Is FOXC1 p.Arg199= (c.597C>G) pathogenic?

FOXC1 p.Arg199= (c.597C>G) is classified Conflicting classifications of pathogenicity in FOXC1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-18). Rare (popmax 0.243%, afr); Associated with Axenfeld-Rieger syndrome type 3.

What condition is associated with FOXC1 p.Arg199= (c.597C>G)?

FOXC1 p.Arg199= (c.597C>G) is associated with Axenfeld-Rieger syndrome type 3 (ClinVar).

How common is FOXC1 p.Arg199= (c.597C>G) in the general population?

FOXC1 p.Arg199= (c.597C>G) is rare (popmax 0.243%, afr) (gnomAD).

FOXC1 p.Arg199=

c.597C>G · rs529227054 · VCV286506

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.243%, afr)

Conditions

Axenfeld-Rieger syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP -0.51, phastCons 1
Overall
CADD	11.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.243% African / African-American · 173/71,082 alleles

Filtering AF 0.214% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.202%

Overall 0.0117% 178/1,520,688 alleles · rare exomes 79/1,369,596 · genomes 99/151,092 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.243%	411
Middle Eastern	0.02%	5,012
Admixed American	0.00413%	24,187
Remaining individualsnot grpmax-eligible	0.00342%	29,281

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.Arg199=
Coding: c.597C>G
MANE Select: NM_001453
dbSNP: rs529227054
Type: single nucleotide variant
Location: chr6:1611042 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 199: the 'disordered' 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.Arg199Leu Uncertain significance ★ ⚠ same residue
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

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-arg199 (accessed [today's date]).

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