Is EPN3 p.Pro345Ala (c.1033C>G) pathogenic?

EPN3 p.Pro345Ala (c.1033C>G) is classified Uncertain significance in EPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: likely benign (0.1579); Absent from gnomAD v4.1.

How common is EPN3 p.Pro345Ala (c.1033C>G) in the general population?

EPN3 p.Pro345Ala (c.1033C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPN3 p.Pro345Ala (c.1033C>G)?

AlphaMissense predicts likely benign (score 0.1579) — an in-silico prediction, not a clinical call.

EPN3 p.Pro345Ala

c.1033C>G · VCV3509530

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1579 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1579	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -8.52	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 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 5,597 bp · p 0.012 · regional, not allelic
Overall
CADD	23.8	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: EPN3
Protein: p.Pro345Ala
Coding: c.1033C>G
MANE Select: NM_017957
Type: single nucleotide variant
Location: chr17:50540846 (GRCh38)
Gene constraint: LOEUF 1.251 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01
Residue 345: the '5 x 3 aa repeats of [de]-p-w' region; the 'disordered' region

Full EPN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPN3 p.Pro345Arg Uncertain significance ★ ⚠ same residue
EPN3 p.Pro345Thr Uncertain significance ★ ⚠ same residue
EPN3 p.Ala244Val Uncertain significance ★ ⚠ same type
EPN3 p.Ala267Thr Uncertain significance ★ ⚠ same type
EPN3 p.Ala270Gly Uncertain significance ★ ⚠ same type
EPN3 p.Ala334Ser Uncertain significance ★ ⚠ same type
EPN3 p.Ala334Thr Uncertain significance ★ ⚠ same type
EPN3 p.Ala390Val Uncertain significance ★ ⚠ same type

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/epn3-p-pro345ala (accessed [today's date]).

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