FOXC1

Chr 6AD

forkhead box C1

Also known as: ARA, ASGD3, FKHL7, FREAC-3, FREAC3, IGDA, IHG1, IRID1

NCBI Gene: 2296 ENSG00000054598 UniProt: Q12948 OMIM: 601090

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.

OMIM ResearchSummary from RefSeq, UniProt

This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it has been shown to play a role in the regulation of embryonic and ocular development. Mutations in this gene cause various glaucoma phenotypes including primary congenital glaucoma, autosomal dominant iridogoniodysgenesis anomaly, and Axenfeld-Rieger anomaly. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.312 OMIM phenotypes

Clinical Summary— FOXC1

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Gene-Disease Validity (ClinGen)

FOXC1-related anterior segment dysgenesis · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

164 unique Pathogenic / Likely Pathogenic· 428 VUS of 789 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?

0.31LOEUF

pLI 0.953

Z-score 2.88

OE 0.00 (0.00–0.31)

Highly constrained

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

Missense Constraint?

0.34Z-score

OE missense 0.94 (0.84–1.05)

213 obs / 227.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.31)

0≤0.351.4

Missense OE?0.94 (0.84–1.05)

0≤0.61.4

Synonymous OE?1.61

0≤1.21.6

LoF obs/exp: 0 / 9.6Missense obs/exp: 213 / 227.5Syn Z: -4.90

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFOXC1-related Axenfeld-Rieger syndromeLOFAD

This gene — mechanism propensity

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 · 68% of P/LP variants are LoF · LOEUF 0.31 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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 FOXC2.1

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 14564054 ↗

ClinVar Variant Classifications

789 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic108

Likely Pathogenic56

VUS428

Likely Benign147

Benign22

Conflicting28

108

Pathogenic

Likely Pathogenic

428

VUS

147

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	77	21	10	0	108
Likely Pathogenic	34	21	1	0	56
VUS	2	376	11	39	428
Likely Benign	0	14	10	123	147
Benign	0	9	5	8	22
Conflicting	—				28
Total	113	441	37	170	789

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

View in ClinVar →

75 pathogenic / likely-pathogenic (of 87) ClinVar copy-number / structural variants overlap FOXC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →