FOXO6

Chr 1

forkhead box O6

NCBI Gene: 100132074ENSG00000204060UniProt: A8MYZ6

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in positive regulation of dendritic spine development and regulation of transcription by RNA polymerase II. Predicted to be located in chromatin and cytoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

16
ClinVar variants
11
Pathogenic / LP
0.41
pLI score
0
Active trials
Clinical Summary— FOXO6
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.21) despite low pLI — interpret in context.
📋
ClinVar Variants
11 Pathogenic / Likely Pathogenic· 4 VUS of 16 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.67LOEUF
pLI 0.405
Z-score 2.23
OE 0.21 (0.09–0.67)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.32Z-score
OE missense 0.70 (0.60–0.82)
110 obs / 156.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.21 (0.09–0.67)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.60–0.82)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.80
0≤1.21.6
LoF obs/exp: 2 / 9.4Missense obs/exp: 110 / 156.4Syn Z: 1.30

ClinVar Variant Classifications

16 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic3
VUS4
Likely Benign1
8
Pathogenic
3
Likely Pathogenic
4
VUS
1
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories· variant type breakdown unavailable

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
————8
Likely Pathogenic
————3
VUS
————4
Likely Benign
————1
Benign
————0
Total—16

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

FOXO6 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
FORKHEAD BOX O6; FOXO6
MIM #611457 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
FOXO transcription factors as therapeutic targets in human diseases.
Orea-Soufi A et al.·Trends Pharmacol Sci
2022Review
FOXO6: A unique transcription factor in disease regulation and therapeutic potential.
Li S et al.·Pharmacol Res
2025Review
Disulfiram/Cu targeting FOXO6 modulates sensitivity of hepatocellular carcinoma to lenvatinib via disrupt choline metabolic.
Wu S et al.·Cell Signal
2025
Upregulation of FoxO6 in nucleus pulposus cells promotes DNA damage repair via activation of RAD51.
Cong L et al.·Eur Rev Med Pharmacol Sci
2021
Knockdown of FOXO6 inhibits high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells.
Zhou Z et al.·J Cell Biochem
2019
The "O" class: crafting clinical care with FoxO transcription factors.
Maiese K et al.·Adv Exp Med Biol
2009Review
A fork in the path: Developing therapeutic inroads with FoxO proteins.
Maiese K et al.·Oxid Med Cell Longev
2009Review
A "FOXO" in sight: targeting Foxo proteins from conception to cancer.
Maiese K et al.·Med Res Rev
2009Review
Candidate gene study of FOXO1, FOXO4, and FOXO6 reveals no association with human longevity in Germans.
Kleindorp R et al.·Aging Cell
2011
The long noncoding RNA NORAD promotes the growth of gastric cancer cells by sponging miR-608.
Miao Z et al.·Gene
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools