Is FOXC1 p.Ser158Pro (c.472T>C) pathogenic?

FOXC1 p.Ser158Pro (c.472T>C) is classified Uncertain significance in FOXC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with anterior segment dysgenesis 3.

What condition is associated with FOXC1 p.Ser158Pro (c.472T>C)?

FOXC1 p.Ser158Pro (c.472T>C) is associated with anterior segment dysgenesis 3 (ClinVar).

How common is FOXC1 p.Ser158Pro (c.472T>C) in the general population?

FOXC1 p.Ser158Pro (c.472T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXC1 p.Ser158Pro (c.472T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

FOXC1 p.Ser158Pro

c.472T>C · VCV4856349

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

anterior segment dysgenesis 3

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 8% in FOXC1
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -13.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 2, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 135 bp · p 1e-06 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FOXC1
Protein: p.Ser158Pro
Coding: c.472T>C
MANE Select: NM_001453
Type: single nucleotide variant
Location: chr6:1610917 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 158: a DNA-binding region

Full FOXC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

anterior segment dysgenesis 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXC1 p.Ser158= Conflicting classifications of pathogenicity ★ same residue
FOXC1 p.Cys135Tyr Likely pathogenic ★★ same condition
FOXC1 p.Ser131Leu Pathogenic/Likely pathogenic ★★ same condition
FOXC1 p.Tyr47Ter Pathogenic/Likely pathogenic ★★ same condition
FOXC1 p.Ala288Val Uncertain significance ★★ ⚠ same condition
FOXC1 p.Ala296Ser Uncertain significance ★★ ⚠ same condition
FOXC1 p.Ala336Val Uncertain significance ★★ ⚠ same condition
FOXC1 p.Ala342Val 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/foxc1-p-ser158pro (accessed [today's date]).

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