Is FOXE3 p.Ala96= (c.288C>T) pathogenic?

FOXE3 p.Ala96= (c.288C>T) is classified Likely benign in FOXE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-12). Very rare (popmax 0.00402%, afr); Associated with Cardiovascular phenotype.

What condition is associated with FOXE3 p.Ala96= (c.288C>T)?

FOXE3 p.Ala96= (c.288C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is FOXE3 p.Ala96= (c.288C>T) in the general population?

FOXE3 p.Ala96= (c.288C>T) is very rare (popmax 0.00402%, afr) (gnomAD).

FOXE3 p.Ala96=

c.288C>T · rs375656937 · VCV3226206

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Conditions

Cardiovascular phenotype

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 0.89	GERP -3.6, phastCons 1
Overall
CADD	15.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00402% African / African-American · 3/74,572 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000311% 5/1,609,010 alleles · very rare exomes 3/1,458,572 · genomes 2/150,438 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00402%	24,857
European (non-Finnish)	0.00017%	588,852

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: FOXE3
Protein: p.Ala96=
Coding: c.288C>T
MANE Select: NM_012186
dbSNP: rs375656937
Type: single nucleotide variant
Location: chr1:47416603 (GRCh38)
Gene constraint: LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 96: a DNA-binding region

Full FOXE3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXE3 p.Ala96Gly Uncertain significance ★★ ⚠ same residue
FOXE3 p.Ala96Thr Likely pathogenic same residue
FOXE3 p.Ala170Thr Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala245Thr Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala255Thr Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala257Ser Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala295Thr Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala44Glu 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/foxe3-p-ala96 (accessed [today's date]).

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