Is FOXE3 p.Pro280Ser (c.838C>T) pathogenic?

FOXE3 p.Pro280Ser (c.838C>T) is classified Uncertain significance in FOXE3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0772); Very rare (popmax 0.00821%, nfe); Associated with anterior segment dysgenesis.

What condition is associated with FOXE3 p.Pro280Ser (c.838C>T)?

FOXE3 p.Pro280Ser (c.838C>T) is associated with anterior segment dysgenesis, congenital primary aphakia (ClinVar).

How common is FOXE3 p.Pro280Ser (c.838C>T) in the general population?

FOXE3 p.Pro280Ser (c.838C>T) is very rare (popmax 0.00821%, nfe) (gnomAD).

What do computational predictors say about FOXE3 p.Pro280Ser (c.838C>T)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

FOXE3 p.Pro280Ser

c.838C>T · rs994486517 · VCV836896

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00821%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

anterior segment dysgenesis

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -8.16	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 0.28	GERP -0.28, phastCons 0.006
Regional constraint	o/e 1.02	unconstrained · MANE · 956 bp · p 0.59 · regional, not allelic
Overall
CADD	20.6	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 0.00821% European (non-Finnish) · 89/1,084,062 alleles

Filtering AF 0.00678% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0063%

Overall 0.00648% 91/1,404,952 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00821%	12,180
Remaining individualsnot grpmax-eligible	0.00188%	53,136
African / African-American	0.00152%	65,972

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.Pro280Ser
Coding: c.838C>T
MANE Select: NM_012186
dbSNP: rs994486517
Type: single nucleotide variant
Location: chr1:47417153 (GRCh38)
Gene constraint: LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68

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

Disease context

anterior segment dysgenesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital primary aphakia

Similar variants

FOXE3 p.Pro280Arg 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-pro280ser (accessed [today's date]).

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