Is ERN2 p.Ala22Val (c.65C>T) pathogenic?

ERN2 p.Ala22Val (c.65C>T) is classified Uncertain significance in ERN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). AlphaMissense: likely benign (0.107); Very rare (popmax 0.00355%, amr).

How common is ERN2 p.Ala22Val (c.65C>T) in the general population?

ERN2 p.Ala22Val (c.65C>T) is very rare (popmax 0.00355%, amr) (gnomAD).

What do computational predictors say about ERN2 p.Ala22Val (c.65C>T)?

AlphaMissense predicts likely benign (score 0.107) — an in-silico prediction, not a clinical call.

ERN2 p.Ala22Val

c.65C>T · VCV3510245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.107 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00355%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.107	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -5.80	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 -0.24	GERP 0.17
Regional constraint	o/e 1.02	unconstrained · MANE · 22 kb · p 0.43 · regional, not allelic
Overall
CADD	4.599	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 0.00355% Admixed American · 2/56,262 alleles

Filtering AF 0.00059% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000221%

Overall 0.000141% 2/1,423,086 alleles · very rare

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.Ala22Val
Coding: c.65C>T
MANE Select: NM_033266
Type: single nucleotide variant
Location: chr16:23713123 (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.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-ala22val (accessed [today's date]).

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