Is ERN1 p.Arg174Trp (c.520C>T) pathogenic?

ERN1 p.Arg174Trp (c.520C>T) is classified Uncertain significance in ERN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-03). AlphaMissense: likely benign (0.3369); Ultra-rare (popmax 0.0129%, nfe).

How common is ERN1 p.Arg174Trp (c.520C>T) in the general population?

ERN1 p.Arg174Trp (c.520C>T) is ultra-rare (popmax 0.0129%, nfe) (gnomAD).

What do computational predictors say about ERN1 p.Arg174Trp (c.520C>T)?

AlphaMissense predicts likely benign (score 0.3369) — an in-silico prediction, not a clinical call.

ERN1 p.Arg174Trp

c.520C>T · VCV3510229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0129%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3369	likely benign
REVEL	0.3	indeterminate
SaProt	LLR -11.26	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 9.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 72 kb · p 4e-07 · regional, not allelic
Overall
CADD	34.0	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 0.0129% European (non-Finnish) · 152/1,179,422 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00992% 160/1,612,770 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0129%	7,759
African / African-American	0.004%	25,008
South Asian	0.00331%	30,241
Remaining individualsnot grpmax-eligible	0.0032%	31,219

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: ERN1
Protein: p.Arg174Trp
Coding: c.520C>T
MANE Select: NM_001433
Type: single nucleotide variant
Location: chr17:64068250 (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.Arg174Gln Uncertain significance ★ ⚠ same residue
ERN1 p.Arg174Gly Uncertain significance ★ ⚠ same residue
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

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-arg174trp (accessed [today's date]).

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