Is FOXE3 p.Phe155Ser (c.464T>C) pathogenic?

FOXE3 p.Phe155Ser (c.464T>C) is classified Uncertain significance in FOXE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-26). AlphaMissense: likely pathogenic (0.9997); Very rare (popmax 0.00231%, eas); Associated with congenital primary aphakia.

What condition is associated with FOXE3 p.Phe155Ser (c.464T>C)?

FOXE3 p.Phe155Ser (c.464T>C) is associated with congenital primary aphakia, anterior segment dysgenesis (ClinVar).

How common is FOXE3 p.Phe155Ser (c.464T>C) in the general population?

FOXE3 p.Phe155Ser (c.464T>C) is very rare (popmax 0.00231%, eas) (gnomAD).

What do computational predictors say about FOXE3 p.Phe155Ser (c.464T>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

FOXE3 p.Phe155Ser

c.464T>C · VCV3759020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00231%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital primary aphakia

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic · top 4% in FOXE3
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -15.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 956 bp · p 0.59 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00231% East Asian · 1/43,300 alleles

Overall 6.91e-05% 1/1,447,780 alleles · very rare

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.Phe155Ser
Coding: c.464T>C
MANE Select: NM_012186
Type: single nucleotide variant
Location: chr1:47416779 (GRCh38)
Gene constraint: LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 155: a DNA-binding region

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

Disease context

congenital primary aphakia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: anterior segment dysgenesis

Similar variants

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
FOXE3 p.Ala214Val 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-phe155ser (accessed [today's date]).

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