Is EPN2 p.Val14Met (c.40G>A) pathogenic?

EPN2 p.Val14Met (c.40G>A) is classified Uncertain significance in EPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely pathogenic (0.9691); Very rare (popmax 0.00335%, amr).

How common is EPN2 p.Val14Met (c.40G>A) in the general population?

EPN2 p.Val14Met (c.40G>A) is very rare (popmax 0.00335%, amr) (gnomAD).

What do computational predictors say about EPN2 p.Val14Met (c.40G>A)?

AlphaMissense predicts likely pathogenic (score 0.9691) — an in-silico prediction, not a clinical call.

EPN2 p.Val14Met

c.40G>A · rs138967323 · VCV3089765

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00335%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9691	likely pathogenic
REVEL	0.526	indeterminate
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 29 kb · p 2.8e-08 · regional, not allelic
Overall
CADD	28.4	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 0.00335% Admixed American · 2/59,684 alleles

Filtering AF 0.000764% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00118% 19/1,612,872 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00335%	29,842
African / African-American	0.00134%	74,840
European (non-Finnish)	0.00127%	78,637
South Asian	0.0011%	90,886

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: EPN2
Protein: p.Val14Met
Coding: c.40G>A
MANE Select: NM_014964
dbSNP: rs138967323
Type: single nucleotide variant
Location: chr17:19283159 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.50
Residue 14: the enth domain

Full EPN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPN2 p.Ala102Thr Uncertain significance ★ ⚠ same type
EPN2 p.Ala253Gly Uncertain significance ★ ⚠ same type
EPN2 p.Ala254Asp Uncertain significance ★ ⚠ same type
EPN2 p.Ala347Thr Uncertain significance ★ ⚠ same type
EPN2 p.Ala347Val Uncertain significance ★ ⚠ same type
EPN2 p.Ala412Val Uncertain significance ★ ⚠ same type
EPN2 p.Ala428Thr Uncertain significance ★ ⚠ same type
EPN2 p.Ala428Val 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/epn2-p-val14met (accessed [today's date]).

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