FOXO1 (Forkhead box protein O1) variants and mutations
FOXO1 (also known as Forkhead box protein O1) is a human protein-coding gene encoding a forkhead box protein O1 protein. It integrates insulin, growth-factor, and stress signals to control glucose metabolism, cell-cycle arrest, oxidative-stress responses, and apoptosis. Inactivation downstream of AKT is central to insulin action, while chromosomal fusions involving FOXO1 drive alveolar rhabdomyosarcoma. This analysis covers 1,139 FOXO1 variants and mutations. Of these, 84% have computational variant effect predictions. Disease context includes Burkitt lymphoma, hypothyroidism, and uterine corpus leiomyoma. Example FOXO1 variants include M1?, A2T, and A4V.
Variant analysis overview
- Gene: FOXO1
- Protein: Forkhead box protein O1
- UniProt accession: Q12778
- Organism: Homo sapiens
- Variants analyzed: 1139
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 708 unspecified-consequence records; 7 in-frame deletions; 222 missense variants; 187 synonymous variants; 2 in-frame insertions; 9 frameshift variants; 1 stop-gained variants; 1 splice-region variants; 2 substitution
- Prediction scores: 960 variants have prediction scores (84% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Burkitt lymphoma, hypothyroidism, uterine corpus leiomyoma, allergic rhinitis, alveolar rhabdomyosarcoma, rhabdomyosarcoma, diffuse large B-cell lymphoma, Eczematoid dermatitis, respiratory system disorder, osteoarthritis, hip, Uterine leiomyoma, embryonal rhabdomyosarcoma.
Protein structure and variant hotspots
- Protein features: 22 post-translational modification sites.
- PTM context: 29 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, MaveDB, LitVar.
Notable FOXO1 variants
Examples include M1?, A2T, A4V, P5L, Q6*, Q6L, V7E, V7G. 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.
- A2T (p.Ala2Thr), TOPMed rs1878246506, REVEL 0.48, MetaLR 0.77
- A4V (p.Ala4Val), Ensembl rs1878246313, REVEL 0.44, MetaLR 0.75
- P5L (p.Pro5Leu), TOPMed rs1036211926, REVEL 0.34, MetaLR 0.69
- Q6* (p.Gln6Ter), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- Q6L (p.Gln6Leu), TOPMed rs1348736585, REVEL 0.15, MetaLR 0.60
- V7E (p.Val7Glu), TOPMed rs1014743942, REVEL 0.19, MetaLR 0.56
- V7G (p.Val7Gly), TOPMed rs1014743942
- V7M (p.Val7Met), TOPMed rs933517374, gnomAD rs933517374, REVEL 0.21, MetaLR 0.62
- I10L (p.Ile10Leu), 1000Genomes rs1593422355, REVEL 0.17, MetaLR 0.63
- I10N (p.Ile10Asn), TOPMed rs1878244973, REVEL 0.23, MetaLR 0.74
- D11H (p.Asp11His), Ensembl rs1878244589
- P12L (p.Pro12Leu), ExAC rs773597669, TOPMed rs773597669, gnomAD rs773597669, REVEL 0.85, MetaLR 0.90
- P12Q (p.Pro12Gln), ExAC rs773597669, TOPMed rs773597669, gnomAD rs773597669, REVEL 0.84, MetaLR 0.90
- P12S (p.Pro12Ser), Ensembl rs2137951152, REVEL 0.80, MetaLR 0.90
- D13A (p.Asp13Ala), TOPMed rs1878243874
- F14L (p.Phe14Leu), TOPMed rs1447420875, gnomAD rs1447420875, REVEL 0.42, MetaLR 0.87
- E15A (p.Glu15Ala), Ensembl rs866963445
- E15G (p.Glu15Gly), Ensembl rs866963445, REVEL 0.59, MetaLR 0.82
- E15Q (p.Glu15Gln), gnomAD rs1403000835, REVEL 0.47, MetaLR 0.88
- L17P (p.Leu17Pro), Ensembl rs866056766, REVEL 0.44, MetaLR 0.65
- P18A (p.Pro18Ala), TOPMed rs1006100999, gnomAD rs1006100999, REVEL 0.16, MetaLR 0.58
- P18H (p.Pro18His), TOPMed rs1434507228, REVEL 0.41, MetaLR 0.75
- P18R (p.Pro18Arg), TOPMed rs1434507228, REVEL 0.32, MetaLR 0.68
- P18S (p.Pro18Ser), TOPMed rs1006100999, gnomAD rs1006100999, REVEL 0.16, MetaLR 0.41
- R19L (p.Arg19Leu), Ensembl rs2137951108, REVEL 0.72, MetaLR 0.89
- R19P (p.Arg19Pro), Ensembl rs2137951108
- P20L (p.Pro20Leu), TOPMed rs1465987375, REVEL 0.57, MetaLR 0.80
- P20Q (p.Pro20Gln), TOPMed rs1465987375, REVEL 0.36, MetaLR 0.72
- P20S (p.Pro20Ser), TOPMed rs1358018260, gnomAD rs1358018260, REVEL 0.47, MetaLR 0.79
- R21L (p.Arg21Leu), Ensembl rs2137951099, REVEL 0.83, MetaLR 0.94
- R21P (p.Arg21Pro), NCI-TCGA Cosmic COSV1044, NCI-TCGA Cosmic COSV6542, Variant assessed as somatic; moderate impact.
- S22* (p.Ser22Ter), NCI-TCGA Cosmic COSV6542, CADD 38.00, Variant assessed as somatic; high impact.
- S22L (p.Ser22Leu), Ensembl rs1878240564, REVEL 0.67, MetaLR 0.87
- S22W (p.Ser22Trp), NCI-TCGA Cosmic COSV6542, REVEL 0.78, MetaLR 0.95, Variant assessed as somatic; moderate impact.
- C23G (p.Cys23Gly), Ensembl rs2137951089
- P26S (p.Pro26Ser), Ensembl rs2137951079, REVEL 0.72, MetaLR 0.88
- P28H (p.Pro28His), 1000Genomes rs1182709050, TOPMed rs1182709050, gnomAD rs1182709050, REVEL 0.71, MetaLR 0.90
- P28R (p.Pro28Arg), 1000Genomes rs1182709050, TOPMed rs1182709050, gnomAD rs1182709050, REVEL 0.67, MetaLR 0.89
- P28S (p.Pro28Ser), gnomAD rs1232364332, REVEL 0.70, MetaLR 0.91
- P30L (p.Pro30Leu), 1000Genomes rs1878239254, REVEL 0.66, MetaLR 0.87
- P30S (p.Pro30Ser), Ensembl rs1878239361, REVEL 0.56, MetaLR 0.88
- F32I (p.Phe32Ile), TOPMed rs1391345095, Uncertain significance
- F32V (p.Phe32Val), rs1391345095, ClinGen CA388007556, ClinVar RCV004394398, TOPMed rs1391345095, AlphaMissense 0.15, MetaLR 0.62, Uncertain significance, not specified
- F32Y (p.Phe32Tyr), TOPMed rs866785231, gnomAD rs866785231, REVEL 0.34, MetaLR 0.67, Uncertain significance, not specified
- S33G (p.Ser33Gly), Ensembl rs1878238725, REVEL 0.26, MetaLR 0.62
- S33I (p.Ser33Ile), TOPMed rs1878238580, REVEL 0.18, MetaLR 0.59, Uncertain significance
- S33T (p.Ser33Thr), rs1878238580, ClinGen CA388007547, ClinVar RCV004138257, TOPMed rs1878238580, REVEL 0.17, MetaLR 0.62, Uncertain significance
- S35P (p.Ser35Pro), NCI-TCGA TCGA novel, REVEL 0.18, MetaLR 0.50, Variant assessed as somatic; moderate impact.
- N36S (p.Asn36Ser), gnomAD rs1401947247, REVEL 0.23, MetaLR 0.43
- N36T (p.Asn36Thr), gnomAD rs1401947247
- S37L (p.Ser37Leu), TOPMed rs1050201433, gnomAD rs1050201433, REVEL 0.34, MetaLR 0.73, Uncertain significance, not specified
- S37P (p.Ser37Pro), TOPMed rs914858058, gnomAD rs914858058, REVEL 0.23, MetaLR 0.64, Uncertain significance, not specified
- A38P (p.Ala38Pro), Ensembl rs2137950996
- A38V (p.Ala38Val), TOPMed rs956635931, gnomAD rs956635931, REVEL 0.24, MetaLR 0.63
- T39I (p.Thr39Ile), TOPMed rs1221703625, gnomAD rs1221703625, REVEL 0.36, MetaLR 0.80
- T39P (p.Thr39Pro), Ensembl rs2137950990
- S41I (p.Ser41Ile), gnomAD rs1279773350, REVEL 0.38, MetaLR 0.87
- S41R (p.Ser41Arg), TOPMed rs1448272875, gnomAD rs1448272875, NCI-TCGA TCGA novel, REVEL 0.35, MetaLR 0.84, Variant assessed as somatic; moderate impact.
- P42A (p.Pro42Ala), TOPMed rs931846569, gnomAD rs931846569, REVEL 0.42, MetaLR 0.81
- P42S (p.Pro42Ser), TOPMed rs931846569, gnomAD rs931846569, REVEL 0.43, MetaLR 0.84
- P44L (p.Pro44Leu), TOPMed rs1359323651, REVEL 0.40, MetaLR 0.65
- P44Q (p.Pro44Gln), TOPMed rs1359323651
- S45* (p.Ser45Ter), NCI-TCGA TCGA novel, CADD 37.00, Variant assessed as somatic; high impact.
- S45A (p.Ser45Ala), Ensembl rs2137950950
- S45P (p.Ser45Pro), Ensembl rs2137950950, REVEL 0.32, MetaLR 0.66
- S45W (p.Ser45Trp), Ensembl rs2137950945
- S47N (p.Ser47Asn), TOPMed rs1207899003, gnomAD rs1207899003, REVEL 0.22, MetaLR 0.54
- S47R (p.Ser47Arg), TOPMed rs1878236765, REVEL 0.18, MetaLR 0.52
- A48G (p.Ala48Gly), TOPMed rs1878236536, REVEL 0.29, MetaLR 0.46
- A48T (p.Ala48Thr), ExAC rs755011775, gnomAD rs755011775, REVEL 0.18, MetaLR 0.58
- A49P (p.Ala49Pro), Ensembl rs2137950922, REVEL 0.27, MetaLR 0.66
- A49T (p.Ala49Thr), Ensembl rs2137950922, REVEL 0.23, MetaLR 0.65
- A49V (p.Ala49Val), Ensembl rs1489258358, REVEL 0.23, MetaLR 0.66
- A50D (p.Ala50Asp), TOPMed rs1003365110, gnomAD rs1003365110, REVEL 0.19, MetaLR 0.57
- A50G (p.Ala50Gly), TOPMed rs1003365110, gnomAD rs1003365110, REVEL 0.21, MetaLR 0.57
- A50T (p.Ala50Thr), TOPMed rs1423943622, REVEL 0.20, MetaLR 0.61
- N51K (p.Asn51Lys), TOPMed rs1878235629, REVEL 0.16, MetaLR 0.58
- N51T (p.Asn51Thr), Ensembl rs2137950894, REVEL 0.21, MetaLR 0.62
- P52R (p.Pro52Arg), TOPMed rs1023555435, REVEL 0.26, MetaLR 0.73
- P52S (p.Pro52Ser), TOPMed rs970585546, gnomAD rs970585546, REVEL 0.13, MetaLR 0.63
- P52T (p.Pro52Thr), TOPMed rs970585546, gnomAD rs970585546, REVEL 0.14, MetaLR 0.68
- D53A (p.Asp53Ala), Ensembl rs2137950866
- D53H (p.Asp53His), TOPMed rs1350774254, gnomAD rs1350774254, REVEL 0.27, MetaLR 0.74
- D53N (p.Asp53Asn), TOPMed rs1350774254, gnomAD rs1350774254, REVEL 0.17, MetaLR 0.67
- D53V (p.Asp53Val), Ensembl rs2137950866
- G57A (p.Gly57Ala), Ensembl rs2137950863, REVEL 0.24, MetaLR 0.67
- S60A (p.Ser60Ala), TOPMed rs1012542344
- S60L (p.Ser60Leu), TOPMed rs1291996842, REVEL 0.20, MetaLR 0.67
- S60T (p.Ser60Thr), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- A61D (p.Ala61Asp), TOPMed rs899092289, gnomAD rs899092289, REVEL 0.23, MetaLR 0.69
- A61V (p.Ala61Val), TOPMed rs899092289, gnomAD rs899092289, REVEL 0.17, MetaLR 0.71
- S62L (p.Ser62Leu), gnomAD rs1878234649, REVEL 0.24, MetaLR 0.66
- S62P (p.Ser62Pro), Ensembl rs2137950839, REVEL 0.18, MetaLR 0.63
- S62W (p.Ser62Trp), gnomAD rs1878234649, REVEL 0.37, MetaLR 0.76
- A63G (p.Ala63Gly), gnomAD rs1878234198, REVEL 0.21, MetaLR 0.66
- A63P (p.Ala63Pro), Ensembl rs556760792, REVEL 0.24, MetaLR 0.72
- A64V (p.Ala64Val), Ensembl rs2137950817, REVEL 0.24, MetaLR 0.66
- A65T (p.Ala65Thr), Ensembl rs1878234110, REVEL 0.31, MetaLR 0.70
- S67R (p.Ser67Arg), TOPMed rs1399173842, gnomAD rs1399173842, REVEL 0.23, MetaLR 0.67
- A68T (p.Ala68Thr), Ensembl rs1335631711, REVEL 0.16, MetaLR 0.49
- A68V (p.Ala68Val), 1000Genomes rs2137950799, REVEL 0.23, MetaLR 0.60
- D69A (p.Asp69Ala), Ensembl rs1878233698, REVEL 0.50, MetaLR 0.81
- D69N (p.Asp69Asn), TOPMed rs1290341552, gnomAD rs1290341552, REVEL 0.43, MetaLR 0.82
- F70L (p.Phe70Leu), NCI-TCGA TCGA novel, REVEL 0.33, MetaLR 0.72, Variant assessed as somatic; moderate impact.
- M71L (p.Met71Leu), Ensembl rs1566089546, REVEL 0.21, MetaLR 0.55
- M71T (p.Met71Thr), TOPMed rs1323268054, REVEL 0.31, MetaLR 0.62
- S72G (p.Ser72Gly), Ensembl rs1878233411, REVEL 0.23, MetaLR 0.67
- N73T (p.Asn73Thr), TOPMed rs1878233220
- S75R (p.Ser75Arg), TOPMed rs1218986039, gnomAD rs1218986039, REVEL 0.28, MetaLR 0.69
- L76F (p.Leu76Phe), NCI-TCGA TCGA novel, REVEL 0.36, MetaLR 0.86, Variant assessed as somatic; moderate impact.
- L76V (p.Leu76Val), 1000Genomes rs543709312, REVEL 0.31, MetaLR 0.83
- L77M (p.Leu77Met), TOPMed rs1197474851, gnomAD rs1197474851, REVEL 0.35, MetaLR 0.85
- L77R (p.Leu77Arg), Ensembl rs2137950743
- L77V (p.Leu77Val), TOPMed rs1197474851, gnomAD rs1197474851, REVEL 0.25, MetaLR 0.71
- E78D (p.Glu78Asp), TOPMed rs1878232433, REVEL 0.33, MetaLR 0.86
- E79D (p.Glu79Asp), TOPMed rs1480728577, gnomAD rs1480728577, REVEL 0.27, MetaLR 0.82
- E79G (p.Glu79Gly), TOPMed rs1878232326, gnomAD rs1878232326, REVEL 0.40, MetaLR 0.89
- S80N (p.Ser80Asn), TOPMed rs1878232134, REVEL 0.24, MetaLR 0.70
- S80R (p.Ser80Arg), TOPMed rs1183757708, REVEL 0.28, MetaLR 0.76
- E81K (p.Glu81Lys), gnomAD rs1878231900, REVEL 0.29, MetaLR 0.69
- D82H (p.Asp82His), 1000Genomes rs34733279, ExAC rs34733279, TOPMed rs34733279, gnomAD rs34733279, REVEL 0.41, MetaLR 0.79
- D82N (p.Asp82Asn), 1000Genomes rs34733279, ExAC rs34733279, TOPMed rs34733279, gnomAD rs34733279, REVEL 0.27, MetaLR 0.04
- D82Y (p.Asp82Tyr), 1000Genomes rs34733279, ExAC rs34733279, TOPMed rs34733279, gnomAD rs34733279, REVEL 0.49, MetaLR 0.81
- F83L (p.Phe83Leu), Ensembl rs1159058187, REVEL 0.31, MetaLR 0.65
- F83S (p.Phe83Ser), Ensembl rs2137950703, REVEL 0.29, MetaLR 0.72
- P84L (p.Pro84Leu), 1000Genomes rs1051829787, TOPMed rs1051829787, gnomAD rs1051829787, REVEL 0.24, MetaLR 0.60
- P84R (p.Pro84Arg), 1000Genomes rs1051829787, TOPMed rs1051829787, gnomAD rs1051829787
- P84T (p.Pro84Thr), gnomAD rs1878231408, REVEL 0.24, MetaLR 0.64
- Q85R (p.Gln85Arg), Ensembl rs2137950683, REVEL 0.24, MetaLR 0.49
- P87L (p.Pro87Leu), Ensembl rs1878231177, REVEL 0.27, MetaLR 0.67
- P87R (p.Pro87Arg), Ensembl rs1878231177
- G88A (p.Gly88Ala), TOPMed rs900638210, gnomAD rs900638210, REVEL 0.18, MetaLR 0.51
- G88D (p.Gly88Asp), TOPMed rs900638210, gnomAD rs900638210, REVEL 0.14, MetaLR 0.57
- G88R (p.Gly88Arg), 1000Genomes rs2137950660, REVEL 0.12, MetaLR 0.63
- G88V (p.Gly88Val), TOPMed rs900638210, gnomAD rs900638210, REVEL 0.17, MetaLR 0.62
- S89C (p.Ser89Cys), gnomAD rs1290983226, REVEL 0.26, MetaLR 0.55
- V90G (p.Val90Gly), rs2501412134, ClinGen CA388007179, ClinVar RCV004217534, Uncertain significance
- V90L (p.Val90Leu), rs1348645141, ClinGen CA388007184, ClinVar RCV004267900, TOPMed rs1348645141, REVEL 0.19, MetaLR 0.69, Uncertain significance
- A91G (p.Ala91Gly), TOPMed rs1284681540, gnomAD rs1284681540
- A91V (p.Ala91Val), TOPMed rs1284681540, gnomAD rs1284681540, REVEL 0.27, MetaLR 0.64
- A92G (p.Ala92Gly), gnomAD rs914847913, Uncertain significance
- A92V (p.Ala92Val), gnomAD rs914847913, REVEL 0.29, MetaLR 0.66, Uncertain significance, not specified
- A93G (p.Ala93Gly), TOPMed rs989533582, gnomAD rs989533582
- A93V (p.Ala93Val), TOPMed rs989533582, gnomAD rs989533582, REVEL 0.17, MetaLR 0.54
- V94A (p.Val94Ala), rs1482440466, gnomAD rs1482440466, REVEL 0.29, AlphaMissense 0.07, Uncertain significance
- V94G (p.Val94Gly), rs1482440466, ClinGen CA388007157, ClinVar RCV004076986, gnomAD rs1482440466, AlphaMissense 0.07, MetaLR 0.51, Uncertain significance
- A95G (p.Ala95Gly), Ensembl rs2137950593
- A96G (p.Ala96Gly), Ensembl rs2137950582
- A96T (p.Ala96Thr), TOPMed rs1878228650, REVEL 0.22, MetaLR 0.61
- A97E (p.Ala97Glu), TOPMed rs970471060, gnomAD rs970471060, REVEL 0.22, MetaLR 0.54
- A97G (p.Ala97Gly), TOPMed rs970471060, gnomAD rs970471060, REVEL 0.11, MetaLR 0.58
- A97V (p.Ala97Val), TOPMed rs970471060, gnomAD rs970471060, REVEL 0.21, MetaLR 0.50
- A98G (p.Ala98Gly), TOPMed rs1334866177, gnomAD rs1334866177
- A98P (p.Ala98Pro), Ensembl rs2137950562
- A98V (p.Ala98Val), TOPMed rs1334866177, gnomAD rs1334866177, REVEL 0.18, MetaLR 0.52
- A99V (p.Ala99Val), gnomAD rs990684812, REVEL 0.19, MetaLR 0.59, Uncertain significance, not specified
- A100V (p.Ala100Val), gnomAD rs1878226648, REVEL 0.31, MetaLR 0.47
- A101T (p.Ala101Thr), rs2501411704, ClinGen CA388007121, ClinVar RCV004272451, REVEL 0.20, MetaLR 0.59, Uncertain significance, not specified
- A101V (p.Ala101Val), TOPMed rs1208565101, REVEL 0.20, MetaLR 0.58
- A102T (p.Ala102Thr), TOPMed rs1878225907, REVEL 0.23, MetaLR 0.50
- T103P (p.Thr103Pro), rs2501411593, ClinGen CA388007110, ClinVar RCV004198576, Uncertain significance
- G104A (p.Gly104Ala), rs963605898, ClinGen CA248985514, ClinVar RCV003976968, 1000Genomes rs963605898, REVEL 0.28, MetaLR 0.39, Likely benign, FOXO1-related disorder
- G104R (p.Gly104Arg), gnomAD rs1878225143, REVEL 0.22, MetaLR 0.44
- G105E (p.Gly105Glu), TOPMed rs1333425848, gnomAD rs1333425848, REVEL 0.22, MetaLR 0.63
- G105R (p.Gly105Arg), Ensembl rs1593422142, REVEL 0.28, MetaLR 0.66
- G105V (p.Gly105Val), TOPMed rs1333425848, gnomAD rs1333425848
- L106M (p.Leu106Met), NCI-TCGA TCGA novel, REVEL 0.19, MetaLR 0.66, Variant assessed as somatic; moderate impact.
- C107R (p.Cys107Arg), rs1005282881, ClinGen CA248985512, ClinVar RCV004232509, TOPMed rs1005282881, REVEL 0.26, MetaLR 0.68, Uncertain significance
- C107Y (p.Cys107Tyr), gnomAD rs1878223994, REVEL 0.27, MetaLR 0.68
- D109G (p.Asp109Gly), TOPMed rs1878223785, gnomAD rs1878223785, REVEL 0.24, MetaLR 0.65
- D109V (p.Asp109Val), TOPMed rs1878223785, gnomAD rs1878223785, REVEL 0.28, MetaLR 0.72
- F110L (p.Phe110Leu), TOPMed rs1295066500, gnomAD rs1295066500, REVEL 0.26, MetaLR 0.73
- F110V (p.Phe110Val), gnomAD rs1878223669, REVEL 0.23, MetaLR 0.74
- Q111E (p.Gln111Glu), gnomAD rs1878223405, REVEL 0.23, MetaLR 0.64
- Q111R (p.Gln111Arg), TOPMed rs886481202, gnomAD rs886481202, REVEL 0.15, MetaLR 0.63, Uncertain significance, not specified
- G112C (p.Gly112Cys), rs1878223078, ClinGen CA388007052, ClinVar RCV004097933, REVEL 0.16, MetaLR 0.51, Uncertain significance
- G112D (p.Gly112Asp), 1000Genomes rs1030291335, TOPMed rs1030291335, gnomAD rs1030291335, REVEL 0.15, MetaLR 0.58, Uncertain significance
- G112S (p.Gly112Ser), Ensembl rs1878223078, REVEL 0.11, MetaLR 0.55
- G112V (p.Gly112Val), rs1030291335, ClinGen CA248985510, ClinVar RCV004214613, 1000Genomes rs1030291335, REVEL 0.13, MetaLR 0.57, Uncertain significance
Public FOXO1 analysis runs
- FOXO1 analysis run — FOXO1 (1,139 variants) — completed 2026-08-20