Is EPN1 p.Pro466Arg (c.1397C>G) pathogenic?

EPN1 p.Pro466Arg (c.1397C>G) is classified Uncertain significance in EPN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely benign (0.1413); Absent from gnomAD v4.1.

How common is EPN1 p.Pro466Arg (c.1397C>G) in the general population?

EPN1 p.Pro466Arg (c.1397C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPN1 p.Pro466Arg (c.1397C>G)?

AlphaMissense predicts likely benign (score 0.1413) — an in-silico prediction, not a clinical call.

EPN1 p.Pro466Arg

c.1397C>G · VCV4018903

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1413 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1413	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -9.04	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 4.6	GERP -0.55, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 9,743 bp · p 0.068 · regional, not allelic
Overall
CADD	21.0	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: EPN1
Protein: p.Pro466Arg
Coding: c.1397C>G
MANE Select: NM_001130072
Type: single nucleotide variant
Location: chr19:55694858 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.87 · 2 PDB
Residue 466: the 'disordered' region

Full EPN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPN1 p.Pro466His Uncertain significance ★ ⚠ same residue
EPN1 c.-101-1336T>C Uncertain significance ★ same type
EPN1 c.-101-1337C>A Uncertain significance ★ same type
EPN1 c.-101-1340T>C Uncertain significance ★ same type
EPN1 c.-101-1351G>T Uncertain significance ★ same type
EPN1 c.-101-813C>T Uncertain significance ★ same type
EPN1 c.-101-834C>T Uncertain significance ★ same type
EPN1 c.-101-838G>C 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/epn1-p-pro466arg (accessed [today's date]).

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