Is FOXC2 p.Pro403fs (c.1208del) pathogenic?

FOXC2 p.Pro403fs (c.1208del) is classified Likely pathogenic in FOXC2 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.00366%, amr); Associated with lymphedema-distichiasis syndrome.

What condition is associated with FOXC2 p.Pro403fs (c.1208del)?

FOXC2 p.Pro403fs (c.1208del) is associated with lymphedema-distichiasis syndrome (ClinVar).

How common is FOXC2 p.Pro403fs (c.1208del) in the general population?

FOXC2 p.Pro403fs (c.1208del) is very rare (popmax 0.00366%, amr) (gnomAD).

FOXC2 p.Pro403fs

c.1208del · VCV4294514

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00366%, amr)

Conditions

lymphedema-distichiasis syndrome

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 2.5	GERP 0.69, phastCons 1
Region caveats
Repeat context	tandem	(CGC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00366% Admixed American · 1/27,326 alleles

Filtering AF 7.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.2e-05%

Overall 0.000438% 5/1,142,146 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00366%	27,326
South Asian	0.00253%	39,472
European (non-Finnish)	0.000294%	340,221

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: FOXC2
Protein: p.Pro403fs
Coding: c.1208del
MANE Select: NM_005251
Type: Deletion
Location: chr16:86568539 (GRCh38)
Gene constraint: LOEUF 1.807 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.45 · 8 PDB
Residue 403: the 'disordered' region

Full FOXC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lymphedema-distichiasis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXC2 p.Tyr305fs Pathogenic ★★ same condition
FOXC2 p.Gln390_His396del Uncertain significance ★★ same condition
FOXC2 c.(?_1 Likely pathogenic ★ same condition
FOXC2 p.Ala325fs Pathogenic ★ same condition
FOXC2 p.Gln407fs Likely pathogenic ★ same condition
FOXC2 p.Lys177del Uncertain significance ★ same condition
FOXC2 p.Gln444fs Pathogenic same condition
FOXC2 p.Gly97fs 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/foxc2-p-pro403fs (accessed [today's date]).

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