FOXF1

Chr 16AD

forkhead box F1

Also known as: ACDMPV, FKHL5, FREAC1

NCBI Gene: 2294 ENSG00000103241 UniProt: Q12946 OMIM: 601089

FOXF1 encodes a forkhead transcription factor that activates lung-specific genes and regulates pulmonary development. Mutations cause alveolar capillary dysplasia with misalignment of pulmonary veins, a severe neonatal respiratory disorder with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.96, LOEUF 0.30), reflecting its critical role in pulmonary vascular development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.301 OMIM phenotype

Clinical Summary— FOXF1

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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.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 54 VUS of 95 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

1.09Z-score

OE missense 0.79 (0.69–0.90)

161 obs / 204.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.30)

0≤0.351.4

Missense OE?0.79 (0.69–0.90)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 0 / 9.9Missense obs/exp: 161 / 204.9Syn Z: -2.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFOXF1-related alveolar capillary dysplasia with misalignment of pulmonary veinsLOFAD

This gene — mechanism propensity

0.4090th %ile

GOF

0.2597th %ile

LOF

0.84top 5%

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

LOFprediction above median · 1 literature citation · 43% of P/LP variants are LoF · LOEUF 0.30 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFPrenatal Diagnosis of Cystic Hygroma related to a Deletion of 16q24.1 with Haploinsufficiency of FOXF1 and FOXC2 Genes.1

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

References

1.PMID 23074687 ↗

ClinVar Variant Classifications

95 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic5

VUS54

Likely Benign18

Benign4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	2	1	0	9
Likely Pathogenic	0	5	0	0	5
VUS	0	52	2	0	54
Likely Benign	0	4	6	8	18
Benign	0	1	2	1	4
Total	6	64	11	9	90

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

View in ClinVar →

5 pathogenic / likely-pathogenic (of 5) ClinVar copy-number / structural variants overlap FOXF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →