Is FOXC1 p.Pro274fs (c.821del) pathogenic?

FOXC1 p.Pro274fs (c.821del) is classified Pathogenic/Likely pathogenic in FOXC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-04). Very rare (popmax 0.00273%, amr); Associated with Axenfeld-Rieger syndrome type 3.

What condition is associated with FOXC1 p.Pro274fs (c.821del)?

FOXC1 p.Pro274fs (c.821del) is associated with Axenfeld-Rieger syndrome type 3 (ClinVar).

How common is FOXC1 p.Pro274fs (c.821del) in the general population?

FOXC1 p.Pro274fs (c.821del) is very rare (popmax 0.00273%, amr) (gnomAD).

FOXC1 p.Pro274fs

c.821del · rs2113112720 · VCV1693144

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00273%, amr)

Conditions

Axenfeld-Rieger syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (1 of 1) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.8	GERP 0.55, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00273% Admixed American · 1/36,588 alleles

Filtering AF 0.0002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000131%

Overall 0.000715% 9/1,258,060 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00273%	36,588
Remaining individualsnot grpmax-eligible	0.00189%	52,782
South Asian	0.00141%	70,728
European (non-Finnish)	0.000555%	180,145

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.Pro274fs
Coding: c.821del
MANE Select: NM_001453
dbSNP: rs2113112720
Type: Deletion
Location: chr6:1611261 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 274: 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.Pro274Ser Uncertain significance ★ ⚠ same residue
FOXC1 p.Ala251fs Pathogenic/Likely pathogenic ★★ same condition
FOXC1 p.Ala28fs Pathogenic/Likely pathogenic ★★ same condition
FOXC1 p.Gln200fs Pathogenic ★★ same condition
FOXC1 p.Ile223fs Pathogenic/Likely pathogenic ★★ same condition
FOXC1 p.Leu168fs Pathogenic/Likely pathogenic ★★ same condition
FOXC1 p.Leu240fs Pathogenic ★★ same condition
FOXC1 p.386GAG[1] Uncertain significance ★★ 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-pro274fs (accessed [today's date]).

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