Is FOXC2 p.Ser191Phe (c.572C>T) pathogenic?

FOXC2 p.Ser191Phe (c.572C>T) is classified Uncertain significance in FOXC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: likely benign (0.126); Rare (popmax 0.613%, eas).

How common is FOXC2 p.Ser191Phe (c.572C>T) in the general population?

FOXC2 p.Ser191Phe (c.572C>T) is rare (popmax 0.613%, eas) (gnomAD).

What do computational predictors say about FOXC2 p.Ser191Phe (c.572C>T)?

AlphaMissense predicts likely benign (score 0.126) — an in-silico prediction, not a clinical call.

FOXC2 p.Ser191Phe

c.572C>T · rs78018668 · VCV2717175

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.126 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.613%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.126	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -8.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP -3.4, phastCons 0.96
Regional constraint	o/e 1.27	unconstrained · MANE · 1,003 bp · p 1.1e-09 · regional, not allelic
Overall
CADD	22.3	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 0.613% East Asian · 274/44,708 alleles

Filtering AF 0.553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.53%

Overall 0.0174% 275/1,580,286 alleles · rare exomes 263/1,428,074 · genomes 12/152,212 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.613%	163
Remaining individualsnot grpmax-eligible	0.00164%	60,992

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.Ser191Phe
Coding: c.572C>T
MANE Select: NM_005251
dbSNP: rs78018668
Type: single nucleotide variant
Location: chr16:86567907 (GRCh38)
Gene constraint: LOEUF 1.807 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.45 · 8 PDB
Residue 191: the 'disordered' region; a UniProt-annotated variant site (in)

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-ser191phe (accessed [today's date]).

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