Is FOXH1 p.Pro304= (c.912G>A) pathogenic?

FOXH1 p.Pro304= (c.912G>A) is classified Benign/Likely benign in FOXH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-19). Rare (popmax 0.158%, eas); Associated with holoprosencephaly.

What condition is associated with FOXH1 p.Pro304= (c.912G>A)?

FOXH1 p.Pro304= (c.912G>A) is associated with holoprosencephaly (ClinVar).

How common is FOXH1 p.Pro304= (c.912G>A) in the general population?

FOXH1 p.Pro304= (c.912G>A) is rare (popmax 0.158%, eas) (gnomAD).

FOXH1 p.Pro304=

c.912G>A · rs141411287 · VCV415739

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.158%, eas)

Conditions

holoprosencephaly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.26	GERP -3.9, phastCons 0.45
Overall
CADD	1.678	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.158% East Asian · 71/44,886 alleles

Filtering AF 0.129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.011% 178/1,613,226 alleles · rare exomes 166/1,460,910 · genomes 12/152,316 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.158%	632
South Asian	0.0472%	2,118
Admixed American	0.03%	3,335
Remaining individualsnot grpmax-eligible	0.0208%	4,806
European (non-Finnish)	0.0028%	35,758

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FOXH1
Protein: p.Pro304=
Coding: c.912G>A
MANE Select: NM_003923
dbSNP: rs141411287
Type: single nucleotide variant
Location: chr8:144474424 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.00 · 2 PDB
Residue 304: the 'smad-interaction domain (sid)' region

Full FOXH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

holoprosencephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXH1 p.Pro304Ala Uncertain significance ★ ⚠ same residue
FOXH1 c.*74G>A Uncertain significance ★★ same condition
FOXH1 p.Ala136Ser Uncertain significance ★★ ⚠ same condition
FOXH1 p.Ala139Asp Uncertain significance ★★ ⚠ same condition
FOXH1 p.Ala249Val Uncertain significance ★★ ⚠ same condition
FOXH1 p.Ala271Val Uncertain significance ★★ ⚠ same condition
FOXH1 p.Ala43Val Uncertain significance ★★ ⚠ same condition
FOXH1 p.Arg129Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/foxh1-p-pro304 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown