Is ERN2 p.Val69Ile (c.205G>A) pathogenic?

ERN2 p.Val69Ile (c.205G>A) is classified Benign in ERN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-29). AlphaMissense: likely benign (0.0634); Common (popmax 5.78%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ERN2 p.Val69Ile (c.205G>A)?

AlphaMissense predicts likely benign (score 0.0634) — an in-silico prediction, not a clinical call.

ERN2 p.Val69Ile

Q: How common is ERN2 p.Val69Ile (c.205G>A) in the general population?

ERN2 p.Val69Ile (c.205G>A) is common (popmax 5.78%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.205G>A · rs9932495 · VCV786289

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0634 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.78%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0634	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -7.52	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 0.84	GERP -3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 22 kb · p 0.43 · regional, not allelic
Overall
CADD	8.557	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 5.78% African / African-American · 4,335/74,996 alleles

Filtering AF 5.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.58%

Overall 0.346% 5,592/1,614,130 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.78%	17
Middle Eastern	0.594%	168
Admixed American	0.575%	174
Remaining individualsnot grpmax-eligible	0.47%	213
South Asian	0.12%	836
European (non-Finnish)	0.0392%	2,554
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
East Asian	0.00668%	14,961
Finnishnot grpmax-eligible	0.00156%	64,042

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.Val69Ile
Coding: c.205G>A
MANE Select: NM_033266
dbSNP: rs9932495
Type: single nucleotide variant
Location: chr16:23710544 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.91 · 2 PDB
Residue 69: a UniProt-annotated variant site (in)

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.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
ERN2 p.Arg576His 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-val69ile (accessed [today's date]).

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