Is FOXE3 p.Ala2= (c.6G>T) pathogenic?

FOXE3 p.Ala2= (c.6G>T) is classified Likely benign in FOXE3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-24). Very rare (popmax 0.00637%, eas); Associated with anterior segment dysgenesis.

What condition is associated with FOXE3 p.Ala2= (c.6G>T)?

FOXE3 p.Ala2= (c.6G>T) is associated with anterior segment dysgenesis, congenital primary aphakia (ClinVar).

How common is FOXE3 p.Ala2= (c.6G>T) in the general population?

FOXE3 p.Ala2= (c.6G>T) is very rare (popmax 0.00637%, eas) (gnomAD).

FOXE3 p.Ala2=

c.6G>T · rs928328635 · VCV2203090

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00637%, eas)

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 -4.5	GERP -3
Overall
CADD	0.532	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00637% East Asian · 2/31,388 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000395%

Overall 0.000519% 7/1,347,470 alleles · very rare exomes 4/1,196,364 · genomes 3/151,106 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00637%	15,694
Ashkenazi Jewishnot grpmax-eligible	0.00442%	22,634
African / African-American	0.00302%	33,120
European (non-Finnish)	0.000192%	522,081

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.Ala2=
Coding: c.6G>T
MANE Select: NM_012186
dbSNP: rs928328635
Type: single nucleotide variant
Location: chr1:47416321 (GRCh38)
Gene constraint: LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 2: 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.Ala2Gly 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-ala2 (accessed [today's date]).

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