Is FOXE3 p.Pro185= (c.555C>T) pathogenic?

FOXE3 p.Pro185= (c.555C>T) is classified Conflicting classifications of pathogenicity in FOXE3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-17). Very rare (popmax 0.00153%, afr); Associated with Cardiovascular phenotype.

What condition is associated with FOXE3 p.Pro185= (c.555C>T)?

FOXE3 p.Pro185= (c.555C>T) is associated with Cardiovascular phenotype, congenital primary aphakia, anterior segment dysgenesis (ClinVar).

How common is FOXE3 p.Pro185= (c.555C>T) in the general population?

FOXE3 p.Pro185= (c.555C>T) is very rare (popmax 0.00153%, afr) (gnomAD).

FOXE3 p.Pro185=

c.555C>T · rs758322369 · VCV1748284

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00153%, afr)

Conditions

Cardiovascular phenotype

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 -0.28	GERP -3.1, phastCons 0.001
Overall
CADD	10.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% African / African-American · 1/65,354 alleles

Overall 7.16e-05% 1/1,396,058 alleles · very rare exomes 1/1,246,198 · genomes 0/149,860 · 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.Pro185=
Coding: c.555C>T
MANE Select: NM_012186
dbSNP: rs758322369
Type: single nucleotide variant
Location: chr1:47416870 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital primary aphakia anterior segment dysgenesis

Similar variants

FOXE3 p.Pro185Leu Uncertain significance ★★ ⚠ same residue
FOXE3 p.Pro185Thr 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

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-pro185 (accessed [today's date]).

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