Is FOXC2 p.Pro352Leu (c.1055C>T) pathogenic?

FOXC2 p.Pro352Leu (c.1055C>T) is classified Uncertain significance in FOXC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-06). AlphaMissense: likely benign (0.1203); Very rare (popmax 0.000188%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FOXC2 p.Pro352Leu (c.1055C>T)?

FOXC2 p.Pro352Leu (c.1055C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FOXC2 p.Pro352Leu (c.1055C>T) in the general population?

FOXC2 p.Pro352Leu (c.1055C>T) is very rare (popmax 0.000188%, nfe) (gnomAD).

What do computational predictors say about FOXC2 p.Pro352Leu (c.1055C>T)?

AlphaMissense predicts likely benign (score 0.1203) — an in-silico prediction, not a clinical call.

FOXC2 p.Pro352Leu

c.1055C>T · rs1974231499 · VCV1304943

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1203 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000188%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1203	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 0.69, phastCons 0.85
Regional constraint	o/e 1.27	unconstrained · MANE · 1,003 bp · p 1.1e-09 · regional, not allelic
Overall
CADD	23.1	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 0.000188% European (non-Finnish) · 2/1,065,656 alleles

Filtering AF 3.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.2e-05%

Overall 0.000144% 2/1,390,504 alleles · very rare exomes 2/1,240,562 · genomes 0/149,942 · 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.Pro352Leu
Coding: c.1055C>T
MANE Select: NM_005251
dbSNP: rs1974231499
Type: single nucleotide variant
Location: chr16:86568390 (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

Disease context

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

Similar variants

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
FOXC2 p.Pro107Ala 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-pro352leu (accessed [today's date]).

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