Is FOXE3 p.Pro276= (c.828C>G) pathogenic?

FOXE3 p.Pro276= (c.828C>G) is classified Benign/Likely benign in FOXE3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-23). Rare (popmax 0.282%, mid); Associated with congenital primary aphakia.

What condition is associated with FOXE3 p.Pro276= (c.828C>G)?

FOXE3 p.Pro276= (c.828C>G) is associated with congenital primary aphakia, anterior segment dysgenesis (ClinVar).

How common is FOXE3 p.Pro276= (c.828C>G) in the general population?

FOXE3 p.Pro276= (c.828C>G) is rare (popmax 0.282%, mid) (gnomAD).

FOXE3 p.Pro276=

c.828C>G · rs887265865 · VCV777909

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.282%, mid)

Conditions

congenital primary aphakia

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 -7.1	GERP -3.5
Overall
CADD	6.837	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.282% Middle Eastern · 11/3,904 alleles

Filtering AF 0.158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.122%

Overall 0.0166% 232/1,401,666 alleles · rare exomes 201/1,249,902 · genomes 31/151,764 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.282%	355
Admixed American	0.0578%	1,731
Remaining individualsnot grpmax-eligible	0.051%	1,960
African / African-American	0.0272%	3,671
European (non-Finnish)	0.0142%	7,023
Ashkenazi Jewishnot grpmax-eligible	0.0123%	8,124

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.Pro276=
Coding: c.828C>G
MANE Select: NM_012186
dbSNP: rs887265865
Type: single nucleotide variant
Location: chr1:47417143 (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.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
FOXE3 p.Ala214Val 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-pro276 (accessed [today's date]).

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