Is FOXE3 p.Val223= (c.669G>T) pathogenic?

FOXE3 p.Val223= (c.669G>T) is classified Likely benign in FOXE3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-17). Ultra-rare (popmax 0.031%, sas); Associated with Cardiovascular phenotype.

What condition is associated with FOXE3 p.Val223= (c.669G>T)?

FOXE3 p.Val223= (c.669G>T) is associated with Cardiovascular phenotype, congenital primary aphakia, anterior segment dysgenesis (ClinVar).

How common is FOXE3 p.Val223= (c.669G>T) in the general population?

FOXE3 p.Val223= (c.669G>T) is ultra-rare (popmax 0.031%, sas) (gnomAD).

FOXE3 p.Val223=

c.669G>T · rs749630303 · VCV2937699

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.031%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.6	GERP -3.6, phastCons 0.004
Overall
CADD	7.78	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.031% South Asian · 21/67,786 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0174%

Overall 0.0017% 23/1,354,372 alleles · ultra-rare exomes 21/1,204,738 · genomes 2/149,634 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.031%	3,228
Remaining individualsnot grpmax-eligible	0.00204%	49,064
African / African-American	0.00155%	64,640

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.Val223=
Coding: c.669G>T
MANE Select: NM_012186
dbSNP: rs749630303
Type: single nucleotide variant
Location: chr1:47416984 (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.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-val223 (accessed [today's date]).

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