RYR1

Chr 19

ryanodine receptor 1

Also known as: CCO, CMYO1A, CMYO1B, CMYP1A, CMYP1B, KDS, MHS, MHS1

NCBI Gene: 6261ENSG00000196218UniProt: P21817

This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

UniProtMalignant hyperthermia 1
UniProtCongenital myopathy 1A, autosomal dominant, with susceptibility to malignant hyperthermia
UniProtCongenital myopathy 1B, autosomal recessive
UniProtKing-Denborough syndrome
0
ClinVar variants
0
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— RYR1
🧬
Gene-Disease Validity (ClinGen)
malignant hyperthermia, susceptibility to, 1 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.46LOEUF
pLI 0.000
Z-score 9.05
OE 0.38 (0.33–0.46)
Moderately constrained

More LoF-intolerant than ~75% 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.
1.92Z-score
OE missense 0.90 (0.87–0.93)
2698 obs / 2993.3 exp
Tolerant

Mild missense constraint

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.0.38 (0.33–0.46)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.90 (0.87–0.93)
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.1.08
0≤1.21.6
LoF obs/exp: 97 / 252.0Missense obs/exp: 2698 / 2993.3Syn Z: -2.17

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

RYR1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

RYR1-related minicore myopathy with external ophthalmoplegia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — RYR1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.
Töpf A et al.·Genet Med
2020Cohort
Panorama of the distal myopathies.
Savarese M et al.·Acta Myol
2020Review
Genetic epidemiology of malignant hyperthermia in the UK.
Miller DM et al.·Br J Anaesth
2018
Update on RYR1-related myopathies.
Ogasawara M et al.·Curr Opin Neurol
2024Review
Intracellular calcium leak as a therapeutic target for RYR1-related myopathies.
Kushnir A et al.·Acta Neuropathol
2020
Genotype-phenotype correlations in recessive RYR1-related myopathies.
Amburgey K et al.·Orphanet J Rare Dis
2013
Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain.
Gonzalez-Quereda L et al.·Genes (Basel)
2020Cohort
Mutations in RYR1 in malignant hyperthermia and central core disease.
Robinson R et al.·Hum Mutat
2006Review
Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service.
Westra D et al.·J Neuromuscul Dis
2019
RYR1-related myopathies: a wide spectrum of phenotypes throughout life.
Snoeck M et al.·Eur J Neurol
2015
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
The Clinical, Histological, and Genetic Spectrum of RYR1 Variants-A Multi-Center Israeli Cohort Study.
Ginsberg M et al.·J Clin Med
2026Cohort
Multilocus pathogenic variants in MCM4, RYR1, and G6PD identified by trio-based whole-exome sequencing in a neonate with multisystem symptoms: a case report.
Zhu K et al.·AME Case Rep
2026🔓 Open AccessCase report
Tamoxifen treatment fails to improve muscle dysfunction in a model of recessive RYR1-linked centronuclear myopathy.
Gineste C et al.·Dis Model Mech
2025🔓 Open AccessFunctional
Clinical and Genetic Characterization of a Novel RYR1 Variant (p.Gln474His) in Malignant Hyperthermia Susceptibility.
Tracy E et al.·Genes (Basel)
2025🔓 Open Access
Serum Calcium Concentration Is Associated with Bone Mineral Density and Synonymous Variants in the RYR1 Gene in a Mexican-Mestizo Population.
López-Pérez TV et al.·Med Sci (Basel)
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Ryanodine Receptor 1-Related MyopathyRyanodine Receptor 1 Related Disorders

A Natural History Study of RYR1-Related Disorders

RECRUITING
NCT06287762National Institutes of Health Clinical Center (CC)Started 2025-03-11
Central Core DiseaseCentronuclear MyopathyCongenital Fiber Type Disproportion

Molecular and Genetic Studies of Congenital Myopathies

RECRUITING
NCT00272883Boston Children's HospitalStarted 2003-08
Inherited Non-Duchenne Myopathies

Clinical and Functional Assessment of Patients With Inherited Non-Duchenne Myopathies in Sohag University Hospital

RECRUITING
NCT06574919Sohag UniversityStarted 2024-08-01
Neuromuscular DiseaseMalignant HyperthermiaCongenital Myopathy

The Prevalence of RYR1-related Disease

NOT YET RECRUITING
NCT06791369King's College LondonStarted 2025-02

External Resources

Links to major genomics databases and tools