Is FOXE3 p.Pro237Ser (c.709C>T) pathogenic?

FOXE3 p.Pro237Ser (c.709C>T) is classified Uncertain significance in FOXE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: likely benign (0.0971); Absent from gnomAD v4.1; Associated with congenital primary aphakia.

What condition is associated with FOXE3 p.Pro237Ser (c.709C>T)?

FOXE3 p.Pro237Ser (c.709C>T) is associated with congenital primary aphakia, anterior segment dysgenesis (ClinVar).

How common is FOXE3 p.Pro237Ser (c.709C>T) in the general population?

FOXE3 p.Pro237Ser (c.709C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXE3 p.Pro237Ser (c.709C>T)?

AlphaMissense predicts likely benign (score 0.0971) — an in-silico prediction, not a clinical call.

FOXE3 p.Pro237Ser

c.709C>T · rs1646888724 · VCV940300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0971 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,338,928)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital primary aphakia

Computational evidence

Protein change
AlphaMissense	0.0971	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -8.41	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 0.98	GERP -1.4, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 956 bp · p 0.59 · regional, not allelic
Overall
CADD	18.45	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

No allele count reported in gnomAD v4.1 (AN 1,338,928). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FOXE3
Protein: p.Pro237Ser
Coding: c.709C>T
MANE Select: NM_012186
dbSNP: rs1646888724
Type: single nucleotide variant
Location: chr1:47417024 (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

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

Also linked: anterior segment dysgenesis

Similar variants

FOXE3 p.Pro237= 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-pro237ser (accessed [today's date]).

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