SHANK3 (Q9BYB0) variants and mutations
SHANK3 (also known as Q9BYB0) is a human protein-coding gene encoding a SH3 and multiple ankyrin repeat domains protein 3 protein. At excitatory synapses, it organizes glutamate receptors, signaling proteins, and the actin cytoskeleton. Haploinsufficiency causes Phelan-McDermid syndrome and is strongly associated with intellectual disability, severe speech impairment, and autism-related features. This analysis covers 275 SHANK3 variants and mutations. Of these, 80% have computational variant effect predictions. Disease context includes Phelan-McDermid syndrome, Monosomy 22q13, and schizophrenia 15. Example SHANK3 variants include Q2S, Q2K, and Q2*.
Variant analysis overview
- Gene: SHANK3
- Protein: Q9BYB0
- UniProt accession: Q9BYB0
- Organism: Homo sapiens
- Variants analyzed: 275
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 112 unspecified-consequence records; 122 missense variants; 27 synonymous variants; 11 frameshift variants; 2 stop-gained variants; 1 substitution
- Prediction scores: 220 variants have prediction scores (80% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Phelan-McDermid syndrome, Monosomy 22q13, schizophrenia 15, hereditary disease, Intellectual disability, autism spectrum disorder, Neurodevelopmental delay, mathematical ability, neurodevelopmental disorder, schizophrenia, psychotic disorder, Neurodevelopmental abnormality.
Protein structure and variant hotspots
- Protein features: 3 domains; 31 post-translational modification sites.
- Structural context: 7 variants have structural context.
- PTM context: 2 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable SHANK3 variants
Examples include Q2S, Q2K, Q2*, Q2E, Q2L, Q2R, Q2Q, Q2H. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- Q2S (p.Gln2Ser), gnomAD 22-50674694-TG-T, CADD 23.20
- Q2K (p.Gln2Lys), gnomAD 22-50674696-C-A, REVEL 0.04, CADD 18.20
- Q2* (p.Gln2Ter), gnomAD 22-50674696-C-T, CADD 36.00
- Q2E (p.Gln2Glu), gnomAD 22-50674696-C-G, REVEL 0.04, CADD 21.70
- Q2L (p.Gln2Leu), gnomAD 22-50674697-A-T, REVEL 0.07, CADD 23.90
- Q2R (p.Gln2Arg), gnomAD 22-50674697-A-G, REVEL 0.05, CADD 23.60
- Q2Q (p.Gln2Gln), gnomAD 22-50674698-G-A, CADD 13.60
- Q2H (p.Gln2His), gnomAD 22-50674698-G-T, REVEL 0.08, CADD 23.10
- Q2P (p.Gln2Pro), gnomAD 22-50674700-A-C, REVEL 0.08, CADD 23.70
- S4A (p.Ser4Ala), gnomAD 22-50674659-CA-C, CADD 24.30
- S4C (p.Ser4Cys), rs2082904705, gnomAD 22-50674660-A-T, REVEL 0.07, CADD 24.40
- S4R (p.Ser4Arg), gnomAD 22-50674660-A-C, REVEL 0.05, CADD 23.00
- S4G (p.Ser4Gly), gnomAD 22-50674660-A-G, REVEL 0.01, CADD 22.50
- S4I (p.Ser4Ile), gnomAD 22-50674661-G-T, REVEL 0.04, CADD 23.10
- S4N (p.Ser4Asn), gnomAD 22-50674661-G-A, REVEL 0.06, CADD 15.10
- S4S (p.Ser4Ser), gnomAD 22-50674662-C-T, CADD 14.60
- R5S (p.Arg5Ser), gnomAD 22-50674675-C-A, REVEL 0.17, CADD 24.70
- R5C (p.Arg5Cys), rs1336089966, gnomAD 22-50674675-C-T, REVEL 0.14, AlphaMissense 0.98
- R5G (p.Arg5Gly), gnomAD 22-50674675-C-G, REVEL 0.15, CADD 23.70
- R5H (p.Arg5His), gnomAD 22-50674676-G-A, REVEL 0.19, CADD 26.00
- R5L (p.Arg5Leu), gnomAD 22-50674676-G-T, REVEL 0.19, CADD 25.50
- R5R (p.Arg5Arg), gnomAD 22-50674677-C-A, CADD 14.50
- A6P (p.Ala6Pro), rs1373216541, gnomAD 22-50674649-GC-G, CADD 24.40
- A6T (p.Ala6Thr), rs753176574, gnomAD 22-50674657-G-A, REVEL 0.04, CADD 17.90
- A6S (p.Ala6Ser), gnomAD 22-50674657-G-T, REVEL 0.02, CADD 15.90
- A6D (p.Ala6Asp), gnomAD 22-50674658-C-A, REVEL 0.03, CADD 20.60
- A6G (p.Ala6Gly), gnomAD 22-50674658-C-G, REVEL 0.03, CADD 17.10
- A6V (p.Ala6Val), gnomAD 22-50674658-C-T, REVEL 0.05, CADD 19.70
- A6A (p.Ala6Ala), gnomAD 22-50674659-C-A, CADD 14.70
- A8S (p.Ala8Ser), gnomAD 22-50674663-G-T, REVEL 0.01, CADD 16.50
- A8T (p.Ala8Thr), gnomAD 22-50674663-G-A, REVEL 0.02, CADD 15.50
- A8P (p.Ala8Pro), rs2082904718, gnomAD 22-50674663-G-C, REVEL 0.11, CADD 24.70
- A8D (p.Ala8Asp), gnomAD 22-50674664-C-A, REVEL 0.13, CADD 23.80
- A8V (p.Ala8Val), gnomAD 22-50674664-C-T, REVEL 0.04, CADD 22.50
- A8A (p.Ala8Ala), gnomAD 22-50674665-C-T, CADD 13.80
- P14S (p.Pro14Ser), gnomAD 22-50674651-C-T, REVEL 0.03, CADD 16.20
- P14T (p.Pro14Thr), gnomAD 22-50674651-C-A, REVEL 0.05, CADD 15.40
- P14A (p.Pro14Ala), gnomAD 22-50674651-C-G, REVEL 0.05, CADD 17.10
- P14R (p.Pro14Arg), rs2146765578, gnomAD 22-50674652-C-G, REVEL 0.04, CADD 23.20
- P14L (p.Pro14Leu), gnomAD 22-50674652-C-T, REVEL 0.05, CADD 21.20
- P14H (p.Pro14His), gnomAD 22-50674652-C-A, REVEL 0.06, CADD 24.50
- P14P (p.Pro14Pro), rs1462166031, gnomAD 22-50674653-C-G, CADD 14.90
- P17R (p.Pro17Arg), gnomAD 22-50674685-TC-T, CADD 25.20
- P17A (p.Pro17Ala), gnomAD 22-50674687-C-G, REVEL 0.08, CADD 23.50
- P17S (p.Pro17Ser), gnomAD 22-50674687-C-T, REVEL 0.09, CADD 22.80
- P17T (p.Pro17Thr), gnomAD 22-50674687-C-A, REVEL 0.09, CADD 23.60
- P17L (p.Pro17Leu), gnomAD 22-50674688-C-T, REVEL 0.12, CADD 24.50
- P17Q (p.Pro17Gln), gnomAD 22-50674688-C-A, REVEL 0.12, CADD 23.00
- P17P (p.Pro17Pro), gnomAD 22-50674689-G-T, CADD 15.70
- L21C (p.Leu21Cys), gnomAD 22-50674691-AC-A, CADD 24.10
- L21M (p.Leu21Met), gnomAD 22-50674693-C-A, REVEL 0.07, CADD 23.70
- L21L (p.Leu21Leu), rs1270970104, gnomAD 22-50674693-C-T, CADD 14.30
- L21P (p.Leu21Pro), rs2082904892, gnomAD 22-50674694-T-C, REVEL 0.19, CADD 28.30
- L21Q (p.Leu21Gln), gnomAD 22-50674694-T-A, REVEL 0.12, CADD 26.50
- L21R (p.Leu21Arg), gnomAD 22-50674694-T-G, REVEL 0.15, CADD 26.80
- L21V (p.Leu21Val), gnomAD 22-50675054-C-G, REVEL 0.05, CADD 22.80
- A30R (p.Ala30Arg), gnomAD 22-50675071-CG-C, CADD 32.00
- A30T (p.Ala30Thr), gnomAD 22-50675072-G-A, REVEL 0.19, CADD 24.80
- A30S (p.Ala30Ser), gnomAD 22-50675072-G-T, REVEL 0.09, CADD 23.30
- A30E (p.Ala30Glu), gnomAD 22-50675073-C-A, REVEL 0.20, CADD 25.80
- A30V (p.Ala30Val), rs2082908870, gnomAD 22-50675073-C-T, REVEL 0.11, CADD 23.70
- A30A (p.Ala30Ala), rs368658976, gnomAD 22-50675074-G-A, CADD 14.40
- A30D (p.Ala30Asp), gnomAD 22-50675085-C-A, REVEL 0.13, CADD 22.20
- A30G (p.Ala30Gly), rs1008917035, gnomAD 22-50675085-C-G, REVEL 0.02, CADD 22.30
- P31T (p.Pro31Thr), gnomAD 22-50675075-C-A, REVEL 0.07, CADD 17.00
- P31S (p.Pro31Ser), gnomAD 22-50675075-C-T, REVEL 0.05, CADD 22.60
- P31H (p.Pro31His), gnomAD 22-50675076-C-A, REVEL 0.10, CADD 26.10
- P31R (p.Pro31Arg), gnomAD 22-50675076-C-G, REVEL 0.14, CADD 26.20
- P31L (p.Pro31Leu), gnomAD 22-50675076-C-T, REVEL 0.11, CADD 26.40
- P31P (p.Pro31Pro), rs891780204, gnomAD 22-50675077-C-G, CADD 13.40
- G33S (p.Gly33Ser), rs1206111283, gnomAD 22-50674648-G-A, REVEL 0.10, CADD 21.60
- G33C (p.Gly33Cys), gnomAD 22-50674648-G-T, REVEL 0.09, CADD 25.30
- G33R (p.Gly33Arg), gnomAD 22-50674648-G-C, REVEL 0.06, CADD 24.40
- G33A (p.Gly33Ala), gnomAD 22-50674649-G-C, REVEL 0.08, CADD 22.90
- G33V (p.Gly33Val), gnomAD 22-50674649-G-T, REVEL 0.08, CADD 23.30
- G33D (p.Gly33Asp), gnomAD 22-50674649-G-A, REVEL 0.07, CADD 17.30
- G33G (p.Gly33Gly), gnomAD 22-50674650-C-A, CADD 14.70
- G33W (p.Gly33Trp), gnomAD 22-50674653-C-CT, CADD 25.90
- G33E (p.Gly33Glu), gnomAD 22-50674655-G-A, REVEL 0.04, CADD 14.90
- L35F (p.Leu35Phe), gnomAD 22-50675102-C-T, REVEL 0.13, CADD 27.70
- L35I (p.Leu35Ile), gnomAD 22-50675102-C-A, REVEL 0.06, CADD 24.20
- L35P (p.Leu35Pro), gnomAD 22-50675103-T-C, REVEL 0.43, CADD 32.00
- L35H (p.Leu35His), gnomAD 22-50675103-T-A, REVEL 0.18, CADD 31.00
- L35L (p.Leu35Leu), gnomAD 22-50675104-C-G, CADD 9.73
- R37C (p.Arg37Cys), gnomAD 22-50675057-C-T, REVEL 0.27, CADD 32.00
- R37S (p.Arg37Ser), gnomAD 22-50675057-C-A, REVEL 0.23, CADD 28.60
- R37H (p.Arg37His), gnomAD 22-50675058-G-A, REVEL 0.19, CADD 32.00
- R37L (p.Arg37Leu), rs1306021312, gnomAD 22-50675058-G-T, REVEL 0.20, CADD 32.00
- R37R (p.Arg37Arg), gnomAD 22-50675059-C-A, CADD 14.70
- R37G (p.Arg37Gly), gnomAD 22-50675096-C-G, REVEL 0.21, CADD 29.10
- S38G (p.Ser38Gly), gnomAD 22-50675120-A-G, REVEL 0.09, CADD 24.80
- S38T (p.Ser38Thr), gnomAD 22-50675121-G-C, REVEL 0.15, CADD 26.80
- S38N (p.Ser38Asn), gnomAD 22-50675121-G-A, REVEL 0.13, CADD 27.40
- S38I (p.Ser38Ile), gnomAD 22-50675121-G-T, REVEL 0.18, CADD 29.60
- S38R (p.Ser38Arg), gnomAD 22-50675122-C-A, REVEL 0.15, CADD 24.80
- S38S (p.Ser38Ser), rs1339959251, gnomAD 22-50675122-C-T, CADD 15.00
- A39S (p.Ala39Ser), gnomAD 22-50675087-G-T, REVEL 0.06, CADD 20.50
- A39T (p.Ala39Thr), gnomAD 22-50675087-G-A, REVEL 0.07, CADD 25.00
- A39D (p.Ala39Asp), gnomAD 22-50675088-C-A, REVEL 0.12, CADD 26.90
- A39V (p.Ala39Val), gnomAD 22-50675088-C-T, REVEL 0.06, CADD 24.30
- A39A (p.Ala39Ala), rs769450356, gnomAD 22-50675089-C-T, CADD 17.20
- D41H (p.Asp41His), gnomAD 22-50674645-G-C, REVEL 0.10, CADD 25.80
- D41Y (p.Asp41Tyr), gnomAD 22-50674645-G-T, REVEL 0.10, CADD 26.30
- D41N (p.Asp41Asn), gnomAD 22-50674645-G-A, REVEL 0.08, CADD 25.70
- D41V (p.Asp41Val), gnomAD 22-50674646-A-T, REVEL 0.09, CADD 26.10
- D41G (p.Asp41Gly), gnomAD 22-50674646-A-G, REVEL 0.06, CADD 27.70
- D41D (p.Asp41Asp), gnomAD 22-50674647-C-T, CADD 14.60
- D41E (p.Asp41Glu), gnomAD 22-50674647-C-A, REVEL 0.04, CADD 17.40
- D41T (p.Asp41Thr), gnomAD 22-50674688-CG-C, CADD 24.90
- A43S (p.Ala43Ser), gnomAD 22-50675108-G-T, REVEL 0.03, CADD 21.70
- A43T (p.Ala43Thr), gnomAD 22-50675108-G-A, REVEL 0.03, CADD 20.60
- A43D (p.Ala43Asp), gnomAD 22-50675109-C-A, REVEL 0.20, CADD 25.00
- A43V (p.Ala43Val), rs1461739965, gnomAD 22-50675109-C-T, REVEL 0.05, CADD 24.90
- A43G (p.Ala43Gly), gnomAD 22-50675109-C-G, REVEL 0.05, CADD 24.50
- A43A (p.Ala43Ala), gnomAD 22-50675110-C-A, CADD 14.40
- K48* (p.Lys48Ter), gnomAD 22-50675048-A-T, CADD 43.00
- K48R (p.Lys48Arg), gnomAD 22-50675049-A-G, REVEL 0.14, CADD 24.00
- K48N (p.Lys48Asn), gnomAD 22-50675050-G-T, REVEL 0.14, CADD 29.20
- K48E (p.Lys48Glu), gnomAD 22-50675090-A-G, REVEL 0.20, CADD 29.70
- K48M (p.Lys48Met), gnomAD 22-50675091-A-T, REVEL 0.18, CADD 28.50
- K48K (p.Lys48Lys), rs1373216249, gnomAD 22-50675092-G-A, CADD 15.60
- G52E (p.Gly52Glu), rs2518367780, ClinGen CA2580099938, ClinVar RCV003140535, Uncertain significance, Phelan-McDermid syndrome
- G52W (p.Gly52Trp), rs1259405399, gnomAD 22-50675144-G-T, REVEL 0.43, CADD 30.00
- G52G (p.Gly52Gly), rs1224305567, gnomAD 22-50675146-G-A, CADD 14.80
- R54G (p.Arg54Gly), gnomAD 22-50675162-TC-T, CADD 25.40
- R54W (p.Arg54Trp), gnomAD 22-50675165-C-T, REVEL 0.15, CADD 25.10
- R54R (p.Arg54Arg), gnomAD 22-50675165-C-A, CADD 12.90
- R54L (p.Arg54Leu), gnomAD 22-50675166-G-T, REVEL 0.12, CADD 23.00
- R54P (p.Arg54Pro), gnomAD 22-50675166-G-C, REVEL 0.21, CADD 23.00
- R54Q (p.Arg54Gln), rs566328506, gnomAD 22-50675166-G-A, REVEL 0.09, CADD 23.00
- R54S (p.Arg54Ser), gnomAD 22-50675171-C-A, REVEL 0.15, CADD 24.10
- R54C (p.Arg54Cys), rs2082909851, gnomAD 22-50675171-C-T, REVEL 0.16, CADD 23.70
- S57P (p.Ser57Pro), gnomAD 22-50675158-GC-G, CADD 27.00
- S57Y (p.Ser57Tyr), gnomAD 22-50675163-C-A, REVEL 0.17, CADD 18.40
- S57F (p.Ser57Phe), rs1422757115, gnomAD 22-50675163-C-T, REVEL 0.18, CADD 20.00
- S57S (p.Ser57Ser), rs753123008, gnomAD 22-50675164-C-T, CADD 11.80
- P58S (p.Pro58Ser), gnomAD 22-50675156-C-T, REVEL 0.18, CADD 24.40
- P58T (p.Pro58Thr), gnomAD 22-50675156-C-A, REVEL 0.20, CADD 24.10
- P58Q (p.Pro58Gln), gnomAD 22-50675157-C-A, REVEL 0.24, CADD 26.50
- P58L (p.Pro58Leu), rs759046926, gnomAD 22-50675157-C-T, REVEL 0.29, CADD 27.20
- P58P (p.Pro58Pro), rs768113393, gnomAD 22-50675158-G-A, CADD 12.80
- P58A (p.Pro58Ala), rs1360167928, gnomAD 22-50675159-C-G, REVEL 0.14, CADD 16.90
- P58H (p.Pro58His), gnomAD 22-50675160-C-A, REVEL 0.21, CADD 26.40
- F62Y (p.Phe62Tyr), gnomAD 22-50675151-T-A, REVEL 0.08, CADD 24.50
- F62S (p.Phe62Ser), rs2082909615, gnomAD 22-50675151-T-C, REVEL 0.27, CADD 30.00
- F62F (p.Phe62Phe), gnomAD 22-50675152-C-T, CADD 13.80
- G64A (p.Gly64Ala), gnomAD 22-50675165-CG-C, CADD 24.30
- G64S (p.Gly64Ser), gnomAD 22-50675168-G-A, REVEL 0.23, CADD 27.60
- G64G (p.Gly64Gly), gnomAD 22-50675170-C-T, CADD 13.00
- G64C (p.Gly64Cys), rs1455489739, gnomAD 22-50675177-G-T, REVEL 0.15, CADD 29.20
- G64D (p.Gly64Asp), gnomAD 22-50675178-G-A, REVEL 0.19, CADD 26.80
- A65P (p.Ala65Pro), gnomAD 22-50675174-G-C, REVEL 0.27, CADD 23.80
- A65T (p.Ala65Thr), rs2082909895, gnomAD 22-50675174-G-A, REVEL 0.17, CADD 22.40
- A65D (p.Ala65Asp), gnomAD 22-50675175-C-A, REVEL 0.09, CADD 14.50
- A65A (p.Ala65Ala), rs992533369, gnomAD 22-50675176-C-G, CADD 9.88
- V84L (p.Val84Leu), rs762621811, gnomAD 22-50675099-G-C, REVEL 0.08, CADD 23.60
- V84M (p.Val84Met), rs762621811, gnomAD 22-50675099-G-A, REVEL 0.08, CADD 26.60
- V84E (p.Val84Glu), gnomAD 22-50675100-T-A, REVEL 0.19, CADD 28.70
- V84V (p.Val84Val), gnomAD 22-50675101-G-T, CADD 14.80
- R87C (p.Arg87Cys), rs1336089966, UniProt VAR 032804, gnomAD rs1336089966, AlphaMissense 0.98, MetaLR 0.12, Uncertain significance
- Q94E (p.Gln94Glu), gnomAD 22-50675153-C-G, REVEL 0.13, CADD 25.10
- Q94R (p.Gln94Arg), gnomAD 22-50675154-A-G, REVEL 0.13, CADD 25.50
- Q94H (p.Gln94His), gnomAD 22-50675155-G-T, REVEL 0.18, CADD 26.20
- Q94Q (p.Gln94Gln), rs773912444, gnomAD 22-50675155-G-A, CADD 13.40
- Q112P (p.Gln112Pro), rs2518368954, ClinGen CA515251126, ClinVar RCV003154090, Likely benign, Phelan-McDermid syndrome
- N119S (p.Asn119Ser), rs2518369006, ClinGen CA515251186, ClinVar RCV003322960, Uncertain significance, not provided
- G137R (p.Gly137Arg), rs2518369112, ClinGen CA515251337, ClinVar RCV002305965, Uncertain significance, not provided
- K168R (p.Lys168Arg), rs2518371253, ClinGen CA515251914, ClinVar RCV004539004, Likely pathogenic, SHANK3-related disorder
- R170Q (p.Arg170Gln), rs976030758, []
- V171L (p.Val171Leu), rs777686693, ClinGen CA515251934, ClinVar RCV002306173, AlphaMissense 0.12, MetaLR 0.06, Uncertain significance, not provided
- N175K (p.Asn175Lys), rs1253839794, ClinGen CA515251973, ClinVar RCV004539016, REVEL 0.36, MetaLR 0.22, Uncertain significance, SHANK3-related disorder
- K192R (p.Lys192Arg), rs2518373750, ClinGen CA515252479, ClinVar RCV003136673, Uncertain significance, Phelan-McDermid syndrome
- P216A (p.Pro216Ala), rs397514705, ClinGen CA263235, ClinVar RCV000043655, ClinVar RCV001804766, AlphaMissense 0.85, MetaLR 0.40, Likely pathogenic, not provided
- C226Y (p.Cys226Tyr), rs767264001, ClinGen CA515253072, ClinVar RCV003129364, AlphaMissense 0.90, MetaLR 0.16, Uncertain significance, not provided
- A261T (p.Ala261Thr), rs2518374445, ClinGen CA515253574, ClinVar RCV003148391, Uncertain significance, Phelan-McDermid syndrome
- A273G (p.Ala273Gly), rs1232069989, UniProt VAR 032805, 1000Genomes rs1232069989, TOPMed rs1232069989, AlphaMissense 0.21, MetaLR 0.16
- A299T (p.Ala299Thr), rs766856815, ClinGen CA10325299, cosmic curated COSV99436, ClinVar RCV002367200, AlphaMissense 0.17, MetaLR 0.43, Uncertain significance, Inborn genetic diseases
- I320T (p.Ile320Thr), rs9616915, ClinGen CA10325308, cosmic curated COSV53184, ClinVar RCV000454654, AlphaMissense 0.05, MetaLR 0.00, Benign, Inborn genetic diseases; not specified; not provided
- G325V (p.Gly325Val), rs747755749, ClinGen CA515254128, ClinVar RCV002290387, AlphaMissense 0.97, MetaLR 0.45, Uncertain significance, Phelan-McDermid syndrome
- Q331E (p.Gln331Glu), rs2518375186, ClinGen CA515254176, ClinVar RCV002396476, ClinVar RCV004785633, Uncertain significance, not provided; Inborn genetic diseases
Public SHANK3 analysis runs
- SHANK3 analysis run — SHANK3 (275 variants) — completed 2026-08-19