Is FOXE3 p.Arg48= (c.144C>G) pathogenic?

FOXE3 p.Arg48= (c.144C>G) is classified Likely benign in FOXE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). Very rare (popmax 0.000219%, nfe); Associated with anterior segment dysgenesis.

What condition is associated with FOXE3 p.Arg48= (c.144C>G)?

FOXE3 p.Arg48= (c.144C>G) is associated with anterior segment dysgenesis, congenital primary aphakia (ClinVar).

How common is FOXE3 p.Arg48= (c.144C>G) in the general population?

FOXE3 p.Arg48= (c.144C>G) is very rare (popmax 0.000219%, nfe) (gnomAD).

FOXE3 p.Arg48=

c.144C>G · rs1646883029 · VCV1114662

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000219%, nfe)

Conditions

anterior segment dysgenesis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.37	GERP -2.8, phastCons 0.73
Overall
CADD	9.031	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000219% European (non-Finnish) · 2/914,046 alleles

Filtering AF 3.6e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000179% 2/1,116,838 alleles · very rare exomes 2/968,620 · genomes 0/148,218 · 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.Arg48=
Coding: c.144C>G
MANE Select: NM_012186
dbSNP: rs1646883029
Type: single nucleotide variant
Location: chr1:47416459 (GRCh38)
Gene constraint: LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 48: 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.Arg48Pro 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-arg48 (accessed [today's date]).

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