Is EPN2 p.Pro356Leu (c.1067C>T) pathogenic?

EPN2 p.Pro356Leu (c.1067C>T) is classified Uncertain significance in EPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: likely benign (0.0656); Ultra-rare (popmax 0.0558%, eas).

How common is EPN2 p.Pro356Leu (c.1067C>T) in the general population?

EPN2 p.Pro356Leu (c.1067C>T) is ultra-rare (popmax 0.0558%, eas) (gnomAD).

What do computational predictors say about EPN2 p.Pro356Leu (c.1067C>T)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

EPN2 p.Pro356Leu

c.1067C>T · rs372779952 · VCV2570551

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0558%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -6.80	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 2.4	GERP 0.74, phastCons 0.24
Regional constraint	o/e 0.97	unconstrained · MANE · 22 kb · p 0.57 · regional, not allelic
Overall
CADD	18.19	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 0.0558% East Asian · 25/44,792 alleles

Filtering AF 0.0387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0331%

Overall 0.00372% 60/1,611,894 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0558%	1,792
South Asian	0.0165%	6,060
Middle Eastern	0.0165%	6,070
Remaining individualsnot grpmax-eligible	0.00962%	10,390
Admixed American	0.00672%	14,878
Finnishnot grpmax-eligible	0.00156%	63,944
European (non-Finnish)	0.000678%	147,402

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.Pro356Leu
Coding: c.1067C>T
MANE Select: NM_014964
dbSNP: rs372779952
Type: single nucleotide variant
Location: chr17:19313199 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.50
Residue 356: 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-pro356leu (accessed [today's date]).

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