Is ERN2 p.Leu64Gln (c.191T>A) pathogenic?

ERN2 p.Leu64Gln (c.191T>A) is classified Uncertain significance in ERN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.191); Absent from gnomAD v4.1.

How common is ERN2 p.Leu64Gln (c.191T>A) in the general population?

ERN2 p.Leu64Gln (c.191T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERN2 p.Leu64Gln (c.191T>A)?

AlphaMissense predicts likely benign (score 0.191) — an in-silico prediction, not a clinical call.

ERN2 p.Leu64Gln

c.191T>A · rs774144894 · VCV2228623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.191 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.191	likely benign
REVEL	0.453	indeterminate
SaProt	LLR -10.26	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 22 kb · p 0.43 · regional, not allelic
Overall
CADD	24.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ERN2
Protein: p.Leu64Gln
Coding: c.191T>A
MANE Select: NM_033266
dbSNP: rs774144894
Type: single nucleotide variant
Location: chr16:23710921 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.91 · 2 PDB

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-leu64gln (accessed [today's date]).

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