Is FOXH1 p.Pro20Ser (c.58C>T) pathogenic?

FOXH1 p.Pro20Ser (c.58C>T) is classified Uncertain significance in FOXH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.084); Very rare (popmax 0.00423%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FOXH1 p.Pro20Ser (c.58C>T)?

FOXH1 p.Pro20Ser (c.58C>T) is associated with Inborn genetic diseases, holoprosencephaly (ClinVar).

How common is FOXH1 p.Pro20Ser (c.58C>T) in the general population?

FOXH1 p.Pro20Ser (c.58C>T) is very rare (popmax 0.00423%, nfe) (gnomAD).

What do computational predictors say about FOXH1 p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely benign (score 0.084) — an in-silico prediction, not a clinical call.

FOXH1 p.Pro20Ser

c.58C>T · rs778783647 · VCV528229

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00423%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.084	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -7.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.27, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 1,515 bp · p 1e-11 · regional, not allelic
Overall
CADD	19.14	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00423% European (non-Finnish) · 46/1,087,982 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0029%

Overall 0.00344% 49/1,423,970 alleles · very rare exomes 47/1,271,762 · genomes 2/152,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00423%	23,652
Remaining individualsnot grpmax-eligible	0.00369%	27,076
South Asian	0.00163%	61,180

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.Pro20Ser
Coding: c.58C>T
MANE Select: NM_003923
dbSNP: rs778783647
Type: single nucleotide variant
Location: chr8:144475699 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.00 · 2 PDB
Residue 20: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: holoprosencephaly

Similar variants

FOXH1 p.Pro20Thr 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-pro20ser (accessed [today's date]).

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