FOXC1 encodes a forkhead transcription factor that regulates embryonic development of the eye, bone, cardiovascular system, kidney, and skin by binding to specific DNA sequences and controlling target gene expression. Mutations cause autosomal dominant ocular malformations including primary congenital glaucoma, Axenfeld-Rieger anomaly, and iridogoniodysgenesis anomaly. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

OMIMResearchSummary from RefSeq, UniProt
LOFmechanismADLOEUF 0.312 OMIM phenotypes
Clinical SummaryFOXC1
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Gene-Disease Validity (ClinGen)
FOXC1-related anterior segment dysgenesis · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.
Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.31LOEUF
pLI 0.953
Z-score 2.88
OE 0.00 (0.000.31)
Highly constrained

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

Missense Constraint
0.34Z-score
OE missense 0.94 (0.841.05)
213 obs / 227.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.00 (0.000.31)
00.351.4
Missense OE0.94 (0.841.05)
00.61.4
Synonymous OE1.61
01.21.6
LoF obs/exp: 0 / 9.6Missense obs/exp: 213 / 227.5Syn Z: -4.90
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveFOXC1-related Axenfeld-Rieger syndromeLOFAD
DN
0.4190th %ile
GOF
0.3292th %ile
LOF
0.83top 5%

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

LOFprediction above median · 1 literature citation · LOEUF 0.31

Literature Evidence

LOFTwo human genetic diseases have recently been associated with loss of function of one allele of different Fox-box genes: Axenfeld-Rieger anomaly of the anterior eye chamber associated with haploinsufficiency of FOXC1 and lymphedema-distichiasis associated with haploinsufficiency of FOXC2.PMID:14564054

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

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

FOXC1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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