Is FOXC2 p.Ser456Phe (c.1367C>T) pathogenic?

FOXC2 p.Ser456Phe (c.1367C>T) is classified Uncertain significance in FOXC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-05). AlphaMissense: ambiguous (0.5605); Very rare (popmax 0.00223%, eas).

How common is FOXC2 p.Ser456Phe (c.1367C>T) in the general population?

FOXC2 p.Ser456Phe (c.1367C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about FOXC2 p.Ser456Phe (c.1367C>T)?

AlphaMissense predicts ambiguous (score 0.5605) — an in-silico prediction, not a clinical call.

FOXC2 p.Ser456Phe

c.1367C>T · VCV4931690

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
AlphaMissense	0.5605	ambiguous
REVEL	0.518	indeterminate
SaProt	LLR -6.72	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 1,003 bp · p 1.1e-09 · regional, not allelic
Overall
CADD	27.7	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 0.00223% East Asian · 1/44,866 alleles

Overall 0.000186% 3/1,612,880 alleles · very rare exomes 3/1,460,652 · genomes 0/152,228 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,866
Remaining individualsnot grpmax-eligible	0.0016%	62,492
European (non-Finnish)	8.47e-05%	1,180,002

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.Ser456Phe
Coding: c.1367C>T
MANE Select: NM_005251
Type: single nucleotide variant
Location: chr16:86568702 (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-ser456phe (accessed [today's date]).

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