FOXO3

Chr 6

forkhead box O3

Also known as: AF6q21, FKHRL1, FKHRL1P2, FOXO2, FOXO3A

NCBI Gene: 2309ENSG00000118689UniProt: O43524

This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. This gene likely functions as a trigger for apoptosis through expression of genes necessary for cell death. Translocation of this gene with the MLL gene is associated with secondary acute leukemia. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

0
Active trials
18
Pathogenic / LP
122
ClinVar variants
312
Pubs (1 yr)
1.7
Missense Z
0.27
LOEUF· LoF intolerant
Clinical Summary— FOXO3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
18 Pathogenic / Likely Pathogenic· 90 VUS of 122 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.27LOEUF
pLI 0.988
Z-score 3.69
OE 0.06 (0.02–0.27)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
1.68Z-score
OE missense 0.76 (0.69–0.83)
288 obs / 380.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.06 (0.02–0.27)
0≤0.351.4
Missense OE0.76 (0.69–0.83)
0≤0.61.4
Synonymous OE1.13
0≤1.21.6
LoF obs/exp: 1 / 17.8Missense obs/exp: 288 / 380.3Syn Z: -1.29
LOF
DN
0.4090th %ile
GOF
0.3590th %ile
LOF
0.81top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.27

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

122 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
VUS90
Likely Benign6
Benign8
18
Pathogenic
90
VUS
6
Likely Benign
8
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
18
0
18
Likely Pathogenic
0
0
0
0
0
VUS
1
82
7
0
90
Likely Benign
0
4
0
2
6
Benign
0
2
3
3
8
Total188285122

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

FOXO3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients