Is FOXC1 p.Pro50Ser (c.148C>T) pathogenic?

FOXC1 p.Pro50Ser (c.148C>T) is classified Uncertain significance in FOXC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-02). AlphaMissense: likely benign (0.086); Very rare (popmax 8.5e-05%, nfe); Associated with Axenfeld-Rieger syndrome type 3.

What condition is associated with FOXC1 p.Pro50Ser (c.148C>T)?

FOXC1 p.Pro50Ser (c.148C>T) is associated with Axenfeld-Rieger syndrome type 3 (ClinVar).

How common is FOXC1 p.Pro50Ser (c.148C>T) in the general population?

FOXC1 p.Pro50Ser (c.148C>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about FOXC1 p.Pro50Ser (c.148C>T)?

AlphaMissense predicts likely benign (score 0.086) — an in-silico prediction, not a clinical call.

FOXC1 p.Pro50Ser

c.148C>T · rs1451752406 · VCV2161709

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Axenfeld-Rieger syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.086	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -7.46	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 7.2	GERP 0.95, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 355 bp · p 0.32 · regional, not allelic
Overall
CADD	23.3	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 8.5e-05% European (non-Finnish) · 1/1,176,982 alleles

Overall 6.88e-05% 1/1,453,484 alleles · very rare

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: FOXC1
Protein: p.Pro50Ser
Coding: c.148C>T
MANE Select: NM_001453
dbSNP: rs1451752406
Type: single nucleotide variant
Location: chr6:1610593 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 50: the 'required for transcriptional activation' region

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

Disease context

Axenfeld-Rieger syndrome type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXC1 p.Arg127His Pathogenic ★★ same condition
FOXC1 p.Arg127Leu Pathogenic/Likely pathogenic ★★ same condition
FOXC1 p.Arg170Trp Pathogenic ★★ same condition
FOXC1 p.Cys135Tyr Likely pathogenic ★★ same condition
FOXC1 p.Gln106Ter Pathogenic ★★ same condition
FOXC1 p.Gln120Ter Pathogenic ★★ same condition
FOXC1 p.Gln70Ter Pathogenic ★★ same condition
FOXC1 p.Gln92Ter Pathogenic ★★ 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-pro50ser (accessed [today's date]).

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