Is ERN1 p.Pro751Ala (c.2251C>G) pathogenic?

ERN1 p.Pro751Ala (c.2251C>G) is classified Uncertain significance in ERN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-14). AlphaMissense: ambiguous (0.5478); Ultra-rare (popmax 0.015%, amr).

How common is ERN1 p.Pro751Ala (c.2251C>G) in the general population?

ERN1 p.Pro751Ala (c.2251C>G) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about ERN1 p.Pro751Ala (c.2251C>G)?

AlphaMissense predicts ambiguous (score 0.5478) — an in-silico prediction, not a clinical call.

ERN1 p.Pro751Ala

c.2251C>G · rs761304824 · VCV2598578

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5478 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Computational evidence

Protein change
AlphaMissense	0.5478	ambiguous
REVEL	0.326	indeterminate
SaProt	LLR -6.69	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 11 kb · p 5.7e-14 · regional, not allelic
Overall
CADD	27.3	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 0.015% Admixed American · 9/60,006 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.000616% 9/1,460,712 alleles · ultra-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: ERN1
Protein: p.Pro751Ala
Coding: c.2251C>G
MANE Select: NM_001433
dbSNP: rs761304824
Type: single nucleotide variant
Location: chr17:64052782 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.50 · 26 PDB
Residue 751: 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-pro751ala (accessed [today's date]).

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