AKT2 (P31751) variants and mutations
AKT2 (also known as P31751) is a human protein-coding gene encoding a RAC-beta serine/threonine-protein kinase protein. Downstream of insulin and PI3K signaling, it promotes glucose uptake, glycogen synthesis, and metabolic homeostasis in insulin-responsive tissues. Loss-of-function variants can cause severe insulin resistance, whereas activating variants can produce hypoglycemia and asymmetric overgrowth. This analysis covers 950 AKT2 variants and mutations. Of these, 57% have computational variant effect predictions. Disease context includes hypoinsulinemic hypoglycemia and body hemihypertrophy, type 2 diabetes mellitus, and breast cancer. Example AKT2 variants include M1?, N2S, and E3K.
Variant analysis overview
- Gene: AKT2
- Protein: P31751
- UniProt accession: P31751
- Organism: Homo sapiens
- Variants analyzed: 950
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 724 unspecified-consequence records; 8 stop lost; 54 synonymous variants; 136 missense variants; 12 frameshift variants; 11 stop-gained variants; 3 in-frame deletions; 2 substitution
- Prediction scores: 540 variants have prediction scores (57% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: hypoinsulinemic hypoglycemia and body hemihypertrophy, type 2 diabetes mellitus, breast cancer, diabetes mellitus, cancer, neoplasm, lung carcinoma, prostate cancer, neurodegenerative disease, AKT2-related familial partial lipodystrophy, Familial partial lipodystrophy due to AKT2 mutations, prostate carcinoma.
Protein structure and variant hotspots
- Protein features: 3 domains; 4 binding sites; 13 post-translational modification sites.
- Structural context: 832 variants have structural context.
- PTM context: 21 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, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable AKT2 variants
Examples include M1?, N2S, E3K, S5C, V6A, V6F, I7F, I7T. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- N2S (p.Asn2Ser), gnomAD rs1227207335, REVEL 0.10, CADD 20.30
- E3K (p.Glu3Lys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- S5C (p.Ser5Cys), Ensembl rs2145363557
- V6A (p.Val6Ala), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10025, Variant assessed as somatic; moderate impact.
- V6F (p.Val6Phe), gnomAD rs1386086141
- I7F (p.Ile7Phe), 1000Genomes rs199748431, ExAC rs199748431, TOPMed rs199748431, gnomAD rs199748431, Uncertain significance
- I7T (p.Ile7Thr), 1000Genomes rs2145363504, REVEL 0.54, CADD 23.80
- I7V (p.Ile7Val), rs199748431, ClinGen CA9442020, ClinVar RCV002005776, 1000Genomes rs199748431, REVEL 0.19, CADD 16.90, Uncertain significance, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- K8R (p.Lys8Arg), gnomAD rs1405458685
- E9K (p.Glu9Lys), ExAC rs748173515, TOPMed rs748173515, gnomAD rs748173515, REVEL 0.57, CADD 25.00
- K14T (p.Lys14Thr), gnomAD rs1476241262
- R15C (p.Arg15Cys), ExAC rs781407242, TOPMed rs781407242, gnomAD rs781407242, REVEL 0.76, CADD 32.00
- R15H (p.Arg15His), rs1976263420, ClinGen CA405874454, ClinVar RCV001335851, ClinVar RCV003770860, REVEL 0.74, CADD 31.00, Uncertain significance, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- E17* (p.Glu17Ter), Ensembl rs387906659, Pathogenic, in HIHGHH
- E17K (p.Glu17Lys), rs387906659, ClinGen CA128662, NCI-TCGA Cosmic COSV6090, cosmic curated COSV60907, AlphaMissense 1.00, MetaLR 0.23, Pathogenic, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- I19F (p.Ile19Phe), TOPMed rs1438443076, gnomAD rs1438443076, REVEL 0.39, CADD 25.40
- I19T (p.Ile19Thr), Ensembl rs1600058964
- T21S (p.Thr21Ser), Ensembl rs2145307230, REVEL 0.22, CADD 24.20
- W22C (p.Trp22Cys), Ensembl rs2145307209
- R23G (p.Arg23Gly), Ensembl rs2145307169
- R23W (p.Arg23Trp), Ensembl rs2145307169
- P24L (p.Pro24Leu), cosmic curated COSV10588, gnomAD rs1272565080, REVEL 0.46, CADD 28.80
- P24S (p.Pro24Ser), TOPMed rs1185991201, gnomAD rs1185991201, REVEL 0.29, CADD 23.00
- R25Q (p.Arg25Gln), cosmic curated COSV60908, ExAC rs746989021, gnomAD rs746989021, REVEL 0.41, CADD 27.80
- R25W (p.Arg25Trp), Ensembl rs2145307119, REVEL 0.55, CADD 28.20
- Y26S (p.Tyr26Ser), gnomAD rs1371021819
- L29M (p.Leu29Met), TOPMed rs1975586566
- K30* (p.Lys30Ter), Ensembl rs2145306999
- K30N (p.Lys30Asn), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10025, Variant assessed as somatic; moderate impact.
- K30R (p.Lys30Arg), TOPMed rs1975586217
- S31N (p.Ser31Asn), ExAC rs779811637, gnomAD rs779811637, REVEL 0.10, CADD 19.10
- D32H (p.Asp32His), TOPMed rs1360665207, gnomAD rs1360665207
- D32N (p.Asp32Asn), cosmic curated COSV60909, TOPMed rs1360665207, gnomAD rs1360665207, REVEL 0.22, CADD 23.90
- D32V (p.Asp32Val), Ensembl rs2145306894
- G33D (p.Gly33Asp), Ensembl rs2145306826, REVEL 0.58, CADD 26.40
- G33S (p.Gly33Ser), cosmic curated COSV60909, TOPMed rs1975585202, REVEL 0.47, CADD 27.20
- G33V (p.Gly33Val), Ensembl rs2145306826
- G37R (p.Gly37Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- G37V (p.Gly37Val), Ensembl rs2145306739
- G37W (p.Gly37Trp), Ensembl rs2145306769
- E40D (p.Glu40Asp), Ensembl rs2145306703
- R41G (p.Arg41Gly), Ensembl rs2145306683
- R41K (p.Arg41Lys), TOPMed rs1197293098, gnomAD rs1197293098, REVEL 0.07, CADD 18.30
- E43Q (p.Glu43Gln), Ensembl rs2145306608
- E43V (p.Glu43Val), Ensembl rs2145306595
- P45A (p.Pro45Ala), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10025, NCI-TCGA Cosmic COSV6090, Uncertain significance, Inborn genetic diseases
- P45L (p.Pro45Leu), Ensembl rs2145306516
- P45R (p.Pro45Arg), Ensembl rs2145306516
- P45S (p.Pro45Ser), cosmic curated COSV60909, ExAC rs763646270, gnomAD rs763646270, REVEL 0.10, CADD 13.90
- D46G (p.Asp46Gly), Ensembl rs2145306451
- D46N (p.Asp46Asn), rs1975583524, ClinGen CA405872922, ClinVar RCV001058890, TOPMed rs1975583524, REVEL 0.31, CADD 22.90, Uncertain significance, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- D46Y (p.Asp46Tyr), TOPMed rs1975583524, Uncertain significance
- Q47* (p.Gln47Ter), Ensembl rs2145306425
- L49P (p.Leu49Pro), 1000Genomes rs201917021, ExAC rs201917021, TOPMed rs201917021, gnomAD rs201917021, REVEL 0.20, CADD 19.40
- L49Q (p.Leu49Gln), 1000Genomes rs201917021, ExAC rs201917021, TOPMed rs201917021, gnomAD rs201917021, REVEL 0.07, CADD 17.40, Uncertain significance, Inborn genetic diseases
- P50A (p.Pro50Ala), 1000Genomes rs184042322, ExAC rs184042322, TOPMed rs184042322, gnomAD rs184042322, REVEL 0.11, CADD 20.20
- P50S (p.Pro50Ser), 1000Genomes rs184042322, ExAC rs184042322, TOPMed rs184042322, gnomAD rs184042322, REVEL 0.11, CADD 21.50
- P50T (p.Pro50Thr), 1000Genomes rs184042322, ExAC rs184042322, TOPMed rs184042322, gnomAD rs184042322, REVEL 0.11, CADD 22.00, Benign, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- P51A (p.Pro51Ala), TOPMed rs201145928, gnomAD rs201145928, REVEL 0.66, CADD 24.20
- P51L (p.Pro51Leu), ExAC rs770250877, TOPMed rs770250877, gnomAD rs770250877, REVEL 0.61, CADD 28.50
- P51R (p.Pro51Arg), ExAC rs770250877, TOPMed rs770250877, gnomAD rs770250877, REVEL 0.83, CADD 28.40
- P51S (p.Pro51Ser), TOPMed rs201145928, gnomAD rs201145928, REVEL 0.73, CADD 24.90
- P51T (p.Pro51Thr), TOPMed rs201145928, gnomAD rs201145928
- L52* (p.Leu52Ter), NCI-TCGA Cosmic COSV1002, Variant assessed as somatic; high impact.
- L52I (p.Leu52Ile), TOPMed rs1975581237
- L52R (p.Leu52Arg), Ensembl rs2145306185
- N53H (p.Asn53His), NCI-TCGA Cosmic COSV6090, cosmic curated COSV60908, Variant assessed as somatic; moderate impact.
- N53Y (p.Asn53Tyr), NCI-TCGA Cosmic COSV6090, Variant assessed as somatic; moderate impact.
- S56A (p.Ser56Ala), Ensembl rs1975580377
- S56F (p.Ser56Phe), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10025, Variant assessed as somatic; moderate impact.
- V57E (p.Val57Glu), Ensembl rs2145306041
- V57I (p.Val57Ile), rs1407888862, ClinGen CA405872708, NCI-TCGA Cosmic COSV1002, NCI-TCGA Cosmic COSV6090, REVEL 0.34, CADD 22.60, Uncertain significance, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- V57L (p.Val57Leu), TOPMed rs1407888862, gnomAD rs1407888862, NCI-TCGA Cosmic COSV1002, cosmic curated COSV10025, Uncertain significance
- A58V (p.Ala58Val), rs2145306024, ClinGen CA405872690, ClinVar RCV002010421, Ensembl rs2145306024, AlphaMissense 0.47, MetaLR 0.21, Likely benign, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- E59* (p.Glu59Ter), Ensembl rs2145306010
- C60Y (p.Cys60Tyr), cosmic curated COSV60909, Ensembl rs2145294194
- Q61R (p.Gln61Arg), gnomAD rs1380555769, REVEL 0.33, CADD 24.30
- M63L (p.Met63Leu), NCI-TCGA Cosmic COSV6090, Variant assessed as somatic; moderate impact.
- T65S (p.Thr65Ser), Ensembl rs2145294157
- E66D (p.Glu66Asp), TOPMed rs1302715414, gnomAD rs1302715414, REVEL 0.17, CADD 15.20
- E66K (p.Glu66Lys), ExAC rs747803532, TOPMed rs747803532, gnomAD rs747803532, REVEL 0.54, CADD 22.90
- R67G (p.Arg67Gly), Ensembl rs2145294066
- R67M (p.Arg67Met), Ensembl rs2145294039
- R67S (p.Arg67Ser), Ensembl rs2145294021
- P68L (p.Pro68Leu), TOPMed rs1410236931, gnomAD rs1410236931, REVEL 0.42, CADD 28.10
- P68S (p.Pro68Ser), Ensembl rs2145293995, REVEL 0.31, AlphaMissense 0.99
- P68T (p.Pro68Thr), rs2145293995, ClinGen CA405871556, ClinVar RCV003208028, AlphaMissense 0.99, MetaLR 0.24, Uncertain significance, Inborn genetic diseases
- R69* (p.Arg69Ter), TOPMed rs1287086134, CADD 33.00
- R69Q (p.Arg69Gln), rs1485745630, NCI-TCGA Cosmic COSV6090, cosmic curated COSV60909, REVEL 0.38, CADD 21.70, Variant assessed as somatic; moderate impact.
- P70A (p.Pro70Ala), rs1170693725, ClinGen CA405871530, ClinVar RCV001318264, gnomAD rs1170693725, REVEL 0.24, CADD 24.10, Uncertain significance, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- N71S (p.Asn71Ser), rs200272953, ClinGen CA9441945, ClinVar RCV000964694, 1000Genomes rs200272953, REVEL 0.53, CADD 22.50, Conflicting interpretations, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- N71T (p.Asn71Thr), 1000Genomes rs200272953, ESP rs200272953, ExAC rs200272953, TOPMed rs200272953, REVEL 0.64, CADD 22.90, Uncertain significance
- T72I (p.Thr72Ile), cosmic curated COSV60909, ExAC rs765768303, gnomAD rs765768303, REVEL 0.69, CADD 24.10
- T72S (p.Thr72Ser), ExAC rs765768303, gnomAD rs765768303, REVEL 0.51, CADD 24.00
- F73V (p.Phe73Val), gnomAD rs1190606056, REVEL 0.92, CADD 27.80
- V74F (p.Val74Phe), ExAC rs754309980, TOPMed rs754309980, gnomAD rs754309980, REVEL 0.19, CADD 22.90
- V74I (p.Val74Ile), ExAC rs754309980, TOPMed rs754309980, gnomAD rs754309980, REVEL 0.10, CADD 14.90
- I75L (p.Ile75Leu), Ensembl rs1975452081
- R76C (p.Arg76Cys), Ensembl rs2145293731, REVEL 0.39, CADD 31.00
- R76H (p.Arg76His), cosmic curated COSV60908, Ensembl rs2145293719, REVEL 0.41, CADD 29.40, Uncertain significance, not provided
- L78M (p.Leu78Met), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L78L (p.Leu78Leu), gnomAD 19-40234555-T-C, CADD 5.39
- L78R (p.Leu78Arg), gnomAD 19-40234556-A-C, CADD 6.44, SIFT 0.01
- L78P (p.Leu78Pro), gnomAD 19-40234556-A-G, CADD 6.75, SIFT 0.02
- L78V (p.Leu78Val), gnomAD 19-40234557-G-C, CADD 8.65, SIFT 0.04
- L78I (p.Leu78Ile), gnomAD 19-40234557-G-T, CADD 7.98, SIFT 0.04
- Q79* (p.Gln79Ter), cosmic curated COSV10966, Ensembl rs1975451678
- W80C (p.Trp80Cys), NCI-TCGA Cosmic COSV6090, cosmic curated COSV60908, Variant assessed as somatic; moderate impact.
- T81I (p.Thr81Ile), Ensembl rs2145293615
- T81S (p.Thr81Ser), Ensembl rs2145293615
- I84M (p.Ile84Met), TOPMed rs868782526, gnomAD rs868782526
- E85K (p.Glu85Lys), cosmic curated COSV60908, TOPMed rs1393896368, gnomAD rs1393896368, REVEL 0.81, CADD 28.50
- E85Q (p.Glu85Gln), cosmic curated COSV60909, TOPMed rs1393896368, gnomAD rs1393896368
- R86K (p.Arg86Lys), Ensembl rs2145293504
- R86S (p.Arg86Ser), rs1396741460, gnomAD 19-40234567-C-A, CADD 3.93, SIFT 0.18
- R86M (p.Arg86Met), gnomAD 19-40234568-C-A, CADD 11.40, SIFT 0.01
- T87A (p.Thr87Ala), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- T87I (p.Thr87Ile), gnomAD rs1975450577, REVEL 0.41, CADD 23.30
- F88L (p.Phe88Leu), gnomAD rs1489834693, CADD 9.93
- F88F (p.Phe88Phe), gnomAD 19-40234558-A-G, CADD 4.12
- F88C (p.Phe88Cys), gnomAD 19-40234559-A-C, CADD 4.30, SIFT 0.01
- F88I (p.Phe88Ile), gnomAD 19-40234560-A-T, CADD 2.72, SIFT 0.03
- F88S (p.Phe88Ser), rs1568515362, gnomAD 19-40234571-A-G, CADD 8.25, SIFT 0.00
- V90M (p.Val90Met), rs1160079555, ClinGen CA405871240, ClinVar RCV002045984, TOPMed rs1160079555, REVEL 0.53, CADD 24.80, Uncertain significance, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- D91Y (p.Asp91Tyr), gnomAD rs1205519703, REVEL 0.84, CADD 33.00
- S92F (p.Ser92Phe), rs764512283, NCI-TCGA Cosmic COSV1002, cosmic curated COSV10025, ExAC rs764512283, REVEL 0.67, CADD 29.10, Variant assessed as somatic; moderate impact.
- S92S (p.Ser92Ser), gnomAD 19-40234534-T-C, CADD 6.16
- S92L (p.Ser92Leu), gnomAD 19-40234535-G-A, CADD 2.61, SIFT 0.24
- S92* (p.Ser92Ter), gnomAD 19-40234535-G-T, CADD 1.42
- P93L (p.Pro93Leu), cosmic curated COSV10732, TOPMed rs965617770, REVEL 0.19, CADD 25.70
- D94A (p.Asp94Ala), Ensembl rs1975448852
- D94E (p.Asp94Glu), rs139125633, ClinGen CA405871158, ClinVar RCV001369557, 1000Genomes rs139125633, REVEL 0.08, CADD 0.00, Uncertain significance, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- D94H (p.Asp94His), Ensembl rs2145293280
- E95=, NCI-TCGA Cosmic COSV6090, Variant assessed as somatic; low impact.
- E95K (p.Glu95Lys), rs374073998, ClinGen CA9441938, cosmic curated COSV60907, ClinVar RCV003780977, REVEL 0.73, CADD 25.00, Uncertain significance, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- E95D (p.Glu95Asp), gnomAD 19-40234549-C-A, CADD 8.43, SIFT 0.08
- E95E (p.Glu95Glu), gnomAD 19-40234549-C-T, CADD 9.30
- E95R (p.Glu95Arg), gnomAD 19-40234550-TC-T, CADD 1.88
- E95G (p.Glu95Gly), gnomAD 19-40234553-T-C, CADD 9.21, SIFT 0.00
- E95* (p.Glu95Ter), gnomAD 19-40234554-C-A, CADD 11.30
- R96T (p.Arg96Thr), TOPMed rs1975448195
- E97G (p.Glu97Gly), gnomAD rs1434565896, REVEL 0.72, CADD 40.00
- W99G (p.Trp99Gly), Ensembl rs2145209028
- W99L (p.Trp99Leu), Ensembl rs2145209014, REVEL 0.94, CADD 33.00
- W99R (p.Trp99Arg), Ensembl rs2145209028
- W99* (p.Trp99Ter), rs1025730163, gnomAD 19-40234508-TCC-T, CADD 4.88
- W99C (p.Trp99Cys), rs879685586, gnomAD 19-40234510-C-G, CADD 6.56
- M100L (p.Met100Leu), ESP rs369128708, ExAC rs369128708, TOPMed rs369128708, gnomAD rs369128708, REVEL 0.20, CADD 23.10
- R101G (p.Arg101Gly), ExAC rs761956794, TOPMed rs761956794, gnomAD rs761956794, REVEL 0.23, CADD 23.40
- R101L (p.Arg101Leu), gnomAD rs968169579, REVEL 0.22, CADD 14.60
- R101Q (p.Arg101Gln), gnomAD rs968169579, REVEL 0.10, CADD 13.10
- R101W (p.Arg101Trp), rs761956794, cosmic curated COSV10460, ExAC rs761956794, TOPMed rs761956794, REVEL 0.31, CADD 24.20, Uncertain significance, Type 2 diabetes mellitus; Hypoinsulinemic hypoglycemia and body hemihypertrophy
- R101S (p.Arg101Ser), gnomAD 19-40234522-C-A, CADD 7.18, SIFT 0.00
- R101R (p.Arg101Arg), rs1973890696, gnomAD 19-40234522-C-T, CADD 6.63
- A102G (p.Ala102Gly), Ensembl rs2145208931
- A102T (p.Ala102Thr), Ensembl rs2145208947, REVEL 0.56, CADD 23.30
- A102V (p.Ala102Val), Ensembl rs2145208931, REVEL 0.62, CADD 23.90
- A102A (p.Ala102Ala), rs762802589, gnomAD 19-40234531-A-T, CADD 2.13
- A102D (p.Ala102Asp), gnomAD 19-40234532-G-T, CADD 1.03, SIFT 0.10
- A102E (p.Ala102Glu), gnomAD 19-40234544-G-T, CADD 4.59, SIFT 0.00
- A102S (p.Ala102Ser), gnomAD 19-40234545-C-A, CADD 0.81, SIFT 0.23
- I103F (p.Ile103Phe), TOPMed rs1186768719
- I103M (p.Ile103Met), Ensembl rs2145208883
- I103T (p.Ile103Thr), Ensembl rs1599985751
- Q104R (p.Gln104Arg), TOPMed rs1260732312, REVEL 0.45, CADD 22.70
- M105I (p.Met105Ile), TOPMed rs1974488590
- M105T (p.Met105Thr), ExAC rs762920486, gnomAD rs762920486, REVEL 0.20, CADD 19.10, Uncertain significance, Inborn genetic diseases
- M105V (p.Met105Val), cosmic curated COSV60908, Ensembl rs2145208849
- V106D (p.Val106Asp), Ensembl rs2145208787
- V106L (p.Val106Leu), Ensembl rs2145208801
- V106V (p.Val106Val), gnomAD 19-40234513-C-A, CADD 0.01
- V106G (p.Val106Gly), gnomAD 19-40234514-A-C, CADD 1.19
- V106M (p.Val106Met), rs544709571, gnomAD 19-40234515-C-T, CADD 0.04, SIFT 0.01
- A107P (p.Ala107Pro), ExAC rs761598534, TOPMed rs761598534, gnomAD rs761598534
- A107T (p.Ala107Thr), ExAC rs761598534, TOPMed rs761598534, gnomAD rs761598534, REVEL 0.15, CADD 24.00
- A107A (p.Ala107Ala), gnomAD 19-40234504-G-C, CADD 2.95
- A107V (p.Ala107Val), gnomAD 19-40234505-G-A, CADD 0.15
- A107D (p.Ala107Asp), gnomAD 19-40234505-G-T, CADD 0.10
- A107S (p.Ala107Ser), gnomAD 19-40234506-C-A, CADD 0.06
Public AKT2 analysis runs
- AKT2 analysis run — AKT2 (950 variants) — completed 2026-08-20