Is FOXC2 p.Ala261Asp (c.782C>A) pathogenic?

FOXC2 p.Ala261Asp (c.782C>A) is classified Uncertain significance in FOXC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-07). AlphaMissense: likely benign (0.1694); Very rare (popmax 0.00613%, afr); Associated with lymphedema-distichiasis syndrome.

What condition is associated with FOXC2 p.Ala261Asp (c.782C>A)?

FOXC2 p.Ala261Asp (c.782C>A) is associated with lymphedema-distichiasis syndrome (ClinVar).

How common is FOXC2 p.Ala261Asp (c.782C>A) in the general population?

FOXC2 p.Ala261Asp (c.782C>A) is very rare (popmax 0.00613%, afr) (gnomAD).

What do computational predictors say about FOXC2 p.Ala261Asp (c.782C>A)?

AlphaMissense predicts likely benign (score 0.1694) — an in-silico prediction, not a clinical call.

FOXC2 p.Ala261Asp

c.782C>A · rs1974225710 · VCV1030897

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1694 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00613%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphedema-distichiasis syndrome

Computational evidence

Protein change
AlphaMissense	0.1694	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -9.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -1.6, phastCons 0.65
Regional constraint	o/e 1.27	unconstrained · MANE · 1,003 bp · p 1.1e-09 · regional, not allelic
Overall
CADD	17.47	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00613% African / African-American · 4/65,266 alleles

Filtering AF 0.00203% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.000293% 4/1,366,240 alleles · very rare exomes 4/1,214,318 · genomes 0/151,922 · 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: FOXC2
Protein: p.Ala261Asp
Coding: c.782C>A
MANE Select: NM_005251
dbSNP: rs1974225710
Type: single nucleotide variant
Location: chr16:86568117 (GRCh38)
Gene constraint: LOEUF 1.807 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.45 · 8 PDB
Residue 261: 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.Ala261Thr Uncertain significance ★ ⚠ same residue
FOXC2 p.Arg121Cys Pathogenic/Likely pathogenic ★★ same condition
FOXC2 p.Gln100Ter Pathogenic ★★ same condition
FOXC2 p.Leu124Phe Likely pathogenic ★★ same condition
FOXC2 p.Tyr99Ter Pathogenic/Likely pathogenic ★★ same condition
FOXC2 p.Gln238Lys Uncertain significance ★★ ⚠ same condition
FOXC2 p.His182Asp Uncertain significance ★★ ⚠ same condition
FOXC2 p.Pro140His 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/foxc2-p-ala261asp (accessed [today's date]).

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