Is FOXC2 p.Ala57Ser (c.169G>T) pathogenic?

FOXC2 p.Ala57Ser (c.169G>T) is classified Uncertain significance in FOXC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-03). AlphaMissense: likely benign (0.067); Very rare (popmax 0.000169%, nfe).

How common is FOXC2 p.Ala57Ser (c.169G>T) in the general population?

FOXC2 p.Ala57Ser (c.169G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about FOXC2 p.Ala57Ser (c.169G>T)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

FOXC2 p.Ala57Ser

c.169G>T · rs2144018400 · VCV2819936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -5.26	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 8.3	GERP -0.15, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 278 bp · p 0.087 · regional, not allelic
Overall
CADD	24.8	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 0.000169% European (non-Finnish) · 2/1,179,982 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,856 alleles · very rare exomes 2/1,461,654 · genomes 0/152,202 · 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.Ala57Ser
Coding: c.169G>T
MANE Select: NM_005251
dbSNP: rs2144018400
Type: single nucleotide variant
Location: chr16:86567504 (GRCh38)
Gene constraint: LOEUF 1.807 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.45 · 8 PDB

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

Similar variants

FOXC2 p.Arg121Cys Pathogenic/Likely pathogenic ★★ same type
FOXC2 p.Gln100Ter Pathogenic ★★ same type
FOXC2 p.Leu124Phe Likely pathogenic ★★ same type
FOXC2 p.Tyr99Ter Pathogenic/Likely pathogenic ★★ same type
FOXC2 p.Ala194Ser Uncertain significance ★★ ⚠ same type
FOXC2 p.Ala326Gly Uncertain significance ★★ ⚠ same type
FOXC2 p.Gln238Lys Uncertain significance ★★ ⚠ same type
FOXC2 p.Gly295Ser Uncertain significance ★★ ⚠ same type

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-ala57ser (accessed [today's date]).

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