Is EPN2 p.Pro378Leu (c.1133C>T) pathogenic?

EPN2 p.Pro378Leu (c.1133C>T) is classified Uncertain significance in EPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-23). AlphaMissense: likely benign (0.0946); Very rare (popmax 0.00738%, sas).

How common is EPN2 p.Pro378Leu (c.1133C>T) in the general population?

EPN2 p.Pro378Leu (c.1133C>T) is very rare (popmax 0.00738%, sas) (gnomAD).

What do computational predictors say about EPN2 p.Pro378Leu (c.1133C>T)?

AlphaMissense predicts likely benign (score 0.0946) — an in-silico prediction, not a clinical call.

EPN2 p.Pro378Leu

c.1133C>T · rs764191775 · VCV2382814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00738%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0946	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -8.87	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 4.8	GERP 0.64, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 22 kb · p 0.57 · regional, not allelic
Overall
CADD	22.3	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

Grpmax group 0.00738% South Asian · 6/81,250 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00214%

Overall 0.00165% 23/1,393,980 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00738%	13,542
Remaining individualsnot grpmax-eligible	0.00168%	59,426
European (non-Finnish)	0.00139%	71,919

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.Pro378Leu
Coding: c.1133C>T
MANE Select: NM_014964
dbSNP: rs764191775
Type: single nucleotide variant
Location: chr17:19313265 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.50
Residue 378: the 'disordered' region; the '6 x 3 aa repeats of [de]-p-w' region

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-pro378leu (accessed [today's date]).

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