FOXO1

Chr 13

forkhead box O1

Also known as: FKH1, FKHR, FOXO1A

NCBI Gene: 2308 ENSG00000150907 UniProt: Q12778

FOXO1 encodes a forkhead transcription factor that regulates metabolic homeostasis, glucose metabolism, and cell survival in response to insulin signaling and oxidative stress. Somatic translocations involving FOXO1 cause alveolar rhabdomyosarcoma, a malignant soft tissue tumor that typically affects children and adolescents. The gene is highly constrained against loss-of-function variants (pLI 0.997), indicating it is essential for normal cellular function.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation. Translocation of this gene with PAX3 has been associated with alveolar rhabdomyosarcoma. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtRhabdomyosarcoma 2

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

1277

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.17

LOEUF· LoF intol.

LOF

Mechanism· predicted

📖

GeneReview available — FOXO1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.17LOEUF

pLI 0.997

Z-score 3.86

OE 0.00 (0.00–0.17)

Highly constrained

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

Missense Constraint?

1.71Z-score

OE missense 0.72 (0.65–0.81)

221 obs / 304.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.17)

0≤0.351.4

Missense OE?0.72 (0.65–0.81)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 0 / 17.3Missense obs/exp: 221 / 304.9Syn Z: -0.62

Background carrier burden — how many people carry a rare variant somewhere in FOXO1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 86

799 rare PASS variants

Rare truncating (LoF)

1 in 11,000

27 rare PASS variants

Rare synonymous (reference)

1 in 120

405 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FOXO1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 36,000
South Asian	~43k	1 in 80	1 in 7,800
Remaining (unassigned)	~30k	1 in 62	≈ 1 in 26,000
European (Finnish)	~27k	1 in 180	1 in 2,300
Admixed American	~22k	1 in 76	none seen
African / African American	~21k	1 in 57	≈ 1 in 10,000
East Asian	~20k	1 in 100	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 240	1 in 2,100
Middle Eastern	~2,884	1 in 81	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 1 of 2 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 2.? see exons ↓