FOXO3 (Forkhead box protein O3) variants and mutations
FOXO3 (also known as Forkhead box protein O3) is a human protein-coding gene encoding a forkhead box protein O3 protein. It activates stress-resistance, autophagy, cell-cycle arrest, and apoptotic programs when growth-factor signaling is low. Variation near FOXO3 has repeatedly been associated with human longevity, while altered activity influences cancer and metabolic disease. This analysis covers 1,256 FOXO3 variants and mutations. Of these, 93% have computational variant effect predictions. Disease context includes Alzheimer disease, intelligence, and neurodegenerative disease. Example FOXO3 variants include A2E, A2T, and A2V.
Variant analysis overview
- Gene: FOXO3
- Protein: Forkhead box protein O3
- UniProt accession: O43524
- Organism: Homo sapiens
- Variants analyzed: 1256
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 805 unspecified-consequence records; 248 missense variants; 162 synonymous variants; 19 stop-gained variants; 6 in-frame deletions; 12 frameshift variants; 3 in-frame insertions
- Prediction scores: 1,167 variants have prediction scores (93% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Alzheimer disease, intelligence, neurodegenerative disease, Abnormality of the skeletal system, schizophrenia, smoking initiation, skin basal cell carcinoma, breast ductal adenocarcinoma, prostate adenocarcinoma, lymphoid neoplasm, bile duct carcinoma, hepatobiliary neoplasm.
Protein structure and variant hotspots
- Protein features: 28 post-translational modification sites.
- PTM context: 38 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, MaveDB, LitVar.
Notable FOXO3 variants
Examples include A2E, A2T, A2V, A2S, A2A, E3*, E3V, A4R. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- A2E (p.Ala2Glu), gnomAD rs1775773594, REVEL 0.48, MetaLR 0.59
- A2T (p.Ala2Thr), gnomAD rs1175724154, REVEL 0.46, MetaLR 0.60
- A2V (p.Ala2Val), cosmic curated COSV59629, REVEL 0.47, MetaLR 0.62
- A2S (p.Ala2Ser), gnomAD 6-108561212-G-T, REVEL 0.35, MetaLR 0.57
- A2A (p.Ala2Ala), gnomAD 6-108561214-A-C, CADD 15.70
- E3* (p.Glu3Ter), gnomAD 6-108561215-G-T, CADD 37.00
- E3V (p.Glu3Val), gnomAD 6-108561216-A-T, REVEL 0.45, MetaLR 0.56
- A4R (p.Ala4Arg), rs1775773648, gnomAD 6-108561217-GGCAC, CADD 27.70
- A4T (p.Ala4Thr), gnomAD 6-108561218-G-A, REVEL 0.30, MetaLR 0.59
- A4V (p.Ala4Val), gnomAD 6-108561219-C-T, REVEL 0.24, MetaLR 0.55
- A4E (p.Ala4Glu), gnomAD 6-108561219-C-A, REVEL 0.35, MetaLR 0.53
- A4A (p.Ala4Ala), rs1775773700, gnomAD 6-108561220-A-G, CADD 13.20
- P5A (p.Pro5Ala), ExAC rs757315159, gnomAD rs757315159, MetaLR 0.34, MetaSVM -0.62
- P5L (p.Pro5Leu), rs1463974336, ClinGen CA365336814, ClinVar RCV004352975, gnomAD rs1463974336, REVEL 0.27, MetaLR 0.38, Uncertain significance, not specified
- p.Pro5 Ala6del, gnomAD 6-108561216-AGGCA, CADD 21.20
- P5S (p.Pro5Ser), gnomAD 6-108561221-C-T, REVEL 0.20, MetaLR 0.39
- P5T (p.Pro5Thr), gnomAD 6-108561221-C-A, REVEL 0.15, MetaLR 0.40
- P5P (p.Pro5Pro), rs779035445, gnomAD 6-108561223-G-A, CADD 13.80
- A6S (p.Ala6Ser), rs1396187319, ClinGen CA365336815, cosmic curated COSV59626, ClinVar RCV004351991, REVEL 0.27, MetaLR 0.16, Uncertain significance, not specified
- A6T (p.Ala6Thr), gnomAD 6-108561224-G-A, REVEL 0.24, MetaLR 0.25
- A6G (p.Ala6Gly), gnomAD 6-108561225-C-G, REVEL 0.26, MetaLR 0.39
- A6A (p.Ala6Ala), gnomAD 6-108561226-T-C, CADD 14.20
- S7A (p.Ser7Ala), Ensembl rs1562223603, REVEL 0.26, MetaLR 0.30
- S7F (p.Ser7Phe), ExAC rs750578104, gnomAD rs750578104, REVEL 0.24, MetaLR 0.42
- S7S (p.Ser7Ser), rs758777302, gnomAD 6-108561229-C-T, CADD 14.10
- P8R (p.Pro8Arg), gnomAD 6-108561227-TC-T, CADD 25.60
- P8A (p.Pro8Ala), gnomAD 6-108561230-C-G, REVEL 0.34, MetaLR 0.44
- P8L (p.Pro8Leu), gnomAD 6-108561231-C-T, REVEL 0.28, MetaLR 0.37
- P8Q (p.Pro8Gln), gnomAD 6-108561231-C-A, REVEL 0.38, MetaLR 0.40
- P8P (p.Pro8Pro), rs780454191, gnomAD 6-108561232-G-A, CADD 13.40
- A9S (p.Ala9Ser), Ensembl rs1775774254, REVEL 0.26, MetaLR 0.22
- A9V (p.Ala9Val), Ensembl rs1775774326, REVEL 0.25, MetaLR 0.21
- A9T (p.Ala9Thr), gnomAD 6-108561233-G-A, REVEL 0.18, MetaLR 0.26
- A9G (p.Ala9Gly), gnomAD 6-108561234-C-G, REVEL 0.21, MetaLR 0.30
- A9A (p.Ala9Ala), gnomAD 6-108561235-C-A, CADD 14.30
- P10A (p.Pro10Ala), TOPMed rs1298438711, gnomAD rs1298438711, REVEL 0.18, MetaLR 0.34
- P10L (p.Pro10Leu), ExAC rs755477843, TOPMed rs755477843, gnomAD rs755477843, REVEL 0.18, MetaLR 0.36
- P10S (p.Pro10Ser), TOPMed rs1298438711, gnomAD rs1298438711, REVEL 0.24, MetaLR 0.45
- P10T (p.Pro10Thr), cosmic curated COSV59626, REVEL 0.17, MetaLR 0.40
- P10R (p.Pro10Arg), gnomAD 6-108561233-GC-G, CADD 23.40
- P10P (p.Pro10Pro), rs1319462687, gnomAD 6-108561238-G-A, CADD 12.70
- L11F (p.Leu11Phe), TOPMed rs1342949133, REVEL 0.33, MetaLR 0.44
- L11P (p.Leu11Pro), TOPMed rs1191293561, gnomAD rs1191293561, REVEL 0.21, MetaLR 0.43, Uncertain significance
- L11R (p.Leu11Arg), rs1191293561, ClinGen CA365336848, ClinVar RCV003431984, TOPMed rs1191293561, REVEL 0.37, MetaLR 0.42, Uncertain significance, not provided
- L11V (p.Leu11Val), gnomAD 6-108561239-C-G, REVEL 0.31, MetaLR 0.36
- L11I (p.Leu11Ile), gnomAD 6-108561239-C-A, REVEL 0.26, MetaLR 0.35
- L11L (p.Leu11Leu), rs965828485, gnomAD 6-108561241-C-T, CADD 12.30
- S12C (p.Ser12Cys), gnomAD rs1250726678, REVEL 0.33, MetaLR 0.37
- p.Ser12 Leu14del, rs2128354139, gnomAD 6-108561235-CCCGC, CADD 19.30
- S12P (p.Ser12Pro), gnomAD 6-108561242-T-C, REVEL 0.37, MetaLR 0.29
- S12F (p.Ser12Phe), gnomAD 6-108561243-C-T, REVEL 0.33, MetaLR 0.36
- S12Y (p.Ser12Tyr), gnomAD 6-108561243-C-A, REVEL 0.34, MetaLR 0.36
- S12S (p.Ser12Ser), rs925027831, gnomAD 6-108561244-T-C, CADD 14.70
- P13S (p.Pro13Ser), TOPMed rs1395926108, MetaLR 0.38, MetaSVM -0.39
- P13A (p.Pro13Ala), gnomAD 6-108561238-GCT-G, CADD 24.30
- P13R (p.Pro13Arg), gnomAD 6-108561246-C-G, REVEL 0.26, MetaLR 0.42
- P13L (p.Pro13Leu), gnomAD 6-108561246-C-T, REVEL 0.23, MetaLR 0.40
- P13Q (p.Pro13Gln), gnomAD 6-108561246-C-A, REVEL 0.23, MetaLR 0.38
- P13P (p.Pro13Pro), gnomAD 6-108561247-G-C, CADD 11.90
- L14F (p.Leu14Phe), TOPMed rs1164825807, REVEL 0.27, MetaLR 0.44
- L14P (p.Leu14Pro), gnomAD rs1775775411, REVEL 0.41, MetaLR 0.40
- L14I (p.Leu14Ile), gnomAD 6-108561248-C-A, REVEL 0.19, MetaLR 0.40
- L14L (p.Leu14Leu), rs747631182, gnomAD 6-108561250-C-G, CADD 6.28
- E15Q (p.Glu15Gln), Ensembl rs921743189, REVEL 0.22, MetaLR 0.24
- E15K (p.Glu15Lys), gnomAD 6-108561251-G-A, REVEL 0.27, MetaLR 0.29
- E15E (p.Glu15Glu), rs1490555516, gnomAD 6-108561253-A-G, CADD 14.10
- V16A (p.Val16Ala), TOPMed rs1049908115, MetaLR 0.57, MetaSVM 0.20
- V16M (p.Val16Met), gnomAD 6-108561254-G-A, REVEL 0.52, MetaLR 0.70
- V16V (p.Val16Val), rs769303050, gnomAD 6-108561256-G-T, CADD 11.50
- E17K (p.Glu17Lys), Ensembl rs1775775761, REVEL 0.38, MetaLR 0.50
- E17G (p.Glu17Gly), gnomAD 6-108561258-A-G, REVEL 0.30, MetaLR 0.48
- E17E (p.Glu17Glu), gnomAD 6-108561259-G-A, CADD 11.80
- E17D (p.Glu17Asp), gnomAD 6-108561259-G-T, REVEL 0.22, MetaLR 0.34
- L18Q (p.Leu18Gln), TOPMed rs1775775867, gnomAD rs1775775867, REVEL 0.45, MetaLR 0.45
- L18V (p.Leu18Val), TOPMed rs1475183338, REVEL 0.18, MetaLR 0.34, Uncertain significance, not specified
- L18M (p.Leu18Met), gnomAD 6-108561260-C-A, REVEL 0.25, MetaLR 0.44
- L18L (p.Leu18Leu), gnomAD 6-108561260-C-T, CADD 12.80
- L18P (p.Leu18Pro), gnomAD 6-108561261-T-C, REVEL 0.51, MetaLR 0.42
- D19H (p.Asp19His), TOPMed rs1775775915, MetaLR 0.82, MetaSVM 0.81
- D19G (p.Asp19Gly), gnomAD 6-108561264-A-G, REVEL 0.70, MetaLR 0.68
- D19E (p.Asp19Glu), gnomAD 6-108561265-C-A, REVEL 0.49, MetaLR 0.63
- P20L (p.Pro20Leu), gnomAD rs1266847313, REVEL 0.65, MetaLR 0.59, Uncertain significance, not specified
- P20S (p.Pro20Ser), gnomAD 6-108561266-C-T, REVEL 0.44, MetaLR 0.54
- P20T (p.Pro20Thr), gnomAD 6-108561266-C-A, REVEL 0.39, MetaLR 0.57
- P20Q (p.Pro20Gln), gnomAD 6-108561267-C-A, REVEL 0.73, MetaLR 0.74
- P20P (p.Pro20Pro), gnomAD 6-108561268-G-T, CADD 8.84
- E21D (p.Glu21Asp), NCI-TCGA TCGA novel, MetaLR 0.07, MetaSVM -1.01, Variant assessed as somatic; moderate impact.
- E21K (p.Glu21Lys), gnomAD 6-108561269-G-A, REVEL 0.56, MetaLR 0.47
- E21G (p.Glu21Gly), gnomAD 6-108561270-A-G, REVEL 0.38, MetaLR 0.43
- E21V (p.Glu21Val), gnomAD 6-108561270-A-T, REVEL 0.53, MetaLR 0.45
- E21E (p.Glu21Glu), rs1194031732, gnomAD 6-108561271-G-A, CADD 12.70
- F22L (p.Phe22Leu), gnomAD 6-108561272-T-C, REVEL 0.43, MetaLR 0.65
- F22F (p.Phe22Phe), gnomAD 6-108561274-C-T, CADD 13.00
- E23* (p.Glu23Ter), gnomAD 6-108561275-G-T, CADD 37.00
- E23K (p.Glu23Lys), gnomAD 6-108561275-G-A, REVEL 0.38, MetaLR 0.59
- E23Q (p.Glu23Gln), gnomAD 6-108561275-G-C, REVEL 0.37, MetaLR 0.52
- E23G (p.Glu23Gly), gnomAD 6-108561276-A-G, REVEL 0.46, MetaLR 0.62
- E23E (p.Glu23Glu), rs1372961627, gnomAD 6-108561277-G-A, CADD 12.20
- E23D (p.Glu23Asp), gnomAD 6-108561277-G-T, REVEL 0.38, MetaLR 0.60
- P24S (p.Pro24Ser), cosmic curated COSV10522, REVEL 0.77, MetaLR 0.98
- P24T (p.Pro24Thr), gnomAD 6-108561278-C-A, REVEL 0.78, MetaLR 0.98
- P24L (p.Pro24Leu), gnomAD 6-108561279-C-T, REVEL 0.81, MetaLR 0.98
- P24P (p.Pro24Pro), rs1460932029, gnomAD 6-108561280-C-A, CADD 9.17
- Q25H (p.Gln25His), ExAC rs773001047, TOPMed rs773001047, gnomAD rs773001047, REVEL 0.41, MetaLR 0.60
- Q25R (p.Gln25Arg), TOPMed rs1223937209, REVEL 0.39, MetaLR 0.54, Uncertain significance, not specified
- Q25K (p.Gln25Lys), gnomAD 6-108561281-C-A, REVEL 0.34, MetaLR 0.60
- Q25* (p.Gln25Ter), gnomAD 6-108561281-C-T, CADD 36.00
- Q25Q (p.Gln25Gln), rs773001047, gnomAD 6-108561283-G-A, CADD 10.90
- S26C (p.Ser26Cys), cosmic curated COSV59631, ExAC rs770706574, gnomAD rs770706574, REVEL 0.43, MetaLR 0.56
- S26T (p.Ser26Thr), TOPMed rs1319756668, MetaLR 0.41, MetaSVM -0.52
- S26I (p.Ser26Ile), gnomAD 6-108561285-G-T, REVEL 0.41, MetaLR 0.50
- S26R (p.Ser26Arg), gnomAD 6-108561286-C-A, REVEL 0.33, MetaLR 0.46
- S26S (p.Ser26Ser), rs1041727540, gnomAD 6-108561286-C-T, CADD 13.50
- R27C (p.Arg27Cys), rs909124051, ClinGen CA365337002, ClinVar RCV004160419, AlphaMissense 1.00, MetaLR 0.75, Uncertain significance, not specified
- R27G (p.Arg27Gly), gnomAD rs909124051, REVEL 0.65, AlphaMissense 1.00
- R27H (p.Arg27His), gnomAD 6-108561288-G-A, REVEL 0.50, MetaLR 0.71
- R27L (p.Arg27Leu), gnomAD 6-108561288-G-T, REVEL 0.63, MetaLR 0.73
- P28Q (p.Pro28Gln), Ensembl rs1775776626, REVEL 0.39, MetaLR 0.47
- P28S (p.Pro28Ser), gnomAD 6-108561290-C-T, REVEL 0.51, MetaLR 0.60
- P28T (p.Pro28Thr), gnomAD 6-108561290-C-A, REVEL 0.51, MetaLR 0.63
- P28L (p.Pro28Leu), gnomAD 6-108561291-C-T, REVEL 0.45, MetaLR 0.58
- P28P (p.Pro28Pro), gnomAD 6-108561292-G-T, CADD 10.60
- R29* (p.Arg29Ter), ExAC rs774330247, gnomAD rs774330247, CADD 36.00
- R29R (p.Arg29Arg), rs774330247, gnomAD 6-108561293-C-A, CADD 13.60
- R29L (p.Arg29Leu), gnomAD 6-108561294-G-T, REVEL 0.81, MetaLR 0.89
- R29Q (p.Arg29Gln), gnomAD 6-108561294-G-A, REVEL 0.78, MetaLR 0.89
- S30F (p.Ser30Phe), TOPMed rs1276237221, REVEL 0.66, MetaLR 0.78
- S30Y (p.Ser30Tyr), gnomAD 6-108561297-C-A, REVEL 0.69, MetaLR 0.80
- S30S (p.Ser30Ser), gnomAD 6-108561298-C-T, CADD 12.70
- C31R (p.Cys31Arg), gnomAD 6-108561299-T-C, REVEL 0.57, MetaLR 0.63
- C31Y (p.Cys31Tyr), gnomAD 6-108561300-G-A, REVEL 0.35, MetaLR 0.54
- C31C (p.Cys31Cys), gnomAD 6-108561301-T-C, CADD 14.70
- T32A (p.Thr32Ala), NCI-TCGA TCGA novel, TOPMed rs1582720237, REVEL 0.55, MetaLR 0.76, Variant assessed as somatic; moderate impact.
- T32K (p.Thr32Lys), cosmic curated COSV10522, MetaLR 0.81, MetaSVM 0.83
- T32M (p.Thr32Met), gnomAD 6-108561303-C-T, REVEL 0.70, MetaLR 0.88
- T32T (p.Thr32Thr), rs767381540, gnomAD 6-108561304-G-A, CADD 9.49
- W33L (p.Trp33Leu), gnomAD 6-108561306-G-T, REVEL 0.66, MetaLR 0.82
- W33* (p.Trp33Ter), gnomAD 6-108561307-G-A, CADD 37.00
- P34L (p.Pro34Leu), cosmic curated COSV10522, REVEL 0.68, MetaLR 0.94
- P34S (p.Pro34Ser), TOPMed rs1775776958, REVEL 0.64, MetaLR 0.93
- P34T (p.Pro34Thr), gnomAD 6-108561308-C-A, REVEL 0.57, MetaLR 0.93
- P34H (p.Pro34His), gnomAD 6-108561309-C-A, REVEL 0.79, MetaLR 0.97
- P34P (p.Pro34Pro), gnomAD 6-108561310-C-G, CADD 13.30
- L35L (p.Leu35Leu), gnomAD 6-108561311-C-T, CADD 12.30
- L35M (p.Leu35Met), gnomAD 6-108561311-C-A, REVEL 0.32, MetaLR 0.53
- Q36* (p.Gln36Ter), gnomAD 6-108561314-C-T, CADD 36.00
- Q36Q (p.Gln36Gln), gnomAD 6-108561316-A-G, CADD 12.40
- R37T (p.Arg37Thr), gnomAD rs1775777108, REVEL 0.38, MetaLR 0.64
- R37M (p.Arg37Met), gnomAD 6-108561318-G-T, REVEL 0.69, MetaLR 0.73
- P38L (p.Pro38Leu), ExAC rs775459697, TOPMed rs775459697, gnomAD rs775459697, REVEL 0.38, MetaLR 0.55
- P38R (p.Pro38Arg), ExAC rs775459697, TOPMed rs775459697, gnomAD rs775459697, REVEL 0.42, MetaLR 0.55
- P38P (p.Pro38Pro), gnomAD 6-108561322-G-T, CADD 9.58
- E39D (p.Glu39Asp), TOPMed rs1246903417, gnomAD rs1246903417, REVEL 0.23, MetaLR 0.31
- E39Q (p.Glu39Gln), TOPMed rs1325837281, MetaLR 0.54, MetaSVM -0.13
- E39V (p.Glu39Val), gnomAD 6-108561324-A-T, REVEL 0.42, MetaLR 0.55
- E39E (p.Glu39Glu), gnomAD 6-108561325-G-A, CADD 9.69
- L40P (p.Leu40Pro), Ensembl rs1775777503
- L40L (p.Leu40Leu), gnomAD 6-108561328-C-G, CADD 3.79
- Q41K (p.Gln41Lys), gnomAD rs1775777589, REVEL 0.22, MetaLR 0.32
- Q41R (p.Gln41Arg), TOPMed rs1402941576, gnomAD rs1402941576, REVEL 0.18, MetaLR 0.36
- Q41Q (p.Gln41Gln), rs761803621, gnomAD 6-108561331-A-G, CADD 6.14
- A42T (p.Ala42Thr), TOPMed rs1171605677, REVEL 0.24, MetaLR 0.31
- A42V (p.Ala42Val), gnomAD 6-108561333-C-T, REVEL 0.22, MetaLR 0.37
- A42A (p.Ala42Ala), rs1358536076, gnomAD 6-108561334-G-A, CADD 9.19
- S43N (p.Ser43Asn), gnomAD 6-108561336-G-A, REVEL 0.19, MetaLR 0.47
- S43T (p.Ser43Thr), gnomAD 6-108561336-G-C, REVEL 0.27, MetaLR 0.44
- S43S (p.Ser43Ser), rs1775777871, gnomAD 6-108561337-C-T, CADD 9.29
- P44L (p.Pro44Leu), gnomAD rs1221996251, REVEL 0.27, MetaLR 0.47
- P44S (p.Pro44Ser), Ensembl rs917692418, REVEL 0.21, MetaLR 0.44
- P44T (p.Pro44Thr), gnomAD 6-108561338-C-A, REVEL 0.27, MetaLR 0.43
- P44A (p.Pro44Ala), gnomAD 6-108561338-C-G, REVEL 0.22, MetaLR 0.37
- P44H (p.Pro44His), gnomAD 6-108561339-C-A, REVEL 0.37, MetaLR 0.45
- P44P (p.Pro44Pro), rs1775778019, gnomAD 6-108561340-T-A, CADD 9.61
- A45D (p.Ala45Asp), cosmic curated COSV10522, gnomAD rs1775778151, REVEL 0.31, MetaLR 0.34
- A45P (p.Ala45Pro), gnomAD rs1289813804, REVEL 0.24, MetaLR 0.38
- A45T (p.Ala45Thr), gnomAD 6-108561341-G-A, REVEL 0.23, MetaLR 0.39
- A45V (p.Ala45Val), gnomAD 6-108561342-C-T, REVEL 0.24, MetaLR 0.31
- A45A (p.Ala45Ala), gnomAD 6-108561343-C-T, CADD 8.55
- K46E (p.Lys46Glu), TOPMed rs1409731500, gnomAD rs1409731500, REVEL 0.28, MetaLR 0.24
- K46R (p.Lys46Arg), gnomAD 6-108561345-A-G, REVEL 0.27, MetaLR 0.43
Public FOXO3 analysis runs
- FOXO3 analysis run — FOXO3 (1,256 variants) — completed 2026-08-20