | Ambiguous | 0.67 | Ambiguous | 0.63 | Ambiguous | -2.56 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.36 | Benign | 0.02 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.2150T>A | L717H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L717H occurs 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 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 | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -11.107 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.317 | Likely Benign | 0.0918 | 0.0558 | 2.27 | Destabilizing | 0.1 | 2.04 | Destabilizing | 2.16 | Destabilizing | 1.05 | Destabilizing | -5.23 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||
| 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 | 0.447 | Likely Benign | 0.3065 | 0.1053 | 3.96 | Destabilizing | 0.2 | 6.56 | Destabilizing | 5.26 | Destabilizing | 1.66 | Destabilizing | -5.32 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.28 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| 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 | 0.353 | Likely Benign | 0.1169 | 0.0558 | 1.66 | Ambiguous | 0.1 | 3.78 | Destabilizing | 2.72 | Destabilizing | 1.57 | Destabilizing | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.28 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.697T>A | C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenicity (3 pathogenic vs 1 benign). Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -10.862 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.764 | Likely Pathogenic | 0.4528 | 0.2833 | 0.61 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.93 | Ambiguous | 1.50 | Destabilizing | -8.89 | Deleterious | 0.421 | Benign | 0.080 | Benign | 5.79 | Benign | 0.03 | Affected | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.697T>C | C233R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and gnomAD presence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -16.789 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.830 | Likely Pathogenic | 0.1733 | 0.2212 | 3.79 | Destabilizing | 3.4 | 2.17 | Destabilizing | 2.98 | Destabilizing | 1.75 | Destabilizing | -10.68 | Deleterious | 0.002 | Benign | 0.002 | Benign | 5.71 | Benign | 0.01 | Affected | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||
| c.697T>G | C233G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233G 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 polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy predictions: AlphaMissense‑Optimized reports Pathogenic; SGM‑Consensus reports Likely Pathogenic; Foldetta is Uncertain. Overall, the majority of available predictions 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. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -14.155 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.849 | Likely Pathogenic | 0.3317 | 0.3570 | 1.29 | Ambiguous | 0.1 | 1.01 | Ambiguous | 1.15 | Ambiguous | 1.31 | Destabilizing | -10.68 | Deleterious | 0.596 | Possibly Damaging | 0.107 | Benign | 5.79 | Benign | 0.09 | Tolerated | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||
| c.698G>A | C233Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are Rosetta and FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -17.893 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.904 | Likely Pathogenic | 0.1324 | 0.5284 | 13.15 | Destabilizing | 4.6 | 0.04 | Likely Benign | 6.60 | Destabilizing | 0.71 | Ambiguous | -9.79 | Deleterious | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | 4.29 | 391 | 0 | -2 | -3.8 | 60.04 | 248.9 | -63.0 | 0.0 | 0.3 | 0.0 | 0.4 | X | X | Potentially Pathogenic | The introduced residue Tyr233 is located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Ala232) and an α helix (residues Ala236-Val250). Although the thiol group of a cysteine side chain is not a strong hydrogen bond acceptor or donor, it facilitates hydrogen bonding between Cys233 and the backbone carbonyl of Ala232 in the WT simulations. In the variant simulations, the bulky phenol ring of the Tyr233 side chain stacks with the indole ring of the Trp242 side chain. This interaction could alter the tertiary assembly of the β sheet and α helix due to the residue swap. Indeed, in the second replica simulation, the protein structure begins to unfold to accommodate the introduced Tyr233 side chain. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||
| c.698G>C | C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of evidence points to a pathogenic impact for C233S, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -10.862 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.830 | Likely Pathogenic | 0.4528 | 0.2833 | 0.61 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.93 | Ambiguous | 1.50 | Destabilizing | -8.89 | Deleterious | 0.421 | Benign | 0.080 | Benign | 5.79 | Benign | 0.03 | Affected | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.698G>T | C233F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include Rosetta, premPS, and FATHMM, whereas the remaining tools—REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and Foldetta—predict a pathogenic or likely pathogenic impact. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -14.564 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.901 | Likely Pathogenic | 0.1524 | 0.5231 | 9.36 | Destabilizing | 3.0 | -0.19 | Likely Benign | 4.59 | Destabilizing | 0.37 | Likely Benign | -9.79 | Deleterious | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 5.73 | Benign | 0.00 | Affected | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||
| c.699T>G | C233W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233W is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome, while Rosetta and premPS are uncertain. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Taken together, the overwhelming majority of evidence indicates that C233W is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -17.899 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.772 | Likely Pathogenic | 0.1727 | 0.5292 | 14.72 | Destabilizing | 6.6 | 1.07 | Ambiguous | 7.90 | Destabilizing | 0.54 | Ambiguous | -9.79 | Deleterious | 0.983 | Probably Damaging | 0.715 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||
| c.700C>G | R234G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that agree on a pathogenic effect are REVEL, PROVEAN, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of individual predictors lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -7.163 | In-Between | 0.923 | Likely Pathogenic | Ambiguous | 0.724 | Likely Pathogenic | 0.3194 | 0.3426 | 1.50 | Ambiguous | 0.2 | 0.88 | Ambiguous | 1.19 | Ambiguous | 0.61 | Ambiguous | -4.31 | Deleterious | 0.276 | Benign | 0.103 | Benign | 5.82 | Benign | 0.12 | Tolerated | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||
| c.700C>T | R234W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234W missense variant is listed in ClinVar (ID 856396.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33435551‑C‑T). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) indicate a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is “Uncertain.” Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertainty rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | Uncertain | 1 | 6-33435551-C-T | 3 | 1.86e-6 | -12.625 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.805 | Likely Pathogenic | 0.1302 | 0.4035 | 0.96 | Ambiguous | 0.3 | 0.69 | Ambiguous | 0.83 | Ambiguous | 0.13 | Likely Benign | -5.52 | Deleterious | 0.997 | Probably Damaging | 0.803 | Possibly Damaging | 5.76 | Benign | 0.01 | Affected | 3.40 | 14 | 2 | -3 | 3.6 | 30.03 | 262.8 | 39.6 | -0.1 | 0.0 | -0.2 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg234, located in a β-α loop between an anti-parallel β sheet strand (residues Gly227-Phe231) and an α helix (res. Ala236-Val250), forms a salt bridge with the carboxylate group of Glu238 in the α helix. Occasionally, it also bonds with the GAP domain residues Ser678 and Glu680. Thus, the positively charged Arg234 could contribute to the tertiary structure assembly between the PH and GAP domains. In contrast, the indole side chain of Trp234 in the variant is located on the protein surface in the variant simulations and is unable to form any interactions. | |||||||||
| c.701G>A | R234Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234Q missense variant is not reported in ClinVar (ClinVar ID = None) but is present in gnomAD (ID = 6‑33435552‑G‑A). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default; premPS is uncertain and treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence points to a benign effect. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | 6-33435552-G-A | 8 | 4.96e-6 | -9.675 | Likely Pathogenic | 0.666 | Likely Pathogenic | Likely Benign | 0.627 | Likely Pathogenic | 0.3256 | 0.2520 | 0.21 | Likely Benign | 0.1 | 0.27 | Likely Benign | 0.24 | Likely Benign | 0.57 | Ambiguous | -2.32 | Neutral | 0.892 | Possibly Damaging | 0.213 | Benign | 5.81 | Benign | 0.11 | Tolerated | 3.40 | 14 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||
| c.701G>C | R234P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R234P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of evaluated algorithms (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -10.126 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.826 | Likely Pathogenic | 0.1972 | 0.4336 | 1.33 | Ambiguous | 0.6 | 1.36 | Ambiguous | 1.35 | Ambiguous | 0.13 | Likely Benign | -4.43 | Deleterious | 0.929 | Possibly Damaging | 0.519 | Possibly Damaging | 5.93 | Benign | 0.04 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.701G>T | R234L 2D AIThe SynGAP1 missense variant R234L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (7 pathogenic vs. 4 benign) and the pathogenic consensus from the high‑accuracy SGM‑Consensus suggest that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -11.153 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 0.734 | Likely Pathogenic | 0.1846 | 0.4783 | 1.38 | Ambiguous | 0.9 | 0.50 | Ambiguous | 0.94 | Ambiguous | 0.20 | Likely Benign | -4.64 | Deleterious | 0.649 | Possibly Damaging | 0.199 | Benign | 5.78 | Benign | 0.11 | Tolerated | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.1204C>A | L402M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402M is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -6.991 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.1064 | 0.4095 | 0.12 | Likely Benign | 0.0 | 1.33 | Ambiguous | 0.73 | Ambiguous | 0.80 | Ambiguous | -0.99 | Neutral | 0.994 | Probably Damaging | 0.938 | Probably Damaging | 3.73 | Benign | 0.02 | Affected | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||
| c.1204C>G | L402V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a benign outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is therefore not considered evidence for pathogenicity. In summary, all available predictions support a benign classification for the L402V 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 Benign | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -3.467 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.203 | Likely Benign | 0.1807 | 0.3657 | 1.91 | Ambiguous | 0.1 | 0.78 | Ambiguous | 1.35 | Ambiguous | -0.11 | Likely Benign | 0.18 | Neutral | 0.004 | Benign | 0.004 | Benign | 4.01 | Benign | 0.29 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| 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 | 0.523 | Likely Pathogenic | 0.1384 | 0.1173 | 2.93 | Destabilizing | 0.0 | 2.55 | Destabilizing | 2.74 | Destabilizing | 2.09 | Destabilizing | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.957 | Probably Damaging | 3.69 | Benign | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| 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 | 0.616 | Likely Pathogenic | 0.3628 | 0.1874 | 7.40 | Destabilizing | 0.1 | 5.82 | Destabilizing | 6.61 | Destabilizing | 2.22 | Destabilizing | -4.80 | Deleterious | 1.000 | Probably Damaging | 0.980 | Probably Damaging | 3.68 | Benign | 0.01 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| 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 | 0.522 | Likely Pathogenic | 0.1467 | 0.1173 | 4.10 | Destabilizing | 0.2 | 3.82 | Destabilizing | 3.96 | Destabilizing | 2.24 | Destabilizing | -4.69 | Deleterious | 0.967 | Probably Damaging | 0.459 | Possibly Damaging | 3.69 | Benign | 0.00 | Affected | 3.38 | 28 | -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.2125C>A | L709M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No predictions are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.243554 | Structured | 0.365830 | Uncertain | 0.934 | 0.379 | 0.000 | -5.242 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.065 | Likely Benign | 0.0629 | 0.2409 | 0.18 | Likely Benign | 0.0 | 0.40 | Likely Benign | 0.29 | Likely Benign | -0.10 | Likely Benign | 0.03 | Neutral | 0.688 | Possibly Damaging | 0.235 | Benign | 3.41 | Benign | 0.17 | Tolerated | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||
| c.2125C>G | L709V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709V is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool that produced a definitive call classifies the variant as benign: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. The only inconclusive results are FoldX (uncertain) and Foldetta (uncertain), which are treated as unavailable evidence. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also benign; Foldetta remains uncertain. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.243554 | Structured | 0.365830 | Uncertain | 0.934 | 0.379 | 0.000 | -4.406 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.063 | Likely Benign | 0.1162 | 0.2460 | 0.75 | Ambiguous | 0.0 | 0.42 | Likely Benign | 0.59 | Ambiguous | 0.03 | Likely Benign | -0.36 | Neutral | 0.062 | Benign | 0.016 | Benign | 3.42 | Benign | 0.45 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.2126T>A | L709Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Thus, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.243554 | Structured | 0.365830 | Uncertain | 0.934 | 0.379 | 0.000 | -5.758 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.0838 | 0.0488 | 0.13 | Likely Benign | 0.0 | 0.40 | Likely Benign | 0.27 | Likely Benign | 0.18 | Likely Benign | -0.78 | Neutral | 0.998 | Probably Damaging | 0.923 | Probably Damaging | 3.52 | Benign | 0.48 | Tolerated | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| 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 | 0.167 | Likely Benign | 0.3004 | 0.0825 | 2.81 | Destabilizing | 0.0 | 5.65 | Destabilizing | 4.23 | Destabilizing | 0.31 | Likely Benign | -1.93 | Neutral | 1.000 | Probably Damaging | 0.975 | Probably Damaging | 3.47 | Benign | 0.37 | Tolerated | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||
| c.2126T>G | L709R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. Tools with uncertain or inconclusive results are Rosetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Overall, the majority of evidence indicates a benign impact for the variant, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.243554 | Structured | 0.365830 | Uncertain | 0.934 | 0.379 | 0.000 | -8.636 | Likely Pathogenic | 0.482 | Ambiguous | Likely Benign | 0.061 | Likely Benign | 0.1127 | 0.0488 | 0.22 | Likely Benign | 0.0 | 0.68 | Ambiguous | 0.45 | Likely Benign | 0.62 | Ambiguous | -1.56 | Neutral | 0.906 | Possibly Damaging | 0.314 | Benign | 3.50 | Benign | 0.44 | Tolerated | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||
| c.2143C>A | P715T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Two tools, Foldetta and premPS, returned uncertain results. High‑accuracy analyses further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenicity; Foldetta remains inconclusive. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -10.501 | Likely Pathogenic | 0.744 | Likely Pathogenic | Likely Benign | 0.368 | Likely Benign | 0.1357 | 0.4072 | 2.55 | Destabilizing | 0.1 | 0.29 | Likely Benign | 1.42 | Ambiguous | 0.72 | Ambiguous | -7.23 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||
| c.2143C>G | P715A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P715A has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments further indicate AlphaMissense‑Optimized predicts Benign, whereas the SGM‑Consensus remains Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is Uncertain. Overall, the majority of evidence points toward a pathogenic effect, 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 | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -9.261 | Likely Pathogenic | 0.597 | Likely Pathogenic | Likely Benign | 0.229 | Likely Benign | 0.2993 | 0.3560 | 2.69 | Destabilizing | 0.0 | 0.28 | Likely Benign | 1.49 | Ambiguous | 0.77 | Ambiguous | -7.13 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.45 | Benign | 0.02 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||
| c.2143C>T | P715S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P715S is listed in ClinVar as pathogenic (ClinVar ID 1804065.0) and is present in gnomAD (ID 6‑33441608‑C‑T). Functional prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. Predictions that are inconclusive are Rosetta, premPS, ESM1b, 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 majority of evidence points to a pathogenic impact, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | Likely Pathogenic | 1 | 6-33441608-C-T | 1 | 6.20e-7 | -7.635 | In-Between | 0.787 | Likely Pathogenic | Ambiguous | 0.277 | Likely Benign | 0.2977 | 0.3755 | 3.54 | Destabilizing | 0.0 | 0.81 | Ambiguous | 2.18 | Destabilizing | 0.94 | Ambiguous | -7.17 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.43 | Benign | 0.01 | Affected | 3.50 | 9 | 1 | -1 | 0.8 | -10.04 | 231.8 | -14.0 | -0.1 | 0.0 | -0.8 | 0.1 | X | Uncertain | Pro715, along with Gly712 and Pro713, are located in a hinge region of an α-helix making a ~90-degree turn (res. Lys705-Leu725). In the WT simulations, the pyrrolidine side chain of Pro715, lacking the backbone amide groups altogether, forces the tight helix turn to take place while also hydrophobically packing with nearby residues (e.g., Leu700, Leu708, Leu714, and Leu718). Leu715, with a normal amide backbone, could potentially affect protein folding and turn formation, although this was not observed in the variant simulations. Additionally, the hydroxyl group of the Ser715 side chain can form hydrogen bonds with the backbone carbonyl group of Gly712 and disrupt the hydrophobic packing arrangement of the leucine residues from the neighboring α-helices, impacting the GAP domain tertiary assembly. | ||||||||||
| c.2144C>A | P715H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of predictors (FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) indicate a pathogenic impact. Tools with inconclusive results (Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the consensus of the majority of evidence points to a pathogenic effect for P715H. Based on the aggregate predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -10.523 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.271 | Likely Benign | 0.1413 | 0.3684 | 2.80 | Destabilizing | 0.0 | 0.28 | Likely Benign | 1.54 | Ambiguous | 0.56 | Ambiguous | -7.73 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.37 | Benign | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||
| c.2144C>G | P715R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715R 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 (SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) classify the change as pathogenic. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, AlphaMissense‑Optimized is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Because the pathogenic predictions outnumber the benign ones and the high‑accuracy consensus supports a deleterious effect, the variant is most likely pathogenic. This assessment does not contradict ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -12.191 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | 0.324 | Likely Benign | 0.1389 | 0.2620 | 2.19 | Destabilizing | 0.1 | 0.53 | Ambiguous | 1.36 | Ambiguous | 0.87 | Ambiguous | -8.09 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.53 | Benign | 0.01 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||
| c.2144C>T | P715L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Because the majority of consensus and individual predictors indicate pathogenicity, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for P715L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -12.207 | Likely Pathogenic | 0.764 | Likely Pathogenic | Likely Benign | 0.318 | Likely Benign | 0.1944 | 0.5105 | 1.43 | Ambiguous | 0.1 | 0.06 | Likely Benign | 0.75 | Ambiguous | 0.58 | Ambiguous | -9.10 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| c.2002T>A | S668T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668T is not reported in ClinVar (ClinVar ID: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from FoldX or Rosetta alone is conclusive. Overall, the balance of predictions leans toward pathogenicity, 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 | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -11.860 | Likely Pathogenic | 0.703 | Likely Pathogenic | Likely Benign | 0.238 | Likely Benign | 0.1212 | 0.5918 | 1.73 | Ambiguous | 0.7 | 0.89 | Ambiguous | 1.31 | Ambiguous | 0.27 | Likely Benign | -2.99 | Deleterious | 0.844 | Possibly Damaging | 0.198 | Benign | 3.24 | Benign | 0.02 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| 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 | 0.612 | Likely Pathogenic | 0.1979 | 0.5137 | 6.40 | Destabilizing | 1.1 | 10.90 | Destabilizing | 8.65 | Destabilizing | 0.61 | Ambiguous | -4.82 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 3.16 | Benign | 0.02 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||
| c.2002T>G | S668A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S668A missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools—AlphaMissense‑Default and FoldX—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Taking all evidence together, the majority of predictions (seven benign versus four pathogenic) and the two high‑accuracy benign calls suggest that the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -12.011 | Likely Pathogenic | 0.506 | Ambiguous | Likely Benign | 0.399 | Likely Benign | 0.4866 | 0.3967 | 0.73 | Ambiguous | 0.3 | -0.44 | Likely Benign | 0.15 | Likely Benign | 0.48 | Likely Benign | -2.99 | Deleterious | 0.887 | Possibly Damaging | 0.738 | Possibly Damaging | 3.28 | Benign | 0.19 | Tolerated | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||
| 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 | 0.641 | Likely Pathogenic | 0.0647 | 0.5693 | 18.34 | Destabilizing | 6.2 | 12.69 | Destabilizing | 15.52 | Destabilizing | 0.06 | Likely Benign | -5.95 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||
| c.2003C>G | S668C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S668C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are returned by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) supports a pathogenic outcome; Foldetta remains inconclusive. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -12.815 | Likely Pathogenic | 0.758 | Likely Pathogenic | Likely Benign | 0.503 | Likely Pathogenic | 0.0962 | 0.5528 | 1.31 | Ambiguous | 0.6 | 1.36 | Ambiguous | 1.34 | Ambiguous | 0.18 | Likely Benign | -4.99 | Deleterious | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 3.27 | Benign | 0.02 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| 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 | 0.643 | Likely Pathogenic | 0.0656 | 0.5849 | 16.72 | Destabilizing | 5.0 | 11.07 | Destabilizing | 13.90 | Destabilizing | 0.00 | Likely Benign | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 3.38 | 28 | -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.2146C>G | R716G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R716G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. Other stability predictors (FoldX, Rosetta, premPS) are also Uncertain. Overall, the balance of evidence from the majority of tools and the SGM‑Consensus indicates a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.419135 | Uncertain | 0.962 | 0.379 | 0.000 | -9.927 | Likely Pathogenic | 0.728 | Likely Pathogenic | Likely Benign | 0.359 | Likely Benign | 0.3437 | 0.2466 | 1.32 | Ambiguous | 0.1 | 1.63 | Ambiguous | 1.48 | Ambiguous | 0.72 | Ambiguous | -5.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.2146C>T | R716W 2D 3DClick to see structure in 3D Viewer AIClinVar has no entry for this SynGAP1 R716W variant, and it is present in the gnomAD database (ID 6‑33441611‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, premPS, and Foldetta, while those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic. With two high‑accuracy tools supporting benign and one supporting pathogenic, the overall prediction leans toward a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.419135 | Uncertain | 0.962 | 0.379 | 0.000 | 6-33441611-C-T | 5 | 3.10e-6 | -11.543 | Likely Pathogenic | 0.766 | Likely Pathogenic | Likely Benign | 0.339 | Likely Benign | 0.1303 | 0.3252 | -0.11 | Likely Benign | 0.0 | 0.87 | Ambiguous | 0.38 | Likely Benign | 0.31 | Likely Benign | -6.72 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.32 | Benign | 0.00 | Affected | 3.50 | 9 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||
| c.2147G>A | R716Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R716Q is listed in ClinVar with an uncertain significance (ClinVar ID 411585.0) and is present in gnomAD (ID 6‑33441612‑G‑A). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b, while premPS is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the balance of evidence leans toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.247041 | Structured | 0.419135 | Uncertain | 0.962 | 0.379 | 0.000 | Conflicting | 2 | 6-33441612-G-A | 4 | 2.48e-6 | -8.338 | Likely Pathogenic | 0.308 | Likely Benign | Likely Benign | 0.210 | Likely Benign | 0.2834 | 0.2180 | -0.01 | Likely Benign | 0.0 | 0.47 | Likely Benign | 0.23 | Likely Benign | 0.58 | Ambiguous | -3.14 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 3.50 | 9 | 1 | 1 | 1.0 | -28.06 | 250.0 | 48.9 | 0.0 | 0.0 | -0.5 | 0.0 | X | Uncertain | The guanidinium group of Arg716, located on the outer surface of an α-helix (res. Leu714-Arg726), forms a salt bridge with the carboxylate group of Asp720. In the variant simulations, the carboxamide group of Gln716 also forms a hydrogen bond with the carboxylate group of Asp720, although this bond is weaker than the Arg716 salt bridge in the WT. Overall, no adverse effects on the protein structure are observed in the simulations. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | ||||||||||
| 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 | 0.320 | Likely Benign | 0.2140 | 0.3576 | 0.18 | Likely Benign | 0.1 | 5.67 | Destabilizing | 2.93 | Destabilizing | 0.49 | Likely Benign | -5.75 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.33 | Benign | 0.01 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.2147G>T | R716L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R716L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, premPS, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions (7/13) lean toward pathogenicity, with a near‑even split and a slight edge for pathogenic. The variant is therefore most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for R716L. 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 | -10.690 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.289 | Likely Benign | 0.1701 | 0.3775 | 0.31 | Likely Benign | 0.0 | 0.51 | Ambiguous | 0.41 | Likely Benign | 0.37 | Likely Benign | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.46 | Benign | 0.01 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.625G>A | V209M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V209M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -8.112 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.115 | Likely Benign | 0.0669 | 0.3982 | 0.70 | Ambiguous | 0.4 | 0.77 | Ambiguous | 0.74 | Ambiguous | 0.78 | Ambiguous | -1.48 | Neutral | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 3.68 | Benign | 0.02 | Affected | 2 | 1 | -2.3 | 32.06 | ||||||||||||||||||||||||||
| c.625G>C | V209L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V209L missense change is not reported in ClinVar and is absent from gnomAD. Consensus‐based predictors that agree on a benign outcome include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Predictors that flag a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -5.516 | Likely Benign | 0.837 | Likely Pathogenic | Ambiguous | 0.084 | Likely Benign | 0.0814 | 0.4188 | 0.26 | Likely Benign | 0.4 | -0.12 | Likely Benign | 0.07 | Likely Benign | 0.08 | Likely Benign | -0.96 | Neutral | 0.787 | Possibly Damaging | 0.259 | Benign | 4.08 | Benign | 0.39 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.625G>T | V209L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209L is not reported in ClinVar and is absent from gnomAD. Consensus predictions from most in silico tools classify the change as benign: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Only two tools predict a pathogenic effect: polyPhen‑2 HumDiv and AlphaMissense‑Default. The AlphaMissense‑Optimized score is uncertain. High‑accuracy assessments further support a benign outcome: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -5.516 | Likely Benign | 0.837 | Likely Pathogenic | Ambiguous | 0.084 | Likely Benign | 0.0814 | 0.4188 | 0.26 | Likely Benign | 0.4 | -0.12 | Likely Benign | 0.07 | Likely Benign | 0.08 | Likely Benign | -0.96 | Neutral | 0.787 | Possibly Damaging | 0.259 | Benign | 4.08 | Benign | 0.39 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.626T>A | V209E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) all predict a pathogenic outcome. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, V209E is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -14.366 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.403 | Likely Benign | 0.0826 | 0.1652 | 3.53 | Destabilizing | 1.3 | 2.35 | Destabilizing | 2.94 | Destabilizing | 1.52 | Destabilizing | -4.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.65 | Benign | 0.00 | Affected | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||
| c.626T>C | V209A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209A is reported in gnomAD (ID 6‑33435268‑T‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL and FATHMM. In contrast, a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Stability‑based methods FoldX, Rosetta, and the combined Foldetta score are uncertain and therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that V209A is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | 6-33435268-T-C | 1 | 6.20e-7 | -9.796 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.236 | Likely Benign | 0.2237 | 0.1919 | 1.56 | Ambiguous | 0.3 | 1.85 | Ambiguous | 1.71 | Ambiguous | 1.60 | Destabilizing | -2.79 | Deleterious | 0.958 | Probably Damaging | 0.581 | Possibly Damaging | 3.70 | Benign | 0.02 | Affected | 3.41 | 13 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||
| c.626T>G | V209G 2D AIThe SynGAP1 missense variant V209G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a pathogenic classification; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of computational evidence indicates that V209G is likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -13.763 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.390 | Likely Benign | 0.1600 | 0.2035 | 3.05 | Destabilizing | 0.5 | 3.99 | Destabilizing | 3.52 | Destabilizing | 1.27 | Destabilizing | -5.49 | Deleterious | 0.829 | Possibly Damaging | 0.995 | Probably Damaging | 3.65 | Benign | 0.04 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| 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 | 0.457 | Likely Benign | 0.1691 | 0.7377 | 2.16 | Destabilizing | 0.7 | 3.42 | Destabilizing | 2.79 | Destabilizing | 1.08 | Destabilizing | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.68 | Pathogenic | 0.01 | Affected | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.874G>C | A292P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely converge on a deleterious effect: only REVEL classifies it as benign, whereas FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a destabilizing, pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -16.897 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.471 | Likely Benign | 0.2101 | 0.5988 | 4.37 | Destabilizing | 0.3 | 9.80 | Destabilizing | 7.09 | Destabilizing | 1.23 | Destabilizing | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.67 | Pathogenic | 0.01 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.874G>T | A292S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292S is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FoldX, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and PROVEAN. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. No prediction or folding‑stability result is missing; uncertain outcomes are treated as unavailable. Overall, the balance of evidence favors a pathogenic classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -8.514 | Likely Pathogenic | 0.804 | Likely Pathogenic | Ambiguous | 0.364 | Likely Benign | 0.2850 | 0.6389 | 0.40 | Likely Benign | 0.2 | 2.13 | Destabilizing | 1.27 | Ambiguous | 0.70 | Ambiguous | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.69 | Pathogenic | 0.03 | Affected | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.875C>A | A292E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for A292E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -14.282 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.475 | Likely Benign | 0.1444 | 0.2205 | 6.07 | Destabilizing | 1.2 | 3.82 | Destabilizing | 4.95 | Destabilizing | 1.54 | Destabilizing | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||
| c.875C>G | A292G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A292G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, whereas the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain, and individual FoldX and Rosetta predictions are also inconclusive. Overall, the majority of evidence points to a pathogenic impact, 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 | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -9.692 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.323 | Likely Benign | 0.2187 | 0.5054 | 0.88 | Ambiguous | 0.1 | 1.83 | Ambiguous | 1.36 | Ambiguous | 1.05 | Destabilizing | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.74 | Pathogenic | 0.10 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| 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 | 0.430 | Likely Benign | 0.1272 | 0.6253 | 2.04 | Destabilizing | 0.5 | 4.60 | Destabilizing | 3.32 | Destabilizing | 0.85 | Ambiguous | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.75 | Pathogenic | 0.03 | Affected | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.1078G>A | E360K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360K is reported in gnomAD (variant ID 6-33437983‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect are limited to FoldX, which scores the variant as benign. In contrast, the majority of algorithms predict a pathogenic impact: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Tools with inconclusive results (Foldetta and premPS) are noted as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, while Foldetta remains uncertain. Overall, the consensus of high‑confidence predictors points to a pathogenic effect for E360K. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | 6-33437983-G-A | -16.006 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.526 | Likely Pathogenic | 0.3106 | 0.8594 | 0.27 | Likely Benign | 0.0 | 2.21 | Destabilizing | 1.24 | Ambiguous | 0.55 | Ambiguous | -3.68 | Deleterious | 0.997 | Probably Damaging | 0.980 | Probably Damaging | 1.68 | Pathogenic | 0.04 | Affected | 3.37 | 25 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||
| c.1078G>C | E360Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and premPS, while a majority of tools predict a pathogenic outcome: SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E360Q, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -11.012 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.343 | Likely Benign | 0.1824 | 0.8282 | 0.55 | Ambiguous | 0.1 | 1.38 | Ambiguous | 0.97 | Ambiguous | -0.02 | Likely Benign | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 1.61 | Pathogenic | 0.03 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1079A>C | E360A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360A is 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 tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Because the majority of consensus tools predict pathogenicity and no ClinVar entry contradicts this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -13.229 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 0.545 | Likely Pathogenic | 0.4295 | 0.8243 | 1.37 | Ambiguous | 0.1 | 1.72 | Ambiguous | 1.55 | Ambiguous | 0.39 | Likely Benign | -5.52 | Deleterious | 0.997 | Probably Damaging | 0.980 | Probably Damaging | 1.63 | Pathogenic | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| 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 | 0.569 | Likely Pathogenic | 0.2993 | 0.6935 | 2.55 | Destabilizing | 0.1 | 2.99 | Destabilizing | 2.77 | Destabilizing | 0.31 | Likely Benign | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.986 | Probably Damaging | 1.68 | Pathogenic | 0.04 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1079A>T | E360V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only premPS, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the overwhelming majority of reliable predictors classify E360V as pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -14.388 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.627 | Likely Pathogenic | 0.1143 | 0.8670 | 1.00 | Ambiguous | 0.1 | 1.11 | Ambiguous | 1.06 | Ambiguous | 0.03 | Likely Benign | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 1.57 | Pathogenic | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1080G>C | E360D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and SIFT. In contrast, a majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are therefore not considered evidence for either side. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus remains Likely Pathogenic, while Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E360D. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -9.383 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.290 | Likely Benign | 0.2339 | 0.5735 | 1.00 | Ambiguous | 0.0 | 0.63 | Ambiguous | 0.82 | Ambiguous | 0.11 | Likely Benign | -2.76 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.77 | Pathogenic | 0.07 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1080G>T | E360D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, premPS, and SIFT, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -9.383 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.290 | Likely Benign | 0.2339 | 0.5735 | 1.00 | Ambiguous | 0.0 | 0.63 | Ambiguous | 0.82 | Ambiguous | 0.11 | Likely Benign | -2.76 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.77 | Pathogenic | 0.07 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1213C>A | R405S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405S 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 pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM‑Consensus itself is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts Pathogenic. Taken together, the overwhelming majority of evidence indicates that R405S 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 | -11.326 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.405 | Likely Benign | 0.2829 | 0.4646 | 2.66 | Destabilizing | 0.5 | 2.08 | Destabilizing | 2.37 | Destabilizing | 1.22 | Destabilizing | -5.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.67 | Benign | 0.05 | Affected | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||
| 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 | 0.419 | Likely Benign | 0.3381 | 0.4139 | 3.22 | Destabilizing | 0.5 | 3.26 | Destabilizing | 3.24 | Destabilizing | 1.38 | Destabilizing | -6.35 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.63 | Benign | 0.01 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.1213C>T | R405C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R405C is listed in ClinVar with an uncertain significance (ClinVar ID 1185858.0) and is present in gnomAD (ID 6‑33438118‑C‑T). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually return uncertain results. Overall, the balance of evidence favors a pathogenic interpretation, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | Conflicting | 2 | 6-33438118-C-T | 6 | 3.72e-6 | -9.206 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.427 | Likely Benign | 0.3227 | 0.3964 | 0.72 | Ambiguous | 0.1 | 1.51 | Ambiguous | 1.12 | Ambiguous | 1.21 | Destabilizing | -7.27 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.61 | Benign | 0.02 | Affected | 3.38 | 28 | -4 | -3 | 7.0 | -53.05 | 221.3 | 82.6 | -0.1 | 0.0 | -0.2 | 0.3 | X | X | Potentially Pathogenic | The guanidinium group of Arg405, located in an anti-parallel β sheet strand of the C2 domain (res. Ala399-Ile411), forms a salt bridge with the carboxylate group of the Glu446 side chain from an opposing α helix (res. Val441-Ser457) in the GAP domain. The positively charged Arg405 side chain also stacks with the aromatic ring of the Phe358 side chain from a loop preceding the β strand (res. Thr359-Thr366), which could assist in maintaining the anti-parallel strand arrangement.In the variant simulations, the thiol-containing side chain of Cys405 is neutral and smaller compared to the arginine side chain. The lack of Arg405-Phe358 stacking affects the loop structure, causing it to assume a β strand form—an effect that could be exacerbated during protein folding. Moreover, the inability of Cys405 to form a salt bridge with Glu446 could affect the tertiary structure assembly, although this is not apparent based on the variant simulations. | ||||||||
| c.1214G>A | R405H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R405H is listed in ClinVar with an uncertain significance (ClinVar ID 863440.0) and is present in gnomAD (variant ID 6‑33438119‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized reports a benign change, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the preponderance of evidence indicates that R405H is most likely pathogenic, which does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | Conflicting | 2 | 6-33438119-G-A | 4 | 2.48e-6 | -9.081 | Likely Pathogenic | 0.706 | Likely Pathogenic | Likely Benign | 0.371 | Likely Benign | 0.3395 | 0.2363 | 2.79 | Destabilizing | 0.6 | 1.85 | Ambiguous | 2.32 | Destabilizing | 1.26 | Destabilizing | -4.54 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.65 | Benign | 0.01 | Affected | 3.38 | 28 | 2 | 0 | 1.3 | -19.05 | 214.0 | 102.2 | -0.1 | 0.0 | -0.7 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg405, located in an anti-parallel β sheet strand of the C2 domain (res. Pro398-Ile411), forms a salt bridge with the carboxylate group of the Glu446 side chain from an opposing α helix (res. Val441-Ser457) in the GAP domain. The positively charged Arg405 side chain also stacks with the aromatic ring of the Phe358 side chain from a loop preceding the β strand (res. Thr359-Thr366), which could assist in maintaining the anti-parallel strand arrangement.In the variant simulations, the imidazole ring of His405 does not stack with the aromatic ring of Phe358 nor form any lasting H-bonds with the loop residues. The imidazole ring of His405 (neutral and epsilon protonated in the simulations) is unable to form a salt bridge with Glu446, which could affect the tertiary structure assembly, although this is not apparent based on the variant simulations. | |||||||||
| 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 | 0.572 | Likely Pathogenic | 0.2140 | 0.5138 | 3.11 | Destabilizing | 0.3 | 5.19 | Destabilizing | 4.15 | Destabilizing | 1.26 | Destabilizing | -6.32 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.62 | Benign | 0.01 | Affected | 3.38 | 28 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||
| c.1214G>T | R405L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R405L missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are Rosetta and FATHMM, while the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) indicate a pathogenic or likely pathogenic impact. Uncertain results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta providing an inconclusive stability prediction. Overall, the preponderance of evidence points to a pathogenic effect for R405L, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | -11.576 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.512 | Likely Pathogenic | 0.2126 | 0.5555 | 1.43 | Ambiguous | 0.7 | 0.40 | Likely Benign | 0.92 | Ambiguous | 0.72 | Ambiguous | -6.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.64 | Benign | 0.01 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.1327G>A | G443S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as benign. Only Rosetta and premPS yield uncertain results, which are treated as unavailable. Grouping by consensus, the benign‑predicting tools outnumber any pathogenic calls (none). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. Therefore, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -1.258 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.087 | Likely Benign | 0.2409 | 0.3416 | 0.25 | Likely Benign | 0.1 | -0.72 | Ambiguous | -0.24 | Likely Benign | -0.65 | Ambiguous | 0.40 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.51 | Benign | 0.34 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||
| c.1327G>C | G443R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM all classify it as benign. Only two tools predict pathogenicity: polyPhen‑2 HumDiv and AlphaMissense‑Default. Predictions that are inconclusive—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are treated as unavailable. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments are: AlphaMissense‑Optimized (uncertain), SGM Consensus (likely benign), and Foldetta (uncertain). Overall, the preponderance of evidence points to a benign impact for G443R, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -6.954 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.132 | Likely Benign | 0.0934 | 0.3197 | -0.88 | Ambiguous | 0.3 | -1.19 | Ambiguous | -1.04 | Ambiguous | 0.28 | Likely Benign | -1.49 | Neutral | 0.832 | Possibly Damaging | 0.286 | Benign | 3.40 | Benign | 0.21 | Tolerated | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.1327G>T | G443C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The remaining tools are inconclusive: Foldetta is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta remains uncertain. Overall, the consensus of the majority of evidence points to a benign impact for G443C, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -4.308 | Likely Benign | 0.208 | Likely Benign | Likely Benign | 0.260 | Likely Benign | 0.1258 | 0.2782 | -0.06 | Likely Benign | 0.0 | -0.95 | Ambiguous | -0.51 | Ambiguous | -0.10 | Likely Benign | -2.94 | Deleterious | 0.977 | Probably Damaging | 0.504 | Possibly Damaging | 3.37 | Benign | 0.16 | Tolerated | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||
| c.1328G>A | G443D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. Uncertain results come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as inconclusive. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical data. The variant is most likely benign based on the current predictive landscape. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -6.818 | Likely Benign | 0.761 | Likely Pathogenic | Likely Benign | 0.072 | Likely Benign | 0.1687 | 0.2090 | -0.19 | Likely Benign | 0.2 | -1.72 | Ambiguous | -0.96 | Ambiguous | 0.32 | Likely Benign | -0.50 | Neutral | 0.345 | Benign | 0.072 | Benign | 3.63 | Benign | 0.43 | Tolerated | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||
| c.1328G>C | G443A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus all indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. The protein‑folding stability predictor Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is therefore treated as unavailable evidence. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion 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 | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -0.332 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.3539 | 0.3192 | -0.59 | Ambiguous | 0.1 | -1.61 | Ambiguous | -1.10 | Ambiguous | -0.52 | Ambiguous | -1.04 | Neutral | 0.022 | Benign | 0.011 | Benign | 3.41 | Benign | 0.54 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.1328G>T | G443V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. Overall, the majority of evidence points to a benign impact for G443V, 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 | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -4.130 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.1089 | 0.3375 | 0.17 | Likely Benign | 0.2 | -2.19 | Stabilizing | -1.01 | Ambiguous | 0.21 | Likely Benign | -2.90 | Deleterious | 0.585 | Possibly Damaging | 0.195 | Benign | 3.36 | Benign | 0.12 | Tolerated | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||
| c.1339G>A | V447I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V447I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Thus, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | -5.067 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.0625 | 0.3059 | -0.33 | Likely Benign | 0.1 | 0.27 | Likely Benign | -0.03 | Likely Benign | -0.44 | Likely Benign | -0.06 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.37 | Benign | 0.28 | Tolerated | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||
| c.1339G>C | V447L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V447L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain results are reported by FoldX, Rosetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | Uncertain | 1 | -5.136 | Likely Benign | 0.491 | Ambiguous | Likely Benign | 0.180 | Likely Benign | 0.0757 | 0.3477 | -1.13 | Ambiguous | 0.1 | 0.54 | Ambiguous | -0.30 | Likely Benign | 0.03 | Likely Benign | -0.29 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.61 | Benign | 0.90 | Tolerated | 3.37 | 32 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||
| c.1339G>T | V447F 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V447F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports an uncertain effect on protein folding. Overall, the majority of predictions lean toward pathogenicity, suggesting the variant is most likely pathogenic, a conclusion that does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | Uncertain | 1 | -8.673 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 0.206 | Likely Benign | 0.0551 | 0.3055 | 1.40 | Ambiguous | 0.3 | 0.61 | Ambiguous | 1.01 | Ambiguous | 0.20 | Likely Benign | -2.62 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||
| 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 | 0.491 | Likely Benign | 0.1424 | 0.0541 | 4.34 | Destabilizing | 0.1 | 3.59 | Destabilizing | 3.97 | Destabilizing | 2.29 | Destabilizing | -5.33 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||
| 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 | 0.266 | Likely Benign | 0.2456 | 0.2124 | 2.18 | Destabilizing | 0.0 | 2.72 | Destabilizing | 2.45 | Destabilizing | 1.56 | Destabilizing | -2.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.15 | Tolerated | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||
| 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 | 0.499 | Likely Benign | 0.1863 | 0.2240 | 3.81 | Destabilizing | 0.1 | 4.62 | Destabilizing | 4.22 | Destabilizing | 2.28 | Destabilizing | -5.43 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.2122C>A | L708I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708I is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the substitution as benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and FATHMM. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, the variant is most likely benign 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 Benign | GAP | 0.250310 | Structured | 0.365875 | Uncertain | 0.931 | 0.378 | 0.000 | -4.406 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 0.0749 | 0.2729 | 0.42 | Likely Benign | 0.0 | -0.21 | Likely Benign | 0.11 | Likely Benign | -0.05 | Likely Benign | 0.02 | Neutral | 0.022 | Benign | 0.021 | Benign | 3.34 | Benign | 0.20 | Tolerated | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||
| c.2122C>G | L708V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (uncertain) and Foldetta (uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta remains uncertain. Overall, the evidence strongly indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.365875 | Uncertain | 0.931 | 0.378 | 0.000 | -4.361 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.122 | Likely Benign | 0.1094 | 0.2460 | 1.59 | Ambiguous | 0.0 | 0.12 | Likely Benign | 0.86 | Ambiguous | -0.02 | Likely Benign | -0.23 | Neutral | 0.158 | Benign | 0.035 | Benign | 3.35 | Benign | 0.94 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.2122C>T | L708F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L708F is not reported in ClinVar and is present in gnomAD (ID 6‑33441587‑C‑T). Functional prediction tools that reach consensus classify the change as benign: REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Pathogenic predictions are limited to polyPhen‑2 HumDiv and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) return uncertain or no result. High‑accuracy assessments give AlphaMissense‑Optimized a benign score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta indicates no significant destabilization (uncertain). Overall, the preponderance of evidence supports a benign effect for L708F, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.250310 | Structured | 0.365875 | Uncertain | 0.931 | 0.378 | 0.000 | 6-33441587-C-T | 2 | 1.24e-6 | -9.154 | Likely Pathogenic | 0.436 | Ambiguous | Likely Benign | 0.110 | Likely Benign | 0.0497 | 0.2366 | 1.48 | Ambiguous | 0.3 | 0.93 | Ambiguous | 1.21 | Ambiguous | 0.37 | Likely Benign | -2.46 | Neutral | 0.931 | Possibly Damaging | 0.326 | Benign | 3.29 | Benign | 0.07 | Tolerated | 3.50 | 9 | 0 | 2 | -1.0 | 34.02 | |||||||||||||||||||||
| c.2123T>A | L708H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708H is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default; the SGM Consensus score is also labeled Likely Pathogenic. Stability‑based methods FoldX and Rosetta return uncertain results, and Foldetta likewise is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, whereas a few high‑accuracy tools suggest benign or are inconclusive. Thus, the variant is most likely pathogenic based on the prevailing predictions, 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 | 0.250310 | Structured | 0.365875 | Uncertain | 0.931 | 0.378 | 0.000 | -8.059 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.243 | Likely Benign | 0.0824 | 0.0288 | 1.84 | Ambiguous | 0.1 | 1.55 | Ambiguous | 1.70 | Ambiguous | 1.44 | Destabilizing | -4.68 | Deleterious | 1.000 | Probably Damaging | 0.981 | Probably Damaging | 3.25 | Benign | 0.02 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||
| 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 | 0.298 | Likely Benign | 0.2800 | 0.0825 | 4.29 | Destabilizing | 0.1 | 6.43 | Destabilizing | 5.36 | Destabilizing | 1.62 | Destabilizing | -4.47 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 3.39 | Benign | 0.04 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.2123T>G | L708R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as Likely Pathogenic. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of tools (six pathogenic vs. four benign) and the SGM Consensus support a pathogenic classification, whereas AlphaMissense‑Optimized suggests benign. The variant is most likely pathogenic based on the collective predictions, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.365875 | Uncertain | 0.931 | 0.378 | 0.000 | -9.154 | Likely Pathogenic | 0.638 | Likely Pathogenic | Likely Benign | 0.249 | Likely Benign | 0.1091 | 0.0488 | 0.87 | Ambiguous | 0.0 | 0.90 | Ambiguous | 0.89 | Ambiguous | 1.24 | Destabilizing | -4.18 | Deleterious | 0.988 | Probably Damaging | 0.598 | Possibly Damaging | 3.27 | Benign | 0.19 | Tolerated | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.703T>A | S235T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while FoldX, Rosetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or folding result is missing or inconclusive. Based on the overall consensus of the available tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -9.422 | Likely Pathogenic | 0.451 | Ambiguous | Likely Benign | 0.453 | Likely Benign | 0.1674 | 0.6337 | 0.80 | Ambiguous | 0.0 | -0.54 | Ambiguous | 0.13 | Likely Benign | 0.21 | Likely Benign | -2.02 | Neutral | 0.057 | Benign | 0.020 | Benign | 5.75 | Benign | 0.13 | Tolerated | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||
| 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 | 0.870 | Likely Pathogenic | 0.2432 | 0.5307 | 4.02 | Destabilizing | 0.1 | 6.91 | Destabilizing | 5.47 | Destabilizing | 1.23 | Destabilizing | -4.24 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 5.47 | Benign | 0.01 | Affected | 3.40 | 14 | 1 | -1 | -0.8 | 10.04 | 201.5 | 17.0 | 0.1 | 0.0 | -0.6 | 0.0 | X | Potentially Pathogenic | In the WT, the hydroxyl group of Ser235, located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Phe231) and an α helix (residues Ala236-Val250), forms hydrogen bonds with the GAP domain loop residue Glu680 and with the backbone amide groups of Ala237 and Glu238 from the α helix. In the variant simulations, the pyrrolidine ring of Pro235 cannot stabilize the α helix end or maintain tertiary bonding interactions between the PH and GAP domains via hydrogen bonding as effectively as serine. | ||||||||||||
| c.703T>G | S235A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235A has no ClinVar entry and is not present in gnomAD. Prediction tools that indicate benign effects include Rosetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic; Foldetta remains uncertain. Overall, the balance of evidence leans toward a benign interpretation, but the SGM Consensus introduces a pathogenic signal, resulting in a conflicting prediction profile. This assessment does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -10.861 | Likely Pathogenic | 0.707 | Likely Pathogenic | Likely Benign | 0.646 | Likely Pathogenic | 0.5168 | 0.4563 | Weaken | 1.92 | Ambiguous | 0.1 | 0.19 | Likely Benign | 1.06 | Ambiguous | 0.48 | Likely Benign | -2.52 | Deleterious | 0.002 | Benign | 0.004 | Benign | 5.49 | Benign | 0.01 | Affected | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||
| c.704C>A | S235Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S235Y, and this conclusion is not contradicted by any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -15.842 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.887 | Likely Pathogenic | 0.0733 | 0.5269 | 3.53 | Destabilizing | 1.8 | 0.43 | Likely Benign | 1.98 | Ambiguous | 0.66 | Ambiguous | -5.14 | Deleterious | 0.971 | Probably Damaging | 0.641 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||
| c.704C>G | S235C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM and Rosetta, whereas a majority of tools (REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Results from high‑accuracy methods are mixed: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta is uncertain. Because the uncertain predictions are treated as unavailable, the overall evidence still favors pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -11.350 | Likely Pathogenic | 0.800 | Likely Pathogenic | Ambiguous | 0.878 | Likely Pathogenic | 0.1284 | 0.6015 | 1.74 | Ambiguous | 0.1 | 0.42 | Likely Benign | 1.08 | Ambiguous | 0.76 | Ambiguous | -4.24 | Deleterious | 0.977 | Probably Damaging | 0.620 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.704C>T | S235F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -14.456 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.919 | Likely Pathogenic | 0.0617 | 0.5393 | 3.03 | Destabilizing | 1.7 | 0.46 | Likely Benign | 1.75 | Ambiguous | 0.56 | Ambiguous | -5.14 | Deleterious | 0.917 | Possibly Damaging | 0.548 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||
| c.1345A>C | S449R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S449R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifying it as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain stability change. No folding‑stability prediction is definitive. Overall, the majority of tools predict a benign outcome, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.145 | Likely Benign | 0.0762 | 0.3250 | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1345A>G | S449G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449G is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (variant ID 6‑33438250‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as “Likely Benign,” and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | Uncertain | 1 | 6-33438250-A-G | 3 | 1.86e-6 | -5.936 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.2600 | 0.3718 | 0.47 | Likely Benign | 0.0 | 0.55 | Ambiguous | 0.51 | Ambiguous | 0.85 | Ambiguous | -2.32 | Neutral | 0.948 | Possibly Damaging | 0.124 | Benign | 3.35 | Benign | 0.13 | Tolerated | 3.37 | 32 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||
| c.1345A>T | S449C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449C is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Based on the unanimous benign predictions and lack of ClinVar evidence, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -2.207 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.067 | Likely Benign | 0.0864 | 0.5012 | 0.48 | Likely Benign | 0.0 | -0.31 | Likely Benign | 0.09 | Likely Benign | -0.57 | Ambiguous | 0.48 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.32 | Benign | 0.21 | Tolerated | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.1346G>A | S449N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449N is not reported in ClinVar (ClinVar status: not listed) but is present in the gnomAD database (gnomAD ID: 6‑33438251‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from premPS (uncertain) and ESM1b (uncertain). High‑accuracy assessments reinforce the benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | 6-33438251-G-A | 1 | 6.19e-7 | -7.692 | In-Between | 0.210 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 0.1085 | 0.3767 | 0.38 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.18 | Likely Benign | 0.81 | Ambiguous | -2.31 | Neutral | 0.372 | Benign | 0.026 | Benign | 3.37 | Benign | 0.18 | Tolerated | 3.37 | 32 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||
| c.1346G>C | S449T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449T is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on these predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -6.262 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.1219 | 0.5077 | 0.36 | Likely Benign | 0.1 | -0.46 | Likely Benign | -0.05 | Likely Benign | -0.15 | Likely Benign | -1.48 | Neutral | 0.038 | Benign | 0.008 | Benign | 3.42 | Benign | 0.33 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.1346G>T | S449I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and ESM1b. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs. 2 pathogenic). Foldetta also remains uncertain. Overall, the majority of evidence (7 benign vs. 3 pathogenic) points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -9.549 | Likely Pathogenic | 0.310 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.0756 | 0.5006 | 0.04 | Likely Benign | 0.1 | -1.39 | Ambiguous | -0.68 | Ambiguous | 0.13 | Likely Benign | -3.23 | Deleterious | 0.559 | Possibly Damaging | 0.044 | Benign | 3.40 | Benign | 0.14 | Tolerated | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||
| c.1347T>A | S449R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments provide a mixed picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an inconclusive result. FoldX and Rosetta predictions are also uncertain and are treated as unavailable. Overall, the evidence is balanced, with an equal number of benign and pathogenic calls, and the high‑accuracy tools do not converge on a single conclusion. Consequently, the variant is most likely pathogenic based on the preponderance of pathogenic predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.168 | Likely Benign | 0.0762 | 0.3250 | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1347T>G | S449R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449R is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include REVEL, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicting a benign effect, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta’s stability prediction is uncertain and therefore treated as unavailable. Overall, the predictions are split, with an equal number of benign and pathogenic calls and conflicting high‑accuracy results. Consequently, the variant’s impact remains inconclusive, and there is no contradiction with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.167 | Likely Benign | 0.0762 | 0.3250 | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1360A>C | I454L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The remaining tools—FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta also uncertain. Overall, the majority of reliable predictors and the SGM Consensus favor a benign classification. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -7.852 | In-Between | 0.786 | Likely Pathogenic | Ambiguous | 0.246 | Likely Benign | 0.0653 | 0.2857 | 0.57 | Ambiguous | 0.1 | 1.36 | Ambiguous | 0.97 | Ambiguous | 0.80 | Ambiguous | -1.98 | Neutral | 0.908 | Possibly Damaging | 0.943 | Probably Damaging | 3.51 | Benign | 0.26 | Tolerated | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1360A>G | I454V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as likely benign, and Foldetta as uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -4.719 | Likely Benign | 0.657 | Likely Pathogenic | Likely Benign | 0.132 | Likely Benign | 0.0833 | 0.2959 | 1.47 | Ambiguous | 0.0 | 1.36 | Ambiguous | 1.42 | Ambiguous | 0.69 | Ambiguous | -0.79 | Neutral | 0.935 | Possibly Damaging | 0.858 | Possibly Damaging | 3.40 | Benign | 0.18 | Tolerated | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.1360A>T | I454F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. premPS is uncertain and does not influence the overall assessment. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, with no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -12.468 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.464 | Likely Benign | 0.0422 | 0.2560 | 4.15 | Destabilizing | 0.7 | 2.96 | Destabilizing | 3.56 | Destabilizing | 0.70 | Ambiguous | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.1361T>A | I454N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454N resides in the GAP domain. ClinVar has no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on benign impact are REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. High‑accuracy methods further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta predicts a destabilizing, pathogenic change. Overall, the evidence strongly favors a pathogenic classification, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -14.246 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.497 | Likely Benign | 0.0750 | 0.0412 | 4.24 | Destabilizing | 0.1 | 3.56 | Destabilizing | 3.90 | Destabilizing | 2.44 | Destabilizing | -6.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.1361T>C | I454T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -9.045 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.502 | Likely Pathogenic | 0.0877 | 0.0708 | 3.20 | Destabilizing | 0.0 | 2.83 | Destabilizing | 3.02 | Destabilizing | 2.02 | Destabilizing | -4.74 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.1361T>G | I454S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -13.025 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.574 | Likely Pathogenic | 0.2116 | 0.0800 | 4.50 | Destabilizing | 0.1 | 4.45 | Destabilizing | 4.48 | Destabilizing | 2.20 | Destabilizing | -5.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||
| c.1362C>G | I454M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools (SGM‑Consensus, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Tools with inconclusive results are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for I454M. This conclusion is not contradicted by ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -8.437 | Likely Pathogenic | 0.871 | Likely Pathogenic | Ambiguous | 0.292 | Likely Benign | 0.0566 | 0.2524 | 1.06 | Ambiguous | 0.1 | 2.32 | Destabilizing | 1.69 | Ambiguous | 1.08 | Destabilizing | -2.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||
| c.1444C>A | L482I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from PROVEAN and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (REVEL, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) indicate pathogenicity. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments give a consistent picture: AlphaMissense‑Optimized predicts a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain outcome. Overall, the preponderance of pathogenic predictions suggests that the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -11.116 | Likely Pathogenic | 0.760 | Likely Pathogenic | Likely Benign | 0.600 | Likely Pathogenic | 0.0677 | 0.2368 | 1.29 | Ambiguous | 0.1 | 1.90 | Ambiguous | 1.60 | Ambiguous | 0.71 | Ambiguous | -1.97 | Neutral | 0.994 | Probably Damaging | 0.994 | Probably Damaging | -1.31 | Pathogenic | 0.05 | Affected | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||
| c.1444C>G | L482V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482V has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for the variant, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -11.676 | Likely Pathogenic | 0.734 | Likely Pathogenic | Likely Benign | 0.709 | Likely Pathogenic | 0.1074 | 0.2027 | 1.97 | Ambiguous | 0.1 | 1.52 | Ambiguous | 1.75 | Ambiguous | 0.76 | Ambiguous | -2.95 | Deleterious | 0.989 | Probably Damaging | 0.984 | Probably Damaging | -1.30 | Pathogenic | 0.10 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1444C>T | L482F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX and premPS, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further reveal AlphaMissense‑Optimized as Uncertain, SGM Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for L482F. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -11.257 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.724 | Likely Pathogenic | 0.0457 | 0.1814 | 0.48 | Likely Benign | 0.0 | 1.09 | Ambiguous | 0.79 | Ambiguous | 0.43 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | -1.22 | Pathogenic | 0.01 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1445T>A | L482H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482H is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are absent; all available pathogenic predictors (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus vote (Likely Pathogenic) uniformly indicate a deleterious impact. Uncertain predictions come from FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. No evidence suggests a benign outcome. Consequently, the variant is most likely pathogenic based on the consensus of pathogenic predictions, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -13.825 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.886 | Likely Pathogenic | 0.1000 | 0.0879 | 1.49 | Ambiguous | 0.0 | 1.44 | Ambiguous | 1.47 | Ambiguous | 1.64 | Destabilizing | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.28 | Pathogenic | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||
| c.1445T>C | L482P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482P is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the substitution as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic impact. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -12.866 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.896 | Likely Pathogenic | 0.2756 | 0.0825 | 3.59 | Destabilizing | 0.1 | 10.87 | Destabilizing | 7.23 | Destabilizing | 1.55 | Destabilizing | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.30 | Pathogenic | 0.01 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1445T>G | L482R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while FoldX, Rosetta, and Foldetta return uncertain results. In a consensus framework, the SGM‑Consensus score is “Likely Pathogenic,” reflecting the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus is Likely Pathogenic, and Foldetta remains inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -14.684 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.878 | Likely Pathogenic | 0.1255 | 0.0679 | 0.74 | Ambiguous | 0.1 | 1.31 | Ambiguous | 1.03 | Ambiguous | 1.53 | Destabilizing | -5.92 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | -1.27 | Pathogenic | 0.01 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.169C>A | L57I 2D AIThe SynGAP1 missense variant L57I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for the L57I variant, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.254060 | Structured | 0.481044 | Uncertain | 0.554 | 0.642 | 0.000 | -3.681 | Likely Benign | 0.275 | Likely Benign | Likely Benign | 0.024 | Likely Benign | 0.0973 | 0.4106 | -0.07 | Neutral | 0.458 | Possibly Damaging | 0.745 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||
| c.169C>G | L57V 2D AIThe SynGAP1 missense variant L57V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.254060 | Structured | 0.481044 | Uncertain | 0.554 | 0.642 | 0.000 | -3.598 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.051 | Likely Benign | 0.1533 | 0.4006 | -0.14 | Neutral | 0.458 | Possibly Damaging | 0.745 | Possibly Damaging | 4.17 | Benign | 0.00 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.169C>T | L57F 2D AIThe SynGAP1 missense variant L57F (ClinVar ID 1973575.0) is listed as “Uncertain” in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion aligns with the ClinVar “Uncertain” status, as it does not contradict the current classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.254060 | Structured | 0.481044 | Uncertain | 0.554 | 0.642 | 0.000 | Uncertain | 2 | -5.096 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.051 | Likely Benign | 0.0679 | 0.3355 | -0.78 | Neutral | 0.824 | Possibly Damaging | 0.879 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||
| c.170T>A | L57H 2D AIThe SynGAP1 missense variant L57H is not reported in ClinVar and has no entry in gnomAD. Prediction tools show a split: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further indicate that AlphaMissense‑Optimized is Uncertain, whereas the SGM‑Consensus remains Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of high‑confidence tools and the consensus score favor a benign effect, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.254060 | Structured | 0.481044 | Uncertain | 0.554 | 0.642 | 0.000 | -6.251 | Likely Benign | 0.796 | Likely Pathogenic | Ambiguous | 0.173 | Likely Benign | 0.1045 | 0.0611 | -1.58 | Neutral | 0.984 | Probably Damaging | 0.971 | Probably Damaging | 3.90 | Benign | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||
| c.170T>C | L57P 2D AIThe SynGAP1 missense variant L57P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (six pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.254060 | Structured | 0.481044 | Uncertain | 0.554 | 0.642 | 0.000 | -10.724 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.242 | Likely Benign | 0.3651 | 0.1703 | -1.77 | Neutral | 0.943 | Possibly Damaging | 0.944 | Probably Damaging | 3.90 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||
| c.170T>G | L57R 2D AIThe SynGAP1 missense variant L57R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively classify the variant as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the balance of evidence leans toward a benign interpretation, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.254060 | Structured | 0.481044 | Uncertain | 0.554 | 0.642 | 0.000 | -6.034 | Likely Benign | 0.810 | Likely Pathogenic | Ambiguous | 0.213 | Likely Benign | 0.1245 | 0.0685 | -1.55 | Neutral | 0.943 | Possibly Damaging | 0.944 | Probably Damaging | 3.91 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.2050G>A | D684N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684N is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus also reports it as likely pathogenic, and the Foldetta stability analysis is inconclusive. Protein‑stability predictors FoldX and Rosetta likewise return uncertain results. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the current ClinVar designation of uncertainty. 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 | -13.155 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.382 | Likely Benign | 0.1157 | 0.6373 | 1.47 | Ambiguous | 0.8 | 1.76 | Ambiguous | 1.62 | Ambiguous | 0.37 | Likely Benign | -4.99 | Deleterious | 0.999 | Probably Damaging | 0.746 | Possibly Damaging | 3.39 | Benign | 0.01 | Affected | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||
| 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 | 0.613 | Likely Pathogenic | 0.1344 | 0.6618 | 3.36 | Destabilizing | 1.0 | 2.95 | Destabilizing | 3.16 | Destabilizing | 0.55 | Ambiguous | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.972 | Probably Damaging | 3.36 | Benign | 0.00 | Affected | 3.42 | 17 | -1 | 1 | 0.3 | 22.05 | |||||||||||||||||||||
| c.2050G>T | D684Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684Y 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: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. Only premPS and FATHMM predict a benign effect. 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 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 the absence of ClinVar reporting. 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 | -15.224 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.600 | Likely Pathogenic | 0.0575 | 0.6564 | 3.65 | Destabilizing | 1.5 | 2.12 | Destabilizing | 2.89 | Destabilizing | -0.06 | Likely Benign | -8.98 | Deleterious | 1.000 | Probably Damaging | 0.963 | Probably Damaging | 3.44 | Benign | 0.00 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| 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 | 0.547 | Likely Pathogenic | 0.3477 | 0.5423 | 3.34 | Destabilizing | 1.1 | 2.85 | Destabilizing | 3.10 | Destabilizing | 0.28 | Likely Benign | -7.98 | Deleterious | 0.994 | Probably Damaging | 0.758 | Possibly Damaging | 3.42 | Benign | 0.01 | Affected | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||
| 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 | 0.561 | Likely Pathogenic | 0.3686 | 0.5403 | 3.34 | Destabilizing | 1.0 | 4.07 | Destabilizing | 3.71 | Destabilizing | -0.30 | Likely Benign | -6.98 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||
| c.2051A>T | D684V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from 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 suggests a benign effect, and the lack of ClinVar annotation means there is no conflicting clinical classification. Therefore, 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 | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -16.128 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.601 | Likely Pathogenic | 0.0775 | 0.6209 | 3.86 | Destabilizing | 1.1 | 2.06 | Destabilizing | 2.96 | Destabilizing | 0.07 | Likely Benign | -8.98 | Deleterious | 0.901 | Possibly Damaging | 0.480 | Possibly Damaging | 3.44 | Benign | 0.00 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| c.2052C>A | D684E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D684E missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. In contrast, a majority of predictors (SGM‑Consensus, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; predictions from Rosetta and premPS are inconclusive and are treated as unavailable. 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 consensus of 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 | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -9.506 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | 0.1316 | 0.6187 | 2.88 | Destabilizing | 0.9 | 1.48 | Ambiguous | 2.18 | Destabilizing | 0.66 | Ambiguous | -3.99 | Deleterious | 0.910 | Possibly Damaging | 0.210 | Benign | 3.37 | Benign | 0.01 | Affected | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.2052C>G | D684E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684E is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of algorithms predict a deleterious effect: FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Two methods (Rosetta and premPS) returned uncertain results. High‑accuracy assessments further support a damaging 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) is pathogenic. Overall, the computational evidence overwhelmingly indicates that D684E 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 | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -9.506 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | 0.1316 | 0.6187 | 2.88 | Destabilizing | 0.9 | 1.48 | Ambiguous | 2.18 | Destabilizing | 0.66 | Ambiguous | -3.99 | Deleterious | 0.910 | Possibly Damaging | 0.210 | Benign | 3.37 | Benign | 0.01 | Affected | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.655T>A | C219S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from FoldX, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. With the majority of evidence pointing to a damaging effect and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -12.962 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.892 | Likely Pathogenic | 0.3568 | 0.1454 | 0.09 | Likely Benign | 0.4 | 1.53 | Ambiguous | 0.81 | Ambiguous | 1.56 | Destabilizing | -8.35 | Deleterious | 0.900 | Possibly Damaging | 0.380 | Benign | 5.95 | Benign | 0.04 | Affected | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.655T>C | C219R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, while the remaining 13 tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts Pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -15.727 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.904 | Likely Pathogenic | 0.1381 | 0.1837 | 3.00 | Destabilizing | 1.5 | 2.20 | Destabilizing | 2.60 | Destabilizing | 1.33 | Destabilizing | -9.90 | Deleterious | 0.969 | Probably Damaging | 0.680 | Possibly Damaging | 5.80 | Benign | 0.00 | Affected | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||
| c.655T>G | C219G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining 11 tools—including REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized returns a pathogenic score, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic effect for C219G. This conclusion aligns with the absence of a ClinVar entry and does not contradict any existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -15.072 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.900 | Likely Pathogenic | 0.2159 | 0.2169 | 0.72 | Ambiguous | 0.3 | 1.98 | Ambiguous | 1.35 | Ambiguous | 1.18 | Destabilizing | -10.09 | Deleterious | 0.900 | Possibly Damaging | 0.461 | Possibly Damaging | 5.83 | Benign | 0.02 | Affected | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||
| c.656G>A | C219Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, 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 or likely pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports 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 predicts pathogenicity. No predictions are inconclusive or missing. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. 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 | -14.797 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.812 | Likely Pathogenic | 0.0772 | 0.3285 | 8.98 | Destabilizing | 2.0 | 2.84 | Destabilizing | 5.91 | Destabilizing | 0.55 | Ambiguous | -9.09 | Deleterious | 0.990 | Probably Damaging | 0.758 | Possibly Damaging | 5.81 | Benign | 0.00 | Affected | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||
| c.656G>C | C219S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, polyPhen‑2 HumVar, and FATHMM, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta’s stability analysis is inconclusive (treated as unavailable). Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic impact for C219S. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -12.962 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.817 | Likely Pathogenic | 0.3568 | 0.1454 | 0.09 | Likely Benign | 0.4 | 1.53 | Ambiguous | 0.81 | Ambiguous | 1.56 | Destabilizing | -8.35 | Deleterious | 0.900 | Possibly Damaging | 0.380 | Benign | 5.95 | Benign | 0.04 | Affected | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.656G>T | C219F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219F is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are premPS and FATHMM, while the remaining 13 tools—including SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -14.322 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.814 | Likely Pathogenic | 0.0959 | 0.3804 | 7.31 | Destabilizing | 1.9 | 2.45 | Destabilizing | 4.88 | Destabilizing | 0.47 | Likely Benign | -9.18 | Deleterious | 0.940 | Possibly Damaging | 0.505 | Possibly Damaging | 5.82 | Benign | 0.00 | Affected | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||
| c.657T>G | C219W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219W is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and premPS are inconclusive. High‑accuracy methods give consistent pathogenic results: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -16.565 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.706 | Likely Pathogenic | 0.1131 | 0.3285 | 10.10 | Destabilizing | 3.6 | 1.20 | Ambiguous | 5.65 | Destabilizing | 0.52 | Ambiguous | -9.23 | Deleterious | 0.997 | Probably Damaging | 0.808 | Possibly Damaging | 5.77 | Benign | 0.00 | Affected | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||
| c.694G>A | A232T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232T is listed in ClinVar as Benign (ClinVar ID 1165963.0) and is present in gnomAD (ID 6‑33435545‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. Predictions that are inconclusive are premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Benign. Overall, the majority of evidence supports a benign impact, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | Benign | 1 | 6-33435545-G-A | 1 | 6.20e-7 | -7.655 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | 0.469 | Likely Benign | 0.1621 | 0.6488 | 0.47 | Likely Benign | 0.1 | -0.04 | Likely Benign | 0.22 | Likely Benign | 0.61 | Ambiguous | -1.42 | Neutral | 0.608 | Possibly Damaging | 0.240 | Benign | 5.80 | Benign | 0.09 | Tolerated | 3.40 | 14 | 1 | 0 | -2.5 | 30.03 | 210.8 | -42.0 | 0.5 | 0.1 | 0.4 | 0.5 | X | Uncertain | The hydroxyl group of Thr232, located at the end of an anti-parallel β sheet strand (res. Thr228-Ala232), forms hydrogen bonds with nearby residues Glu217, Cys233, and Cys219 in the variant simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and prevent it from unfolding. The new hydrogen bond interactions may be more favorable for structural stability than the steric interactions of the methyl side chain of Ala with the side chains of Gln216 and Cys219 in the WT. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||
| c.694G>C | A232P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, SIFT, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from Rosetta, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta remains uncertain. Overall, the majority of evaluated tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -12.697 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.748 | Likely Pathogenic | 0.2163 | 0.5259 | 0.05 | Likely Benign | 0.8 | 1.25 | Ambiguous | 0.65 | Ambiguous | 0.71 | Ambiguous | -2.75 | Deleterious | 0.917 | Possibly Damaging | 0.502 | Possibly Damaging | 5.78 | Benign | 0.06 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
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