Is ERN1 p.Arg356Ser (c.1068G>C) pathogenic?

ERN1 p.Arg356Ser (c.1068G>C) is classified Uncertain significance in ERN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1692); Absent from gnomAD v4.1.

How common is ERN1 p.Arg356Ser (c.1068G>C) in the general population?

ERN1 p.Arg356Ser (c.1068G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERN1 p.Arg356Ser (c.1068G>C)?

AlphaMissense predicts likely benign (score 0.1692) — an in-silico prediction, not a clinical call.

ERN1 p.Arg356Ser

c.1068G>C · VCV4250926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1692 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1692	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -5.40	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 1.9	GERP 0.008, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 72 kb · p 4e-07 · regional, not allelic
Overall
CADD	22.5	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

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: ERN1
Protein: p.Arg356Ser
Coding: c.1068G>C
MANE Select: NM_001433
Type: single nucleotide variant
Location: chr17:64064005 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.50 · 26 PDB

Full ERN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERN1 p.Leu786= Benign ★★ same type
ERN1 p.Pro550Arg Benign ★★ same type
ERN1 p.Ala427Thr Uncertain significance ★ ⚠ same type
ERN1 p.Ala431Pro Uncertain significance ★ ⚠ same type
ERN1 p.Ala435Asp Uncertain significance ★ ⚠ same type
ERN1 p.Ala435Thr Uncertain significance ★ ⚠ same type
ERN1 p.Ala435Val Uncertain significance ★ ⚠ same type
ERN1 p.Ala641Gly 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/ern1-p-arg356ser (accessed [today's date]).

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