RYR2

Chr 1AD

ryanodine receptor 2

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

NCBI Gene: 6262ENSG00000198626UniProt: Q92736

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]

Primary Disease Associations & Inheritance

Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndromeMIM #115000
AD
Ventricular tachycardia, catecholaminergic polymorphic, 1MIM #604772
AD
600
ClinVar variants
9
Pathogenic / LP
1.00
pLI score· haploinsufficient
3
Active trials
Clinical Summary— RYR2
🧬
Gene-Disease Validity (ClinGen)
hypertrophic cardiomyopathy · ADLimited

Limited evidence — not for standalone diagnostic reporting

4 total gene-disease associations curated

⚡
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.
📋
ClinVar Variants
9 Pathogenic / Likely Pathogenic· 355 VUS of 600 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.16–0.25)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.66–0.71)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 50 / 253.4Missense obs/exp: 1804 / 2639.8Syn Z: -0.20

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic5
VUS355
Likely Benign233
Benign3
4
Pathogenic
5
Likely Pathogenic
355
VUS
233
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
1
0
4
Likely Pathogenic
0
5
0
0
5
VUS
17
307
25
6
355
Likely Benign
0
3
119
111
233
Benign
0
0
3
0
3
Total17318148117600

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in 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.

Gene2Phenotype Curations

RYR2-related catecholaminergic polymorphic ventricular tachycardia

definitive
ADGain Of FunctionAltered Gene Product Structure
Cardiac
G2P ↗
missense variant

RYR2-related hypertrophic cardiomyopathy

limited
ADUndeterminedUncertain
Cardiac
G2P ↗

RYR2-related arrhythmogenic right ventricular cardiomyopathy

refuted
ADUndeterminedUncertain
Cardiac
G2P ↗

RYR2-related catecholaminergic polymorphic ventricular tachycardia and intellectual disability

limited
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome

MIM #115000

Molecular basis of disorder known

Autosomal dominant

Ventricular tachycardia, catecholaminergic polymorphic, 1

MIM #604772

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — RYR2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Catecholaminergic Polymorphic Ventricular Tachycardia: A Review of Therapeutic Strategies.
Bergeman AT et al.·Card Electrophysiol Clin
2023Review
RYR2-ryanodinopathies: from calcium overload to calcium deficiency.
Steinberg C et al.·Europace
2023
Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target.
Dridi H et al.·Nat Rev Cardiol
2020Review
De novo mutations in moderate or severe intellectual disability.
Hamdan FF et al.·PLoS Genet
2014
Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.
Mazzarotto F et al.·Genet Med
2021
RBM20 Mutations Induce an Arrhythmogenic Dilated Cardiomyopathy Related to Disturbed Calcium Handling.
van den Hoogenhof MMG et al.·Circulation
2018
Exploring prognostic indicators in the pathological images of hepatocellular carcinoma based on deep learning.
Shi JY et al.·Gut
2021
Hippo-Yap Signaling Maintains Sinoatrial Node Homeostasis.
Zheng M et al.·Circulation
2022
Integrated analyses of multi-omic data derived from paired primary lung cancer and brain metastasis reveal the metabolic vulnerability as a novel therapeutic target.
Duan H et al.·Genome Med
2024
Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC model.
Qiu H et al.·Nat Commun
2024Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Neurocardiogenetics: Exploring the association of rare RYR2 variants with neuropsychiatric disorders in general and disease populations.
Dababneh SF et al.·J Neurogenet
2026
Characterization of cardiac disease-associated mutations in RyR2 Ca2+ and caffeine binding sites.
Chirasani VR et al.·Am J Physiol Cell Physiol
2026
Type 2 Diabetes disrupts T-tubule and RyR2 organisation in male but not female rat ventricular muscle.
Rahmani M et al.·Am J Physiol Heart Circ Physiol
2026
MYBPC3 (c.194 C > T) mutation-mediated RyR2 dysfunction contributes to pathogenic phenotypes of DCM revealed by HiPSC modeling.
Xie M et al.·Cell Mol Life Sci
2026🔓 Open AccessFunctional
Conventional Antiarrhythmics Class I-IV, Late INa Inhibitors, IKs Enhancers, RyR2 Stabilizers, Gap Junction Modulators, Atrial-Selective Antiarrhythmics, and Stable Gastric Pentadecapeptide BPC 157 as Useful Cytoprotective Therapy in Arrhythmias.
Sikiric P et al.·Pharmaceuticals (Basel)
2026
Top 5 resultsSearch Europe PMC ↗

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
Calcium Release Deficiency Syndrome

International CRDS Registry

RECRUITING
NCT06508164Population Health Research InstituteStarted 2024-11-21
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

External Resources

Links to major genomics databases and tools