Is FOXE3 p.Arg48Pro (c.143G>C) pathogenic?

FOXE3 p.Arg48Pro (c.143G>C) is classified Uncertain significance in FOXE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-16). AlphaMissense: likely benign (0.0565); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with FOXE3 p.Arg48Pro (c.143G>C)?

FOXE3 p.Arg48Pro (c.143G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is FOXE3 p.Arg48Pro (c.143G>C) in the general population?

FOXE3 p.Arg48Pro (c.143G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXE3 p.Arg48Pro (c.143G>C)?

AlphaMissense predicts likely benign (score 0.0565) — an in-silico prediction, not a clinical call.

FOXE3 p.Arg48Pro

c.143G>C · rs1646883018 · VCV2448364

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0565 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0565	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -4.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -2.4, phastCons 0.72
Regional constraint	o/e 1.02	unconstrained · MANE · 956 bp · p 0.59 · regional, not allelic
Overall
CADD	16.28	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FOXE3
Protein: p.Arg48Pro
Coding: c.143G>C
MANE Select: NM_012186
dbSNP: rs1646883018
Type: single nucleotide variant
Location: chr1:47416458 (GRCh38)
Gene constraint: LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 48: the 'disordered' region

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

Similar variants

FOXE3 p.Arg48= Likely benign ★ same residue
FOXE3 p.Ala170Thr Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala245Thr Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala255Thr Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala257Ser Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala295Thr Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala44Glu Uncertain significance ★★ ⚠ same condition
FOXE3 p.Ala51Ser 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-arg48pro (accessed [today's date]).

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