FOXC2

Chr 16AD

forkhead box C2

Also known as: FKHL14, LD, MFH-1, MFH1

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 may play a role in the development of mesenchymal tissues. [provided by RefSeq, Jul 2008]

OMIMResearchGenerating clinical summary…
LOFmechanismADLOEUF 0.792 OMIM phenotypes
Clinical SummaryFOXC2
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Gene-Disease Validity (ClinGen)
lymphedema-distichiasis syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint?
0.79LOEUF
pLI 0.134
Z-score 2.02
OE 0.30 (0.140.79)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?
-0.25Z-score
OE missense 1.05 (0.941.17)
236 obs / 225.4 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?
LoF OE?0.30 (0.140.79)
00.351.4
Missense OE?1.05 (0.941.17)
00.61.4
Synonymous OE?1.53
01.21.6
LoF obs/exp: 3 / 9.8Missense obs/exp: 236 / 225.4Syn Z: -4.25
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveFOXC2-related lymphedema-distichiasis syndromeLOFAD

This gene — mechanism propensity

DN
0.6455th %ile
GOF
0.4480th %ile
LOF
0.60top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · ClinGen HI: Sufficient evidence for dosage pathogenicity
DNprediction above median
GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFOur results suggest that gain-of-function mutations may also cause lymphedema. One would expect that in this case, lymphatic hypoplasia would be the underlying abnormality. Patients with activating mutations might present with Meige disease.1
LOFMutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome2

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

FOXC2 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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