FOXH1
Chr 8forkhead box H1
Also known as: FAST-1, FAST1
The FOXH1 protein is a transcriptional activator that binds specific DNA sequences and forms complexes with SMAD2/SMAD4 to regulate TGF-beta and activin signaling pathways, particularly in activating the goosecoid promoter. Mutations in FOXH1 cause holoprosencephaly-12, an autosomal dominant disorder affecting forebrain development. The gene shows tolerance to loss-of-function variants (pLI 0.04, LOEUF 0.84), suggesting that complete loss of function may not be the primary disease mechanism in affected individuals.
Limited evidence — not for standalone diagnostic reporting
Some data sources returned errors (1)
omim: Error: OMIM fetch failed: 503
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
358 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 51 | 0 | 51 |
Likely Pathogenic | 0 | 6 | 5 | 0 | 11 |
VUS | 3 | 163 | 41 | 2 | 209 |
Likely Benign | 0 | 7 | 5 | 42 | 54 |
Benign | 0 | 1 | 14 | 7 | 22 |
Conflicting | — | 9 | |||
| Total | 3 | 177 | 116 | 51 | 356 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
FOXH1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools