Is ERN1 p.Val625Met (c.1873G>A) pathogenic?

ERN1 p.Val625Met (c.1873G>A) is classified Uncertain significance in ERN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.9811); Ultra-rare (popmax 0.0297%, sas).

How common is ERN1 p.Val625Met (c.1873G>A) in the general population?

ERN1 p.Val625Met (c.1873G>A) is ultra-rare (popmax 0.0297%, sas) (gnomAD).

What do computational predictors say about ERN1 p.Val625Met (c.1873G>A)?

AlphaMissense predicts likely pathogenic (score 0.9811) — an in-silico prediction, not a clinical call.

ERN1 p.Val625Met

c.1873G>A · VCV4250918

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9811 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9811	likely pathogenic
REVEL	0.541	indeterminate
SaProt	LLR -15.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 11 kb · p 5.7e-14 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0297% South Asian · 27/90,856 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00614% 99/1,613,284 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0297%	3,365
African / African-American	0.0107%	9,366
European (non-Finnish)	0.00492%	20,339
Remaining individualsnot grpmax-eligible	0.0048%	20,814
Finnishnot grpmax-eligible	0.00313%	31,990
East Asian	0.00223%	44,886

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.Val625Met
Coding: c.1873G>A
MANE Select: NM_001433
Type: single nucleotide variant
Location: chr17:64054330 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.50 · 26 PDB
Residue 625: the protein kinase domain

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-val625met (accessed [today's date]).

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