FOXF1

Chr 16AD

forkhead box F1

Also known as: ACDMPV, FKHL5, FREAC1

NCBI Gene: 2294ENSG00000103241UniProt: Q12946

This gene belongs to the forkhead family of transcription factors which is characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in the regulation of pulmonary genes as well as embryonic development. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Alveolar capillary dysplasia with misalignment of pulmonary veinsMIM #265380
AD
288
ClinVar variants
112
Pathogenic / LP
0.96
pLI score· haploinsufficient
0
Active trials
Clinical Summary— FOXF1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
112 Pathogenic / Likely Pathogenic· 99 VUS of 288 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.30LOEUF
pLI 0.958
Z-score 2.92
OE 0.00 (0.00–0.30)
Highly constrained

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

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.
1.09Z-score
OE missense 0.79 (0.69–0.90)
161 obs / 204.9 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.0.00 (0.00–0.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.69–0.90)
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.1.28
0≤1.21.6
LoF obs/exp: 0 / 9.9Missense obs/exp: 161 / 204.9Syn Z: -2.15

ClinVar Variant Classifications

288 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic86
Likely Pathogenic26
VUS99
Likely Benign40
Benign31
Conflicting6
86
Pathogenic
26
Likely Pathogenic
99
VUS
40
Likely Benign
31
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
21
10
55
0
86
Likely Pathogenic
5
15
6
0
26
VUS
1
80
18
0
99
Likely Benign
0
6
11
23
40
Benign
0
4
20
7
31
Conflicting
—6
Total2711511030288

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

View in ClinVar →

Protein Context — Lollipop Plot

FOXF1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

FOXF1-related alveolar capillary dysplasia with misalignment of pulmonary veins

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
FORKHEAD BOX F1; FOXF1
MIM #601089 · *

Alveolar capillary dysplasia with misalignment of pulmonary veins

MIM #265380

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Foxf1 knockdown promotes BMSC osteogenesis in part by activating the Wnt/β-catenin signalling pathway and prevents ovariectomy-induced bone loss.
Shen G et al.·EBioMedicine
2020
Identification of endothelial and mesenchymal FOXF1 enhancers involved in alveolar capillary dysplasia.
Wang G et al.·Nat Commun
2024
Single Cell Multiomics Identifies Cells and Genetic Networks Underlying Alveolar Capillary Dysplasia.
Guo M et al.·Am J Respir Crit Care Med
2023
The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma.
Lamhamedi-Cherradi SE et al.·Nat Commun
2022
FOXF1 inhibits invasion and metastasis of lung adenocarcinoma cells and enhances anti-tumor immunity via MFAP4/FAK signal axis.
Wang Z et al.·Sci Rep
2024
Differentiation of BCMA-specific induced pluripotent stem cells into rejuvenated CD8αβ+ T cells targeting multiple myeloma.
Bae J et al.·Blood
2024
Molecular and clinical analyses of 16q24.1 duplications involving FOXF1 identify an evolutionarily unstable large minisatellite.
Dharmadhikari AV et al.·BMC Med Genet
2014
Genetic factors in esophageal atresia, tracheo-esophageal fistula and the VACTERL association: roles for FOXF1 and the 16q24.1 FOX transcription factor gene cluster, and review of the literature.
Shaw-Smith C·Eur J Med Genet
2010Review
FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor.
Ran L et al.·Cancer Discov
2018
Clinical, Histopathological, and Molecular Diagnostics in Lethal Lung Developmental Disorders.
Vincent M et al.·Am J Respir Crit Care Med
2019Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Deregulation of FOXF1/FENDRR from t(14;16)(q32;q24) defines a subtype of high-risk lineage ambiguous leukemia.
Di Giacomo D et al.·Blood
2026
FOXF1 and SHH participate in the regulation of iron signaling in pulmonary fibrosis.
Wang X et al.·Redox Biol
2025🔓 Open Access
DKK3, regulated by FOXF1-EZH2 axis, takes action on tubular epithelial cells senescence to trigger glomerular endothelial cells ferroptosis involving in renal fibrosis.
Cao H et al.·Mech Ageing Dev
2025
Foxf1-mediated co-regulation of miR-495 and let-7c modulates epicardial cell migration and myocardial specification.
Castillo-Casas JM et al.·Cell Mol Life Sci
2025🔓 Open Access
Bronchopulmonary dysplasia with pulmonary hypertension associates with semaphorin signaling loss and functionally decreased FOXF1 expression.
Shirazi SP et al.·Nat Commun
2025🔓 Open AccessFunctional
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