Is FOXC2 p.Ala384Val (c.1151C>T) pathogenic?

FOXC2 p.Ala384Val (c.1151C>T) is classified Uncertain significance in FOXC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.1239); Ultra-rare (popmax 0.028%, mid); Associated with Inborn genetic diseases.

What condition is associated with FOXC2 p.Ala384Val (c.1151C>T)?

FOXC2 p.Ala384Val (c.1151C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FOXC2 p.Ala384Val (c.1151C>T) in the general population?

FOXC2 p.Ala384Val (c.1151C>T) is ultra-rare (popmax 0.028%, mid) (gnomAD).

What do computational predictors say about FOXC2 p.Ala384Val (c.1151C>T)?

AlphaMissense predicts likely benign (score 0.1239) — an in-silico prediction, not a clinical call.

FOXC2 p.Ala384Val

c.1151C>T · VCV4620209

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1239 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1239	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -8.41	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 4.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 1,003 bp · p 1.1e-09 · regional, not allelic
Overall
CADD	18.78	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 0.028% Middle Eastern · 1/3,570 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00364%

Overall 0.00077% 10/1,298,408 alleles · ultra-rare exomes 9/1,148,496 · genomes 1/149,912 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.028%	3,570
South Asian	0.0125%	7,991
Remaining individualsnot grpmax-eligible	0.00212%	47,278
European (non-Finnish)	0.000196%	510,173

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.Ala384Val
Coding: c.1151C>T
MANE Select: NM_005251
Type: single nucleotide variant
Location: chr16:86568486 (GRCh38)
Gene constraint: LOEUF 1.807 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.45 · 8 PDB
Residue 384: 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.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-ala384val (accessed [today's date]).

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