Is RYR2 p.Pro1580= (c.4740G>A) pathogenic?

RYR2 p.Pro1580= (c.4740G>A) is classified Benign/Likely benign in RYR2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-02). Low-frequency (popmax 4.97%, eas); Associated with Cardiovascular phenotype.

What condition is associated with RYR2 p.Pro1580= (c.4740G>A)?

RYR2 p.Pro1580= (c.4740G>A) is associated with Cardiovascular phenotype, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Pro1580= (c.4740G>A) in the general population?

RYR2 p.Pro1580= (c.4740G>A) is low-frequency (popmax 4.97%, eas) (gnomAD).

RYR2 p.Pro1580=

c.4740G>A · rs79811945 · VCV43795

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.97%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.2	GERP -4
Overall
CADD	0.788	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.97% East Asian · 2,225/44,752 alleles

Filtering AF 4.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.73%

Overall 0.174% 2,804/1,611,832 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	4.97%	20
Remaining individualsnot grpmax-eligible	0.263%	380
South Asian	0.114%	879
Middle Eastern	0.0685%	1,460
Admixed American	0.0452%	2,212
African / African-American	0.0373%	2,678
Finnishnot grpmax-eligible	0.0219%	4,564
European (non-Finnish)	0.02%	4,997
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,850

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: RYR2
Protein: p.Pro1580=
Coding: c.4740G>A
MANE Select: NM_001035
dbSNP: rs79811945
Type: single nucleotide variant
Location: chr1:237610818 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 1580: the '4 x approximate repeats' region

Full RYR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy catecholaminergic polymorphic ventricular tachycardia 1 catecholaminergic polymorphic ventricular tachycardia

Similar variants

RYR2 p.Pro1580Leu Uncertain significance ★★ same residue
RYR2 p.Pro1580Ala Uncertain significance ★ same residue
RYR2 p.Pro1580Ser Uncertain significance ★ same residue
RYR2 p.Ala2387Thr Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala2387Val Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala391Asp Likely pathogenic ★★ same condition
RYR2 p.Ala4091Val Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala4510Pro Pathogenic/Likely pathogenic ★★ same condition

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/ryr2-p-pro1580 (accessed [today's date]).

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