Is FOXH1 p.Pro183= (c.549G>A) pathogenic?

FOXH1 p.Pro183= (c.549G>A) is classified Likely benign in FOXH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-18). Very rare (popmax 0.00555%, sas); Associated with holoprosencephaly.

What condition is associated with FOXH1 p.Pro183= (c.549G>A)?

FOXH1 p.Pro183= (c.549G>A) is associated with holoprosencephaly (ClinVar).

How common is FOXH1 p.Pro183= (c.549G>A) in the general population?

FOXH1 p.Pro183= (c.549G>A) is very rare (popmax 0.00555%, sas) (gnomAD).

FOXH1 p.Pro183=

c.549G>A · VCV4806839

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00555%, sas)

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 0.28	GERP -2.8, phastCons 0.98
Overall
CADD	3.195	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00555% South Asian · 5/90,034 alleles

Filtering AF 0.00212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00138%

Overall 0.000686% 11/1,602,652 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00555%	18,007
East Asian	0.00449%	22,250
Admixed American	0.00169%	59,150
Remaining individualsnot grpmax-eligible	0.00162%	61,896
European (non-Finnish)	0.00017%	587,109

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.Pro183=
Coding: c.549G>A
MANE Select: NM_003923
Type: single nucleotide variant
Location: chr8:144474787 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.00 · 2 PDB
Residue 183: the 'disordered' 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.Pro183Leu 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-pro183 (accessed [today's date]).

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