AKT1 (P31749) variants and mutations
AKT1 (also known as P31749) is a human protein-coding gene encoding a RAC-alpha serine/threonine-protein kinase protein. It integrates PI3K-dependent growth-factor signals to promote cell survival, proliferation, glucose metabolism, and protein synthesis. Somatic activating variants occur in multiple cancers, while mosaic activation, especially E17K, causes Proteus syndrome. This analysis covers 1,384 AKT1 variants and mutations. Of these, 37% have computational variant effect predictions. Disease context includes Proteus syndrome, cancer, and Cowden syndrome 6. Example AKT1 variants include S2C, S2G, and S2N.
Variant analysis overview
- Gene: AKT1
- Protein: P31749
- UniProt accession: P31749
- Organism: Homo sapiens
- Variants analyzed: 1384
- Variant scope: all variants
- Completed: 2026-08-21
Variant and mutation evidence
- Variant composition: 1,282 unspecified-consequence records; 5 frameshift variants; 4 stop lost; 1 stop retained variant; 39 synonymous variants; 47 missense variants; 3 splice-region variants; 4 in-frame deletions; 3 stop-gained variants; 3 substitution
- Prediction scores: 517 variants have prediction scores (37% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Proteus syndrome, cancer, Cowden syndrome 6, breast cancer, breast adenocarcinoma, breast carcinoma, colorectal adenocarcinoma, ovarian carcinoma, meningioma, neoplasm, neurodegenerative disease, endometrial cancer.
Protein structure and variant hotspots
- Protein features: 3 domains; 6 binding sites; 18 post-translational modification sites.
- Structural context: 1,280 variants have structural context.
- PTM context: 37 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable AKT1 variants
Examples include S2C, S2G, S2N, S2R, D3N, D3Y, V4G, V4L. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- S2C (p.Ser2Cys), Ensembl rs1566826869, Uncertain significance
- S2G (p.Ser2Gly), rs1566826869, ClinGen CA391223990, ClinVar RCV000688933, Ensembl rs1566826869, AlphaMissense 0.07, MetaLR 0.21, Uncertain significance, Cowden syndrome 6
- S2N (p.Ser2Asn), Ensembl rs1893686640, CADD 0.30, PolyPhen-2 0.00
- S2R (p.Ser2Arg), ESP rs371534192, ExAC rs371534192, TOPMed rs371534192, gnomAD rs371534192, CADD 17.00, PolyPhen-2 0.10, Likely benign
- D3N (p.Asp3Asn), rs140532443, ClinGen CA7374951, cosmic curated COSV62577, ClinVar RCV000461062, CADD 22.80, PolyPhen-2 0.00, Uncertain significance, Cowden syndrome 6
- D3Y (p.Asp3Tyr), cosmic curated COSV62571
- V4G (p.Val4Gly), cosmic curated COSV62573
- V4L (p.Val4Leu), NCI-TCGA Cosmic COSV6257, cosmic curated COSV62574, ExAC rs754031503, TOPMed rs754031503, CADD 22.40, PolyPhen-2 0.00, Uncertain significance
- V4M (p.Val4Met), rs754031503, ClinGen CA7374949, ClinVar RCV000472618, ExAC rs754031503, CADD 22.70, PolyPhen-2 0.01, Uncertain significance, Cowden syndrome 6
- A5G (p.Ala5Gly), gnomAD rs1338237897, CADD 22.80, PolyPhen-2 0.01
- A5T (p.Ala5Thr), ExAC rs766546254, gnomAD rs766546254, CADD 18.80, PolyPhen-2 0.00
- A5V (p.Ala5Val), gnomAD rs1338237897
- I6T (p.Ile6Thr), rs1404637346, ClinGen CA391223931, ClinVar RCV002908309, gnomAD rs1404637346, CADD 23.70, PolyPhen-2 0.04, Uncertain significance, Cowden syndrome 6
- I6V (p.Ile6Val), rs1893685625, ClinGen CA391223937, ClinVar RCV001306742, Ensembl rs1893685625, CADD 11.90, PolyPhen-2 0.00, Uncertain significance, Cowden syndrome 6
- K8R (p.Lys8Arg), gnomAD rs1173631887, CADD 24.10, PolyPhen-2 0.25
- E9D (p.Glu9Asp), gnomAD rs1471154736, Likely benign
- W11* (p.Trp11Ter), ExAC rs760853972, gnomAD rs760853972, CADD 39.00
- W11C (p.Trp11Cys), cosmic curated COSV62572
- H13Q (p.His13Gln), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- H13Y (p.His13Tyr), rs1235749501, ClinGen CA391223843, ClinVar RCV002363954, TOPMed rs1235749501, CADD 21.20, PolyPhen-2 0.16, Uncertain significance, Inborn genetic diseases
- K14I (p.Lys14Ile), cosmic curated COSV62572
- K14N (p.Lys14Asn), cosmic curated COSV62572
- R15Q (p.Arg15Gln), rs368797346, cosmic curated COSV62572, ESP rs368797346, ExAC rs368797346, AlphaMissense 0.96, MetaLR 0.19, Variant assessed as somatic; moderate impact.
- G16=, NCI-TCGA Cosmic COSV1008, Variant assessed as somatic; low impact.
- G16E (p.Gly16Glu), cosmic curated COSV62573
- E17* (p.Glu17Ter), cosmic curated COSV62576, ExAC rs121434592, gnomAD rs121434592, Pathogenic, in PROTEUSS and breast cancer
- E17D (p.Glu17Asp), ExAC rs779114873, gnomAD rs779114873
- E17G (p.Glu17Gly), Ensembl rs2140950016
- E17K (p.Glu17Lys), rs121434592, cosmic curated COSV10466, ClinGen CA123660, NCI-TCGA Cosmic COSV6257, AlphaMissense 1.00, MetaLR 0.22, Pathogenic, not provided; Cowden syndrome 6; Proteus syndrome
- E17Q (p.Glu17Gln), ExAC rs121434592, gnomAD rs121434592, Pathogenic, in PROTEUSS and breast cancer
- E17R (p.Glu17Arg), rs1595251483, ClinGen CA915946437, ClinVar RCV000984546, Ensembl rs1595251483, Pathogenic, Proteus syndrome
- E17V (p.Glu17Val), Ensembl rs2140950016
- Y18* (p.Tyr18Ter), gnomAD rs1317567840, Likely benign
- Y18C (p.Tyr18Cys), Ensembl rs2140949969
- Y18D (p.Tyr18Asp), Ensembl rs2140949989
- Y18F (p.Tyr18Phe), Ensembl rs2140949969
- Y18H (p.Tyr18His), Ensembl rs2140949989
- Y18N (p.Tyr18Asn), Ensembl rs2140949989
- Y18S (p.Tyr18Ser), Ensembl rs2140949969
- I19F (p.Ile19Phe), Ensembl rs2140949945
- I19L (p.Ile19Leu), cosmic curated COSV10527, CADD 28.30, PolyPhen-2 1.00
- I19M (p.Ile19Met), cosmic curated COSV62572, Ensembl rs2140949920
- I19N (p.Ile19Asn), Ensembl rs2140949932
- I19S (p.Ile19Ser), Ensembl rs2140949932
- I19T (p.Ile19Thr), Ensembl rs2140949932
- I19V (p.Ile19Val), rs2140949945, ClinGen CA391221838, ClinVar RCV003540323, AlphaMissense 0.95, MetaLR 0.28, Uncertain significance, Cowden syndrome 6; Inborn genetic diseases
- K20* (p.Lys20Ter), gnomAD rs1380514442
- K20E (p.Lys20Glu), gnomAD rs1380514442, CADD 29.70, PolyPhen-2 0.94
- K20M (p.Lys20Met), Ensembl rs2140949902
- K20N (p.Lys20Asn), gnomAD rs1367344673, Uncertain significance, Inborn genetic diseases
- K20R (p.Lys20Arg), Ensembl rs2140949902
- T21A (p.Thr21Ala), cosmic curated COSV62571, Ensembl rs2140949876
- T21I (p.Thr21Ile), cosmic curated COSV62571, Ensembl rs1892954980
- T21P (p.Thr21Pro), Ensembl rs2140949876
- T21S (p.Thr21Ser), Ensembl rs1892954980
- W22* (p.Trp22Ter), cosmic curated COSV62575, CADD 47.00
- W22R (p.Trp22Arg), Ensembl rs2140949839, cosmic curated COSV62574
- R23L (p.Arg23Leu), cosmic curated COSV10083
- R23P (p.Arg23Pro), Ensembl rs1892954317, Uncertain significance
- R23Q (p.Arg23Gln), rs1892954317, ClinGen CA391221777, cosmic curated COSV62573, ClinVar RCV001294691, CADD 27.10, PolyPhen-2 1.00, Uncertain significance, not provided; Cowden syndrome 6
- R23W (p.Arg23Trp), cosmic curated COSV10744, gnomAD rs1892954511, Likely benign
- P24A (p.Pro24Ala), Ensembl rs2140949768
- P24L (p.Pro24Leu), cosmic curated COSV62575, Ensembl rs2140949758, CADD 29.00, PolyPhen-2 0.98
- P24R (p.Pro24Arg), Ensembl rs2140949758
- P24S (p.Pro24Ser), cosmic curated COSV62576, Ensembl rs2140949768
- P24T (p.Pro24Thr), Ensembl rs2140949768
- R25C (p.Arg25Cys), rs397514644, ClinGen CA130749, cosmic curated COSV62575, ClinVar RCV000033177, CADD 26.20, PolyPhen-2 1.00, Pathogenic, Cowden syndrome 6
- R25G (p.Arg25Gly), TOPMed rs397514644, gnomAD rs397514644, Pathogenic, in CWS6
- R25H (p.Arg25His), rs1184173073, cosmic curated COSV10527, TOPMed rs1184173073, CADD 26.80, PolyPhen-2 0.99, Variant assessed as somatic; moderate impact., in CWS6
- R25L (p.Arg25Leu), TOPMed rs1184173073
- R25P (p.Arg25Pro), TOPMed rs1184173073
- R25S (p.Arg25Ser), TOPMed rs397514644, gnomAD rs397514644, Pathogenic, in CWS6
- Y26* (p.Tyr26Ter), ExAC rs769253794, gnomAD rs769253794, Likely benign
- Y26C (p.Tyr26Cys), Ensembl rs2140949661
- Y26F (p.Tyr26Phe), Ensembl rs2140949661
- Y26H (p.Tyr26His), Ensembl rs2140949680
- Y26N (p.Tyr26Asn), Ensembl rs2140949680
- Y26S (p.Tyr26Ser), Ensembl rs2140949661
- F27I (p.Phe27Ile), Ensembl rs2140949635
- F27L (p.Phe27Leu), Ensembl rs2140949635, Likely benign
- F27S (p.Phe27Ser), rs2140949629, ClinGen CA391221725, ClinVar RCV002419489, AlphaMissense 0.96, MetaLR 0.76, Uncertain significance, Inborn genetic diseases
- F27Y (p.Phe27Tyr), Ensembl rs2140949629
- L28F (p.Leu28Phe), TOPMed rs990046031
- L28H (p.Leu28His), Ensembl rs2140949598
- L28P (p.Leu28Pro), Ensembl rs2140949598
- L28V (p.Leu28Val), cosmic curated COSV62575
- L29F (p.Leu29Phe), cosmic curated COSV10466, Ensembl rs2140949569
- L29H (p.Leu29His), cosmic curated COSV10527
- L29I (p.Leu29Ile), Ensembl rs2140949569
- L29V (p.Leu29Val), Ensembl rs2140949569
- K30M (p.Lys30Met), Ensembl rs2140949553
- K30N (p.Lys30Asn), cosmic curated COSV10083
- N31D (p.Asn31Asp), Ensembl rs2140949542
- N31I (p.Asn31Ile), ExAC rs780173607, TOPMed rs780173607, gnomAD rs780173607, Uncertain significance
- N31K (p.Asn31Lys), Ensembl rs2140949519
- N31S (p.Asn31Ser), rs780173607, ClinGen CA7374908, ClinVar RCV002637370, ExAC rs780173607, CADD 5.65, PolyPhen-2 0.00, Uncertain significance, Cowden syndrome 6
- N31Y (p.Asn31Tyr), Ensembl rs2140949542
- D32E (p.Asp32Glu), 1000Genomes rs201636005, ExAC rs201636005, gnomAD rs201636005, Likely benign
- D32G (p.Asp32Gly), Ensembl rs2140949495
- D32H (p.Asp32His), Ensembl rs2140949504
- D32N (p.Asp32Asn), cosmic curated COSV62575, Ensembl rs2140949504
- D32V (p.Asp32Val), Ensembl rs2140949495
- G33A (p.Gly33Ala), Ensembl rs2140949446
- G33C (p.Gly33Cys), Ensembl rs2140949468
- G33D (p.Gly33Asp), NCI-TCGA Cosmic COSV6257, cosmic curated COSV62572, Ensembl rs2140949446, Variant assessed as somatic; moderate impact.
- G33R (p.Gly33Arg), Ensembl rs2140949468
- G33S (p.Gly33Ser), Ensembl rs2140949468
- G33V (p.Gly33Val), Ensembl rs2140949446
- T34A (p.Thr34Ala), cosmic curated COSV10527, Ensembl rs2140949420
- T34I (p.Thr34Ile), ExAC rs750653493, TOPMed rs750653493, gnomAD rs750653493, Uncertain significance
- T34N (p.Thr34Asn), rs750653493, ClinGen CA7374906, ClinVar RCV001060365, ExAC rs750653493, CADD 22.70, PolyPhen-2 0.06, Uncertain significance, Cowden syndrome 6
- T34P (p.Thr34Pro), Ensembl rs2140949420
- T34S (p.Thr34Ser), ExAC rs750653493, TOPMed rs750653493, gnomAD rs750653493, Uncertain significance
- F35I (p.Phe35Ile), cosmic curated COSV62574, Ensembl rs2140949369
- F35L (p.Phe35Leu), Ensembl rs2140949354
- F35S (p.Phe35Ser), Ensembl rs2140949360
- F35Y (p.Phe35Tyr), Ensembl rs2140949360
- I36F (p.Ile36Phe), rs781339141, ClinGen CA391221610, ClinVar RCV002410959, ExAC rs781339141, AlphaMissense 0.09, MetaLR 0.11, Uncertain significance, Inborn genetic diseases
- I36L (p.Ile36Leu), ExAC rs781339141, gnomAD rs781339141, Uncertain significance
- I36N (p.Ile36Asn), ExAC rs758157217, TOPMed rs758157217, gnomAD rs758157217, CADD 20.80, PolyPhen-2 0.41, Uncertain significance
- I36S (p.Ile36Ser), ExAC rs758157217, TOPMed rs758157217, gnomAD rs758157217, Uncertain significance
- I36T (p.Ile36Thr), rs758157217, ClinGen CA7374904, ClinVar RCV000686512, ExAC rs758157217, CADD 22.70, PolyPhen-2 0.83, Uncertain significance, Cowden syndrome 6
- I36V (p.Ile36Val), rs781339141, ClinGen CA7374905, ClinVar RCV000465998, ExAC rs781339141, AlphaMissense 0.09, MetaLR 0.11, Uncertain significance, Cowden syndrome 6
- G37A (p.Gly37Ala), Ensembl rs2140949285
- G37C (p.Gly37Cys), Ensembl rs2140949303
- G37D (p.Gly37Asp), cosmic curated COSV62571, Ensembl rs2140949285
- G37R (p.Gly37Arg), Ensembl rs2140949303
- G37S (p.Gly37Ser), Ensembl rs2140949303
- G37V (p.Gly37Val), Ensembl rs2140949285
- Y38* (p.Tyr38Ter), ExAC rs752588225, gnomAD rs752588225, Likely benign
- Y38C (p.Tyr38Cys), Ensembl rs2140949260
- Y38F (p.Tyr38Phe), Ensembl rs2140949260
- Y38H (p.Tyr38His), gnomAD rs1223729648
- Y38N (p.Tyr38Asn), gnomAD rs1223729648
- Y38S (p.Tyr38Ser), Ensembl rs2140949260
- K39* (p.Lys39Ter), ExAC rs764931115, gnomAD rs764931115
- K39E (p.Lys39Glu), ExAC rs764931115, gnomAD rs764931115
- K39M (p.Lys39Met), Ensembl rs2140949222
- K39N (p.Lys39Asn), Ensembl rs1595251382, Uncertain significance
- K39R (p.Lys39Arg), Ensembl rs2140949222
- E40D (p.Glu40Asp), ESP rs370287382, ExAC rs370287382, TOPMed rs370287382, gnomAD rs370287382, Likely benign
- E40G (p.Glu40Gly), cosmic curated COSV10744, Ensembl rs2140949199, Uncertain significance, Inborn genetic diseases
- E40K (p.Glu40Lys), NCI-TCGA Cosmic COSV6257, cosmic curated COSV62573, Variant assessed as somatic; moderate impact.
- E40V (p.Glu40Val), rs2140949199, ClinGen CA391221563, ClinVar RCV003344154, Ensembl rs2140949199, AlphaMissense 0.61, MetaLR 0.20, Uncertain significance, Inborn genetic diseases
- R41G (p.Arg41Gly), ExAC rs753765116, gnomAD rs753765116
- R41L (p.Arg41Leu), ExAC rs766000895, TOPMed rs766000895, gnomAD rs766000895, CADD 23.80, PolyPhen-2 0.36, Uncertain significance
- R41P (p.Arg41Pro), ExAC rs766000895, TOPMed rs766000895, gnomAD rs766000895, Uncertain significance
- R41Q (p.Arg41Gln), rs766000895, ClinGen CA7374899, ClinVar RCV001227660, ClinVar RCV005012642, CADD 22.60, PolyPhen-2 0.07, Uncertain significance, Cowden syndrome 6; Familial cancer of breast; Proteus syndrome
- R41W (p.Arg41Trp), ExAC rs753765116, gnomAD rs753765116, CADD 23.60, PolyPhen-2 0.04
- P42A (p.Pro42Ala), Ensembl rs2140949138
- P42L (p.Pro42Leu), rs1892951094, ClinGen CA391221552, ClinVar RCV002949467, TOPMed rs1892951094, CADD 25.10, PolyPhen-2 0.46, Uncertain significance, Cowden syndrome 6
- P42Q (p.Pro42Gln), TOPMed rs1892951094, Uncertain significance
- P42R (p.Pro42Arg), TOPMed rs1892951094, Uncertain significance
- P42S (p.Pro42Ser), Ensembl rs2140949138
- P42T (p.Pro42Thr), Ensembl rs2140949138
- Q43* (p.Gln43Ter), Ensembl rs11555436
- Q43E (p.Gln43Glu), Ensembl rs11555436
- Q43H (p.Gln43His), Ensembl rs2140949061, Likely benign
- Q43K (p.Gln43Lys), cosmic curated COSV62573
- Q43L (p.Gln43Leu), Ensembl rs2140949078, Uncertain significance
- Q43R (p.Gln43Arg), rs2140949078, ClinGen CA391221548, ClinVar RCV004521308, Ensembl rs2140949078, AlphaMissense 0.09, MetaLR 0.07, Uncertain significance, Inborn genetic diseases
- D44A (p.Asp44Ala), TOPMed rs1301434623, CADD 20.40
- D44E (p.Asp44Glu), TOPMed rs1347356104, gnomAD rs1347356104, cosmic curated COSV62572, Likely benign
- D44G (p.Asp44Gly), TOPMed rs1301434623
- D44H (p.Asp44His), Ensembl rs2140949051
- D44N (p.Asp44Asn), NCI-TCGA Cosmic COSV6257, cosmic curated COSV62576, Ensembl rs2140949051, Variant assessed as somatic; moderate impact.
- D44V (p.Asp44Val), TOPMed rs1301434623
- D44Y (p.Asp44Tyr), Ensembl rs2140949051
- V45A (p.Val45Ala), Ensembl rs2140948997
- V45E (p.Val45Glu), Ensembl rs2140948997
- V45G (p.Val45Gly), Ensembl rs2140948997
- V45L (p.Val45Leu), cosmic curated COSV10582, Ensembl rs2140949011
- V45M (p.Val45Met), Ensembl rs2140949011
- D46E (p.Asp46Glu), rs146875699, ClinGen CA156577, cosmic curated COSV62571, ClinVar RCV000119959, CADD 13.10, PolyPhen-2 0.17, Conflicting interpretations, Hereditary cancer; Cowden syndrome 6; not provided
- D46H (p.Asp46His), Ensembl rs2140948968
- D46N (p.Asp46Asn), Ensembl rs2140948968
- D46Y (p.Asp46Tyr), Ensembl rs2140948968
- Q47* (p.Gln47Ter), NCI-TCGA Cosmic COSV6257, cosmic curated COSV62573, Ensembl rs2140948924, Variant assessed as somatic; high impact.
- Q47E (p.Gln47Glu), Ensembl rs2140948924
- Q47H (p.Gln47His), rs532268608, 1000Genomes rs532268608, ExAC rs532268608, gnomAD rs532268608, CADD 0.05, PolyPhen-2 0.01, Uncertain significance, Cowden syndrome 6
Public AKT1 analysis runs
- AKT1 analysis run — AKT1 (1,384 variants) — completed 2026-08-21
- AKT1 analysis run — AKT1 (1,391 variants) — completed 2026-08-18