Is ERN1 p.Val26Met (c.76G>A) pathogenic?

ERN1 p.Val26Met (c.76G>A) is classified Uncertain significance in ERN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-21). AlphaMissense: ambiguous (0.3605); Ultra-rare (popmax 0.0164%, mid).

How common is ERN1 p.Val26Met (c.76G>A) in the general population?

ERN1 p.Val26Met (c.76G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ERN1 p.Val26Met (c.76G>A)?

AlphaMissense predicts ambiguous (score 0.3605) — an in-silico prediction, not a clinical call.

ERN1 p.Val26Met

c.76G>A · rs758546929 · VCV2603674

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3605 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3605	ambiguous
REVEL	0.153	moderately benign-leaning
SaProt	LLR -8.52	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 72 kb · p 4e-07 · regional, not allelic
Overall
CADD	26.0	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,613,870 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.000678%	147,486

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.Val26Met
Coding: c.76G>A
MANE Select: NM_001433
dbSNP: rs758546929
Type: single nucleotide variant
Location: chr17:64098220 (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.Val26Leu 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
ERN1 p.Ala435Val 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-val26met (accessed [today's date]).

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