Is FOXE3 p.Pro112Ser (c.334C>T) pathogenic?

FOXE3 p.Pro112Ser (c.334C>T) is classified Uncertain significance in FOXE3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.2793); Very rare (popmax 0.00518%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with FOXE3 p.Pro112Ser (c.334C>T)?

FOXE3 p.Pro112Ser (c.334C>T) is associated with Cardiovascular phenotype, congenital primary aphakia, anterior segment dysgenesis (ClinVar).

How common is FOXE3 p.Pro112Ser (c.334C>T) in the general population?

FOXE3 p.Pro112Ser (c.334C>T) is very rare (popmax 0.00518%, nfe) (gnomAD).

What do computational predictors say about FOXE3 p.Pro112Ser (c.334C>T)?

AlphaMissense predicts likely benign (score 0.2793) — an in-silico prediction, not a clinical call.

FOXE3 p.Pro112Ser

c.334C>T · rs745571457 · VCV617853

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00518%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2793	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -7.19	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 0.53	GERP -3.6, phastCons 0.79
Regional constraint	o/e 1.02	unconstrained · MANE · 956 bp · p 0.59 · regional, not allelic
Overall
CADD	16.83	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 0.00518% European (non-Finnish) · 61/1,178,312 alleles

Filtering AF 0.00411% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00385% 62/1,610,476 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00518%	19,317
Remaining individualsnot grpmax-eligible	0.0016%	62,356

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.Pro112Ser
Coding: c.334C>T
MANE Select: NM_012186
dbSNP: rs745571457
Type: single nucleotide variant
Location: chr1:47416649 (GRCh38)
Gene constraint: LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 112: 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

Also linked: congenital primary aphakia anterior segment dysgenesis aortic aneurysm, familial thoracic 1

Similar variants

FOXE3 p.Pro112Gln Uncertain significance ★ ⚠ same residue
FOXE3 p.Ala78Thr Pathogenic/Likely pathogenic ★★ same condition
FOXE3 p.Cys240Ter Pathogenic ★★ same condition
FOXE3 p.Gly49Ter Pathogenic/Likely pathogenic ★★ same condition
FOXE3 p.Ser211Ter Pathogenic/Likely pathogenic ★★ same condition
FOXE3 p.Ala170Thr Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala189Val Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala206Asp 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-pro112ser (accessed [today's date]).

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