Is EPN3 p.Pro345Arg (c.1034C>G) pathogenic?

EPN3 p.Pro345Arg (c.1034C>G) is classified Uncertain significance in EPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely benign (0.3141); Very rare (popmax 0.000339%, nfe).

How common is EPN3 p.Pro345Arg (c.1034C>G) in the general population?

EPN3 p.Pro345Arg (c.1034C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about EPN3 p.Pro345Arg (c.1034C>G)?

AlphaMissense predicts likely benign (score 0.3141) — an in-silico prediction, not a clinical call.

EPN3 p.Pro345Arg

c.1034C>G · VCV3509536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3141	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -11.05	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
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	24.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,980 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,782 alleles · very rare

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: EPN3
Protein: p.Pro345Arg
Coding: c.1034C>G
MANE Select: NM_017957
Type: single nucleotide variant
Location: chr17:50540847 (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.Pro345Ala 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-pro345arg (accessed [today's date]).

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