Is FOXC2 p.Leu296= (c.888G>C) pathogenic?

FOXC2 p.Leu296= (c.888G>C) is classified Likely benign in FOXC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-06). Very rare (popmax 0.00393%, amr); Associated with Inborn genetic diseases.

What condition is associated with FOXC2 p.Leu296= (c.888G>C)?

FOXC2 p.Leu296= (c.888G>C) is associated with Inborn genetic diseases (ClinVar).

How common is FOXC2 p.Leu296= (c.888G>C) in the general population?

FOXC2 p.Leu296= (c.888G>C) is very rare (popmax 0.00393%, amr) (gnomAD).

FOXC2 p.Leu296=

c.888G>C · VCV4871501

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00393%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.9, phastCons 1
Overall
CADD	8.472	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00393% Admixed American · 1/25,446 alleles

Filtering AF 9.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.2e-05%

Overall 0.00047% 6/1,277,806 alleles · very rare exomes 4/1,127,060 · genomes 2/150,746 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00393%	25,446
African / African-American	0.00156%	64,142
European (non-Finnish)	0.000393%	254,465

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.Leu296=
Coding: c.888G>C
MANE Select: NM_005251
Type: single nucleotide variant
Location: chr16:86568223 (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-leu296 (accessed [today's date]).

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