Is FOXC1 p.Pro17Ser (c.49C>T) pathogenic?

FOXC1 p.Pro17Ser (c.49C>T) is classified Uncertain significance in FOXC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-06). AlphaMissense: likely pathogenic (0.8817); Very rare (popmax 0.00141%, afr); Associated with Axenfeld-Rieger syndrome type 3.

What condition is associated with FOXC1 p.Pro17Ser (c.49C>T)?

FOXC1 p.Pro17Ser (c.49C>T) is associated with Axenfeld-Rieger syndrome type 3 (ClinVar).

How common is FOXC1 p.Pro17Ser (c.49C>T) in the general population?

FOXC1 p.Pro17Ser (c.49C>T) is very rare (popmax 0.00141%, afr) (gnomAD).

What do computational predictors say about FOXC1 p.Pro17Ser (c.49C>T)?

AlphaMissense predicts likely pathogenic (score 0.8817) — an in-silico prediction, not a clinical call.

FOXC1 p.Pro17Ser

c.49C>T · rs1450176374 · VCV2983621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00141%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Axenfeld-Rieger syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.8817	likely pathogenic
REVEL	0.434	indeterminate
SaProt	LLR -8.51	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 0.96, 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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00141% African / African-American · 1/71,050 alleles

Filtering AF 8.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.6e-05%

Overall 0.000399% 6/1,502,452 alleles · very rare exomes 5/1,350,952 · genomes 1/151,500 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00173%	57,810
African / African-Americangrpmax	0.00141%	71,050
European (non-Finnish)	0.000355%	281,853

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro17Ser
Coding: c.49C>T
MANE Select: NM_001453
dbSNP: rs1450176374
Type: single nucleotide variant
Location: chr6:1610494 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 17: 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-pro17ser (accessed [today's date]).

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