Is FOXC2 p.Pro402Thr (c.1204C>A) pathogenic?

FOXC2 p.Pro402Thr (c.1204C>A) is classified Uncertain significance in FOXC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: likely benign (0.0771); Very rare (popmax 0.00742%, sas); Associated with Inborn genetic diseases.

What condition is associated with FOXC2 p.Pro402Thr (c.1204C>A)?

FOXC2 p.Pro402Thr (c.1204C>A) is associated with Inborn genetic diseases (ClinVar).

How common is FOXC2 p.Pro402Thr (c.1204C>A) in the general population?

FOXC2 p.Pro402Thr (c.1204C>A) is very rare (popmax 0.00742%, sas) (gnomAD).

What do computational predictors say about FOXC2 p.Pro402Thr (c.1204C>A)?

AlphaMissense predicts likely benign (score 0.0771) — an in-silico prediction, not a clinical call.

FOXC2 p.Pro402Thr

c.1204C>A · rs1402873848 · VCV2487529

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00742%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0771	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -11.68	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 0.68, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 1,003 bp · p 1.1e-09 · regional, not allelic
Overall
CADD	18.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00742% South Asian · 3/40,416 alleles

Filtering AF 0.00197% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000349% 4/1,147,262 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00742%	13,472
Remaining individualsnot grpmax-eligible	0.00209%	47,754

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.Pro402Thr
Coding: c.1204C>A
MANE Select: NM_005251
dbSNP: rs1402873848
Type: single nucleotide variant
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 402: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXC2 p.Pro402Leu Pathogenic ⚠ same residue
FOXC2 p.Ala194Ser Uncertain significance ★★ ⚠ same condition
FOXC2 p.Ala326Gly Uncertain significance ★★ ⚠ same condition
FOXC2 p.Gly295Ser Uncertain significance ★★ ⚠ same condition
FOXC2 p.Gly314Asp Uncertain significance ★★ ⚠ same condition
FOXC2 p.Gly467Glu Uncertain significance ★★ ⚠ same condition
FOXC2 p.Ile120Val Uncertain significance ★★ ⚠ same condition
FOXC2 p.Met453Ile 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-pro402thr (accessed [today's date]).

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