Is ERN2 p.Val794Ile (c.2380G>A) pathogenic?

ERN2 p.Val794Ile (c.2380G>A) is classified Uncertain significance in ERN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-10). AlphaMissense: likely benign (0.1166); Ultra-rare (popmax 0.048%, afr).

How common is ERN2 p.Val794Ile (c.2380G>A) in the general population?

ERN2 p.Val794Ile (c.2380G>A) is ultra-rare (popmax 0.048%, afr) (gnomAD).

What do computational predictors say about ERN2 p.Val794Ile (c.2380G>A)?

AlphaMissense predicts likely benign (score 0.1166) — an in-silico prediction, not a clinical call.

ERN2 p.Val794Ile

c.2380G>A · rs144279415 · VCV2463703

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1166 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1166	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -7.99	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 4.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 22 kb · p 0.43 · regional, not allelic
Overall
CADD	24.1	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 0.048% African / African-American · 36/75,032 alleles

Filtering AF 0.0356% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00369% 59/1,598,770 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.048%	2,084
South Asian	0.0121%	8,259
Admixed American	0.00334%	29,949
Remaining individualsnot grpmax-eligible	0.0016%	62,392
European (non-Finnish)	0.000763%	131,062

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: ERN2
Protein: p.Val794Ile
Coding: c.2380G>A
MANE Select: NM_033266
dbSNP: rs144279415
Type: single nucleotide variant
Location: chr16:23691422 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.91 · 2 PDB
Residue 794: the ken domain

Full ERN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERN2 p.Arg868Ter Uncertain significance ★★ same type
ERN2 p.Val69Ile Benign ★★ ⚠ same type
ERN2 p.Ala22Val Uncertain significance ★ ⚠ same type
ERN2 p.Ala318Asp Uncertain significance ★ ⚠ same type
ERN2 p.Ala395Val Uncertain significance ★ ⚠ same type
ERN2 p.Ala4Thr Uncertain significance ★ ⚠ same type
ERN2 p.Ala760Thr Uncertain significance ★ ⚠ same type
ERN2 p.Ala80Thr 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/ern2-p-val794ile (accessed [today's date]).

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