Is FOXE3 p.Pro72Ser (c.214C>T) pathogenic?

FOXE3 p.Pro72Ser (c.214C>T) is classified Uncertain significance in FOXE3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.9989); Very rare (popmax 0.000355%, nfe); Associated with congenital primary aphakia.

What condition is associated with FOXE3 p.Pro72Ser (c.214C>T)?

FOXE3 p.Pro72Ser (c.214C>T) is associated with congenital primary aphakia, anterior segment dysgenesis (ClinVar).

How common is FOXE3 p.Pro72Ser (c.214C>T) in the general population?

FOXE3 p.Pro72Ser (c.214C>T) is very rare (popmax 0.000355%, nfe) (gnomAD).

What do computational predictors say about FOXE3 p.Pro72Ser (c.214C>T)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

FOXE3 p.Pro72Ser

c.214C>T · rs2521316560 · VCV2611624

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000355%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital primary aphakia

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic · top 7% in FOXE3
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -13.49	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 5.5	GERP -0.086, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 956 bp · p 0.59 · regional, not allelic
Overall
CADD	29.3	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 0.000355% European (non-Finnish) · 4/1,127,326 alleles

Filtering AF 8.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.6e-05%

Overall 0.000265% 4/1,511,378 alleles · very rare exomes 4/1,361,822 · genomes 0/149,556 · 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.Pro72Ser
Coding: c.214C>T
MANE Select: NM_012186
dbSNP: rs2521316560
Type: single nucleotide variant
Location: chr1:47416529 (GRCh38)
Gene constraint: LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 72: 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.Pro72= Likely benign 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-pro72ser (accessed [today's date]).

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