Is EPN1 p.Pro359Leu (c.1076C>T) pathogenic?

EPN1 p.Pro359Leu (c.1076C>T) is classified Uncertain significance in EPN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.0863); Ultra-rare (popmax 0.0199%, amr).

How common is EPN1 p.Pro359Leu (c.1076C>T) in the general population?

EPN1 p.Pro359Leu (c.1076C>T) is ultra-rare (popmax 0.0199%, amr) (gnomAD).

What do computational predictors say about EPN1 p.Pro359Leu (c.1076C>T)?

AlphaMissense predicts likely benign (score 0.0863) — an in-silico prediction, not a clinical call.

EPN1 p.Pro359Leu

c.1076C>T · rs771176714 · VCV2231203

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0863 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0199%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0863	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -8.89	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 4.5	GERP 0.32, phastCons 0.44
Regional constraint	o/e 1.07	unconstrained · MANE · 9,743 bp · p 0.068 · regional, not allelic
Overall
CADD	18.69	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 0.0199% Admixed American · 10/50,254 alleles

Filtering AF 0.0107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00819%

Overall 0.00408% 63/1,543,088 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0199%	5,025
Remaining individualsnot grpmax-eligible	0.0151%	6,634
South Asian	0.00487%	20,525
European (non-Finnish)	0.0035%	28,574

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: EPN1
Protein: p.Pro359Leu
Coding: c.1076C>T
MANE Select: NM_001130072
dbSNP: rs771176714
Type: single nucleotide variant
Location: chr19:55692695 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.87 · 2 PDB
Residue 359: the 'disordered' region; the '8 x 3 aa repeats of [ed]-p-w' region

Full EPN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPN1 c.-101-1336T>C Uncertain significance ★ same type
EPN1 c.-101-1337C>A Uncertain significance ★ same type
EPN1 c.-101-1340T>C Uncertain significance ★ same type
EPN1 c.-101-1351G>T Uncertain significance ★ same type
EPN1 c.-101-813C>T Uncertain significance ★ same type
EPN1 c.-101-834C>T Uncertain significance ★ same type
EPN1 c.-101-838G>C Uncertain significance ★ same type
EPN1 c.-101-846C>T 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/epn1-p-pro359leu (accessed [today's date]).

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