Is FOXC1 p.Phe511= (c.1533C>T) pathogenic?

FOXC1 p.Phe511= (c.1533C>T) is classified Uncertain significance in FOXC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-15). Very rare (popmax 8.48e-05%, nfe); Associated with Axenfeld-Rieger syndrome type 3.

What condition is associated with FOXC1 p.Phe511= (c.1533C>T)?

FOXC1 p.Phe511= (c.1533C>T) is associated with Axenfeld-Rieger syndrome type 3 (ClinVar).

How common is FOXC1 p.Phe511= (c.1533C>T) in the general population?

FOXC1 p.Phe511= (c.1533C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

FOXC1 p.Phe511=

c.1533C>T · VCV3623742

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Axenfeld-Rieger syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.012	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP -0.54, phastCons 1
Overall
CADD	10.74	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,926 alleles

Overall 6.21e-05% 1/1,611,132 alleles · very rare exomes 1/1,458,828 · genomes 0/152,304 · joint denominator

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.Phe511=
Coding: c.1533C>T
MANE Select: NM_001453
Type: single nucleotide variant
Location: chr6:1611978 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 511: 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-phe511 (accessed [today's date]).

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