Is FOXE3 p.Pro28Ser (c.82C>T) pathogenic?

FOXE3 p.Pro28Ser (c.82C>T) is classified Uncertain significance in FOXE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-23). AlphaMissense: likely benign (0.0822); Very rare (popmax 0.000293%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with FOXE3 p.Pro28Ser (c.82C>T)?

FOXE3 p.Pro28Ser (c.82C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is FOXE3 p.Pro28Ser (c.82C>T) in the general population?

FOXE3 p.Pro28Ser (c.82C>T) is very rare (popmax 0.000293%, nfe) (gnomAD).

What do computational predictors say about FOXE3 p.Pro28Ser (c.82C>T)?

AlphaMissense predicts likely benign (score 0.0822) — an in-silico prediction, not a clinical call.

FOXE3 p.Pro28Ser

c.82C>T · VCV3279575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000293%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0822	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -6.08	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 1.8	GERP 0.24, phastCons 0.9
Regional constraint	o/e 1.02	unconstrained · MANE · 956 bp · p 0.59 · regional, not allelic
Overall
CADD	21.0	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 0.000293% European (non-Finnish) · 3/1,022,496 alleles

Filtering AF 7.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.2e-05%

Overall 0.000229% 3/1,310,280 alleles · very rare exomes 3/1,159,884 · genomes 0/150,396 · joint denominator

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.Pro28Ser
Coding: c.82C>T
MANE Select: NM_012186
Type: single nucleotide variant
Location: chr1:47416397 (GRCh38)
Gene constraint: LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 28: the 'disordered' 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.Pro28Thr Uncertain significance ★★ ⚠ same residue
FOXE3 p.Pro28Arg Uncertain significance ★ ⚠ same residue
FOXE3 p.Pro28= Likely benign ★ 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

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-pro28ser (accessed [today's date]).

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