Is EPN3 p.Ser18Pro (c.52T>C) pathogenic?

EPN3 p.Ser18Pro (c.52T>C) is classified Uncertain significance in EPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-24). AlphaMissense: likely pathogenic (0.9615); Very rare (popmax 0.00873%, nfe).

How common is EPN3 p.Ser18Pro (c.52T>C) in the general population?

EPN3 p.Ser18Pro (c.52T>C) is very rare (popmax 0.00873%, nfe) (gnomAD).

What do computational predictors say about EPN3 p.Ser18Pro (c.52T>C)?

AlphaMissense predicts likely pathogenic (score 0.9615) — an in-silico prediction, not a clinical call.

EPN3 p.Ser18Pro

c.52T>C · rs774486633 · VCV2529627

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9615 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00873%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9615	likely pathogenic · top 7% in EPN3
REVEL	0.555	indeterminate
SaProt	LLR -12.55	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.87, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 5,597 bp · p 0.012 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00873% European (non-Finnish) · 103/1,179,990 alleles

Filtering AF 0.00733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00684%

Overall 0.00644% 104/1,613,790 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00873%	11,456
African / African-American	0.00134%	74,866

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.Ser18Pro
Coding: c.52T>C
MANE Select: NM_017957
dbSNP: rs774486633
Type: single nucleotide variant
Location: chr17:50536608 (GRCh38)
Gene constraint: LOEUF 1.251 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01
Residue 18: the enth domain

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

Similar variants

EPN3 p.Ser18= Likely benign ★ 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
EPN3 p.Ala492Val 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-ser18pro (accessed [today's date]).

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