Is FOXC2 p.Arg242Ser (c.724C>A) pathogenic?

FOXC2 p.Arg242Ser (c.724C>A) is classified Uncertain significance in FOXC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-26). AlphaMissense: likely benign (0.2889); Very rare (popmax 0.00891%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FOXC2 p.Arg242Ser (c.724C>A)?

FOXC2 p.Arg242Ser (c.724C>A) is associated with Inborn genetic diseases (ClinVar).

How common is FOXC2 p.Arg242Ser (c.724C>A) in the general population?

FOXC2 p.Arg242Ser (c.724C>A) is very rare (popmax 0.00891%, nfe) (gnomAD).

What do computational predictors say about FOXC2 p.Arg242Ser (c.724C>A)?

AlphaMissense predicts likely benign (score 0.2889) — an in-silico prediction, not a clinical call.

FOXC2 p.Arg242Ser

c.724C>A · rs1022844166 · VCV2320426

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2889	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -5.17	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 3	GERP -3.9, phastCons 0.98
Regional constraint	o/e 1.27	unconstrained · MANE · 1,003 bp · p 1.1e-09 · regional, not allelic
Overall
CADD	21.1	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 0.00891% European (non-Finnish) · 99/1,111,236 alleles

Filtering AF 0.00746% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00692%

Overall 0.00698% 101/1,447,376 alleles · very rare exomes 95/1,295,446 · genomes 6/151,930 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00891%	11,225
Remaining individualsnot grpmax-eligible	0.0018%	55,620
African / African-American	0.00148%	67,348

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.Arg242Ser
Coding: c.724C>A
MANE Select: NM_005251
dbSNP: rs1022844166
Type: single nucleotide variant
Location: chr16:86568059 (GRCh38)
Gene constraint: LOEUF 1.807 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.45 · 8 PDB
Residue 242: 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-arg242ser (accessed [today's date]).

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