FOXE3 p.Pro227=
c.681G>A · rs1484601405 · VCV1755621
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0117%, amr)
Conditions
2
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 -2.1 | GERP -3.6 |
| Overall | ||
| CADD | 6.957 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0117%
Admixed American · 4/34,296 alleles
Filtering AF
0.00759%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00705%
Overall
0.00762%
103/1,351,600 alleles · ultra-rare
exomes 96/1,201,970 · genomes 7/149,630 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0117% | 8,574 |
| European (non-Finnish) | 0.00909% | 11,003 |
| Remaining individualsnot grpmax-eligible | 0.00816% | 12,256 |
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.Pro227=
- Coding
- c.681G>A
- MANE Select
- NM_012186
- dbSNP
- rs1484601405
- Type
- single nucleotide variant
- Location
- chr1:47416996 (GRCh38)
- Gene constraint
- LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 66.68
Similar variants
- FOXE3 p.Pro227Arg 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-pro227 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown