Is FOXC2 p.Pro89Ser (c.265C>T) pathogenic?

FOXC2 p.Pro89Ser (c.265C>T) is classified Uncertain significance in FOXC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.2942); Very rare (popmax 0.00381%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FOXC2 p.Pro89Ser (c.265C>T)?

FOXC2 p.Pro89Ser (c.265C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FOXC2 p.Pro89Ser (c.265C>T) in the general population?

FOXC2 p.Pro89Ser (c.265C>T) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about FOXC2 p.Pro89Ser (c.265C>T)?

AlphaMissense predicts likely benign (score 0.2942) — an in-silico prediction, not a clinical call.

FOXC2 p.Pro89Ser

c.265C>T · VCV4259017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2942	likely benign
REVEL	0.701	pathogenic-leaning
SaProt	LLR -9.19	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 278 bp · p 0.087 · regional, not allelic
Overall
CADD	25.2	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 0.00381% European (non-Finnish) · 45/1,180,012 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00291% 47/1,614,004 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00381%	26,222
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Pro89Ser
Coding: c.265C>T
MANE Select: NM_005251
Type: single nucleotide variant
Location: chr16:86567600 (GRCh38)
Gene constraint: LOEUF 1.807 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.45 · 8 PDB
Residue 89: a DNA-binding region; a β-strand

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.Pro89= Likely benign ★ 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-pro89ser (accessed [today's date]).

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