RYR2

Chr 1AD

ryanodine receptor 2

Also known as: ARVC2, ARVD2, RYR-2, RyR, VACRDS, VTSIP

NCBI Gene: 6262 ENSG00000198626 UniProt: Q92736 OMIM: 180902

This gene encodes a cardiac ryanodine receptor that functions as a cytosolic calcium-activated calcium channel, mediating calcium release from the sarcoplasmic reticulum to trigger cardiac muscle contraction. Mutations cause catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, indicating that haploinsufficiency is likely not tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.252 OMIM phenotypes

Clinical Summary— RYR2

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Gene-Disease Validity (ClinGen)

hypertrophic cardiomyopathy · ADLimited

Limited evidence — not for standalone diagnostic reporting

4 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.25LOEUF

pLI 1.000

Z-score 11.84

OE 0.20 (0.16–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

5.78Z-score

OE missense 0.68 (0.66–0.71)

1804 obs / 2639.8 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.20 (0.16–0.25)

0≤0.351.4

Missense OE?0.68 (0.66–0.71)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 50 / 253.4Missense obs/exp: 1804 / 2639.8Syn Z: -0.20

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRYR2-related catecholaminergic polymorphic ventricular tachycardiaGOFAD

limitedRYR2-related hypertrophic cardiomyopathyOTHERAD

limitedRYR2-related arrhythmogenic right ventricular cardiomyopathyOTHERAD

limitedRYR2-related catecholaminergic polymorphic ventricular tachycardia and intellectual disabilityOTHERAD

This gene — mechanism propensity

0.4586th %ile

GOF

0.5563th %ile

LOF

0.63top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.25

GOF1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThe G4935R mutation completely abolished caffeine activation of and [3H]ryanodine binding to RyR2. Co-expression studies showed that the G4935R mutation exerted dominant negative impact on the RyR2 wildtype (WT) channel.1

GOFUnlike the gain-of-function mechanism observed in RYR2-mediated CPVT, the homozygous multiexon duplication precipitated a dramatic reduction in RYR2 transcription and RyR2 protein translation, a loss of function in calcium handling, and a calcium-induced calcium release apparatus that is insensitive2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

RYR2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Catecholaminergic Polymorphic Ventricular Tachycardia

A Study of SGT-501 Gene Therapy in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

RECRUITING

NCT07148089Phase PHASE1Solid Biosciences Inc.Started 2026-02-23

SGT-501

Arrhythmogenic Cardiomyopathies

Tissue and Metabolic Characterization of Arrhythmogenic Cardiomyopathies by Hybrid PET-MRI Imaging, Impact of the Observed Profiles on the Phenotype and on the Evolution of Cardiomyopathy

RECRUITING

NCT05450783Nantes University HospitalStarted 2022-09-01

Biocollection

Calcium Release Deficiency Syndrome

International CRDS Registry

RECRUITING

NCT06508164Population Health Research InstituteStarted 2024-11-21

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3