Is EPN3 p.Glu90Lys (c.268G>A) pathogenic?

EPN3 p.Glu90Lys (c.268G>A) is classified Uncertain significance in EPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: ambiguous (0.3405); Very rare (popmax 0.00333%, amr).

How common is EPN3 p.Glu90Lys (c.268G>A) in the general population?

EPN3 p.Glu90Lys (c.268G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about EPN3 p.Glu90Lys (c.268G>A)?

AlphaMissense predicts ambiguous (score 0.3405) — an in-silico prediction, not a clinical call.

EPN3 p.Glu90Lys

c.268G>A · rs760142577 · VCV3089779

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3405 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Computational evidence

Protein change
AlphaMissense	0.3405	ambiguous
REVEL	0.412	indeterminate
SaProt	LLR -12.54	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 5,597 bp · p 0.012 · regional, not allelic
Overall
CADD	29.9	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 0.00333% Admixed American · 2/60,016 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00204% 33/1,614,132 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,837
Admixed Americangrpmax	0.00333%	30,008
East Asian	0.00223%	44,878
South Asian	0.0022%	45,542
European (non-Finnish)	0.00212%	47,201

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu90Lys
Coding: c.268G>A
MANE Select: NM_017957
dbSNP: rs760142577
Type: single nucleotide variant
Location: chr17:50536824 (GRCh38)
Gene constraint: LOEUF 1.251 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01
Residue 90: the enth domain

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

Similar variants

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
EPN3 p.Ala541Glu 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-glu90lys (accessed [today's date]).

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