FOXH1

Chr 8

forkhead box H1

Also known as: FAST-1, FAST1

NCBI Gene: 8928 ENSG00000160973 UniProt: O75593 OMIM: 603621

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.

OMIM ResearchSummary from RefSeq, UniProt

FOXH1 encodes a human homolog of Xenopus forkhead activin signal transducer-1. FOXH1 protein binds SMAD2 and activates an activin response element via binding the DNA motif TGT(G/T)(T/G)ATT. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.84

Clinical Summary— FOXH1

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Gene-Disease Validity (ClinGen)

congenital heart disease · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 191 VUS of 281 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.042

Z-score 1.93

OE 0.37 (0.18–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-2.55Z-score

OE missense 1.53 (1.39–1.69)

278 obs / 181.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.37 (0.18–0.84)

0≤0.351.4

Missense OE?1.53 (1.39–1.69)

0≤0.61.4

Synonymous OE?1.37

0≤1.21.6

LoF obs/exp: 4 / 10.9Missense obs/exp: 278 / 181.5Syn Z: -2.59

This gene — mechanism propensity

0.6841th %ile

GOF

0.6345th %ile

LOF

0.4038th %ile

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.

DNprediction above median

GOFprediction above median

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

281 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic6

VUS191

Likely Benign53

Benign20

Conflicting9

Likely Pathogenic

191

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	6	0	0	6
VUS	3	163	23	2	191
Likely Benign	0	7	4	42	53
Benign	0	1	12	7	20
Conflicting	—				9
Total	3	177	39	51	279

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

View in ClinVar →

56 pathogenic / likely-pathogenic (of 77) ClinVar copy-number / structural variants overlap FOXH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →