Is FOXC1 p.Ala489Val (c.1466C>T) pathogenic?

FOXC1 p.Ala489Val (c.1466C>T) is classified Uncertain significance in FOXC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-18). AlphaMissense: likely benign (0.2177); Very rare (popmax 0.00359%, sas); Associated with anterior segment dysgenesis 3.

What condition is associated with FOXC1 p.Ala489Val (c.1466C>T)?

FOXC1 p.Ala489Val (c.1466C>T) is associated with anterior segment dysgenesis 3, Axenfeld-Rieger syndrome type 3 (ClinVar).

How common is FOXC1 p.Ala489Val (c.1466C>T) in the general population?

FOXC1 p.Ala489Val (c.1466C>T) is very rare (popmax 0.00359%, sas) (gnomAD).

What do computational predictors say about FOXC1 p.Ala489Val (c.1466C>T)?

AlphaMissense predicts likely benign (score 0.2177) — an in-silico prediction, not a clinical call.

FOXC1 p.Ala489Val

c.1466C>T · VCV3593387

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2177 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00359%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

anterior segment dysgenesis 3

Computational evidence

Protein change
AlphaMissense	0.2177	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -10.43	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 1,130 bp · p 2.5e-07 · regional, not allelic
Overall
CADD	24.5	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 0.00359% South Asian · 3/83,632 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000464%

Overall 0.000581% 9/1,548,686 alleles · very rare exomes 8/1,397,756 · genomes 1/150,930 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00359%	27,877
Remaining individualsnot grpmax-eligible	0.00167%	59,988
African / African-American	0.00137%	72,762
European (non-Finnish)	0.000349%	286,645

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.Ala489Val
Coding: c.1466C>T
MANE Select: NM_001453
Type: single nucleotide variant
Location: chr6:1611911 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 489: the 'required for transcriptional activation' 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

Also linked: Axenfeld-Rieger syndrome type 3

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-ala489val (accessed [today's date]).

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