Is FOXE3 p.Arg65Pro (c.194G>C) pathogenic?

FOXE3 p.Arg65Pro (c.194G>C) is classified Uncertain significance in FOXE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-28). AlphaMissense: likely benign (0.3124); Very rare (popmax 0.00201%, sas); Associated with anterior segment dysgenesis.

What condition is associated with FOXE3 p.Arg65Pro (c.194G>C)?

FOXE3 p.Arg65Pro (c.194G>C) is associated with anterior segment dysgenesis, congenital primary aphakia (ClinVar).

How common is FOXE3 p.Arg65Pro (c.194G>C) in the general population?

FOXE3 p.Arg65Pro (c.194G>C) is very rare (popmax 0.00201%, sas) (gnomAD).

What do computational predictors say about FOXE3 p.Arg65Pro (c.194G>C)?

AlphaMissense predicts likely benign (score 0.3124) — an in-silico prediction, not a clinical call.

FOXE3 p.Arg65Pro

c.194G>C · rs1646883510 · VCV2939475

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3124 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00201%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

anterior segment dysgenesis

Computational evidence

Protein change
AlphaMissense	0.3124	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -6.93	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 6	GERP 0.79, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 956 bp · p 0.59 · regional, not allelic
Overall
CADD	23.3	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 0.00201% South Asian · 1/49,654 alleles

Overall 0.000151% 2/1,320,264 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00201%	49,654
European (non-Finnish)	9.75e-05%	1,026,042

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.Arg65Pro
Coding: c.194G>C
MANE Select: NM_012186
dbSNP: rs1646883510
Type: single nucleotide variant
Location: chr1:47416509 (GRCh38)
Gene constraint: LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 65: the 'disordered' region

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.Arg65Gln Uncertain significance ★ ⚠ same residue
FOXE3 p.Arg65_Pro66insArgArg Uncertain significance ★★ same residue
FOXE3 p.Arg65dup Uncertain significance ★★ same residue
FOXE3 p.Arg65del Conflicting classifications of pathogenicity ★ 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

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-arg65pro (accessed [today's date]).

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