Is ERN1 p.Pro516Leu (c.1547C>T) pathogenic?

ERN1 p.Pro516Leu (c.1547C>T) is classified Likely benign in ERN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely benign (0.0612); Rare (popmax 0.119%, eas).

How common is ERN1 p.Pro516Leu (c.1547C>T) in the general population?

ERN1 p.Pro516Leu (c.1547C>T) is rare (popmax 0.119%, eas) (gnomAD).

What do computational predictors say about ERN1 p.Pro516Leu (c.1547C>T)?

AlphaMissense predicts likely benign (score 0.0612) — an in-silico prediction, not a clinical call.

ERN1 p.Pro516Leu

c.1547C>T · VCV4250921

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0612 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.119%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0612	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -5.55	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 0.86	GERP -3.8, phastCons 0.056
Regional constraint	o/e 1.05	unconstrained · MANE · 1,086 bp · p 0.58 · regional, not allelic
Overall
CADD	1.714	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 0.119% East Asian · 52/43,590 alleles

Filtering AF 0.0934% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0841%

Overall 0.0117% 185/1,586,990 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.119%	838
African / African-American	0.107%	931
Remaining individualsnot grpmax-eligible	0.0586%	1,708
South Asian	0.00342%	29,211
Admixed American	0.0018%	55,452
European (non-Finnish)	0.00111%	89,780

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.Pro516Leu
Coding: c.1547C>T
MANE Select: NM_001433
Type: single nucleotide variant
Location: chr17:64055800 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.50 · 26 PDB
Residue 516: the 'disordered' region

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-pro516leu (accessed [today's date]).

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