Is FOXC1 p.Arg281= (c.843G>T) pathogenic?

FOXC1 p.Arg281= (c.843G>T) is classified Likely benign in FOXC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). Rare (popmax 0.108%, afr); Associated with Axenfeld-Rieger syndrome type 3.

What condition is associated with FOXC1 p.Arg281= (c.843G>T)?

FOXC1 p.Arg281= (c.843G>T) is associated with Axenfeld-Rieger syndrome type 3 (ClinVar).

How common is FOXC1 p.Arg281= (c.843G>T) in the general population?

FOXC1 p.Arg281= (c.843G>T) is rare (popmax 0.108%, afr) (gnomAD).

FOXC1 p.Arg281=

c.843G>T · rs1006154109 · VCV729554

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.108%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -3.3, phastCons 1
Overall
CADD	7.009	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.108% African / African-American · 71/65,452 alleles

Filtering AF 0.0882% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0807%

Overall 0.0057% 79/1,386,148 alleles · rare exomes 45/1,235,928 · genomes 34/150,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.108%	922
Remaining individualsnot grpmax-eligible	0.0135%	7,397
Admixed American	0.00309%	32,312

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.Arg281=
Coding: c.843G>T
MANE Select: NM_001453
dbSNP: rs1006154109
Type: single nucleotide variant
Location: chr6:1611288 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 281: the 'disordered' region; the 'required for transcriptional inhibition' 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-arg281 (accessed [today's date]).

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