CASQ2

Chr 1AR

calsequestrin 2

Also known as: PDIB2

NCBI Gene: 845ENSG00000118729UniProt: O14958OMIM: 114251

Calsequestrin 2 is a high-capacity calcium-binding protein that stores calcium in the sarcoplasmic reticulum of cardiac muscle and regulates calcium release through the ryanodine receptor RYR2, playing a critical role in excitation-contraction coupling and heart rate regulation. Mutations cause catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2), characterized by stress-induced bidirectional ventricular tachycardia that can lead to cardiac arrest. CPVT2 follows autosomal recessive inheritance, and CASQ2 is highly intolerant to loss-of-function variants.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 1.381 OMIM phenotype
Clinical Summary— CASQ2
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Gene-Disease Validity (ClinGen)
hypertrophic cardiomyopathy · ADDisputed

Disputed — evidence questions this relationship

3 total gene-disease associations curated

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
69 unique Pathogenic / Likely Pathogenic· 219 VUS of 588 total submissions
Explore recent and relevant literature in Research Assistant →
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GeneReview available — CASQ2
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.38LOEUF
pLI 0.000
Z-score 0.26
OE 0.94 (0.65–1.38)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.20Z-score
OE missense 1.04 (0.93–1.16)
217 obs / 209.1 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.94 (0.65–1.38)
0≤0.351.4
Missense OE1.04 (0.93–1.16)
0≤0.61.4
Synonymous OE1.07
0≤1.21.6
LoF obs/exp: 19 / 20.3Missense obs/exp: 217 / 209.1Syn Z: -0.47
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
limitedCASQ2-related hypertrophic cardiomyopathyOTHERAD
definitiveCASQ2-related catecholaminergic polymorphic ventricular tachycardiaLOFAR
moderateCASQ2-related catecholaminergic polymorphic ventricular tachycardiaOTHERAD
DN
0.6647th %ile
GOF
0.4874th %ile
LOF
0.2970th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

588 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic36
VUS219
Likely Benign249
Benign15
Conflicting33
33
Pathogenic
36
Likely Pathogenic
219
VUS
249
Likely Benign
15
Benign
33
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
22
3
8
0
33
Likely Pathogenic
30
5
1
0
36
VUS
2
182
34
1
219
Likely Benign
2
5
131
111
249
Benign
0
1
14
0
15
Conflicting
—33
Total56196188112585

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

View in ClinVar →

Protein Context — Lollipop Plot

CASQ2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals.
Landstrom AP et al.·Circ Arrhythm Electrophysiol
2017Cohort
Maturation of human cardiac organoids enables complex disease modeling and drug discovery.
Pocock MW et al.·Nat Cardiovasc Res
2025Functional
Catecholaminergic polymorphic ventricular tachycardia (and seizure) caused by a novel homozygous likely pathogenic variant in CASQ2 gene.
Askarinejad A et al.·Gene
2024Review
Clinical and genetic insights into non-compaction: a meta-analysis and systematic review on 7598 individuals.
Kayvanpour E et al.·Clin Res Cardiol
2019Meta-analysis
Genetic Background and Clinical Phenotype in an Italian Cohort with Inherited Arrhythmia Syndromes and Arrhythmogenic Cardiomyopathy (ACM): A Whole-Exome Sequencing Study.
d'Apolito M et al.·Int J Mol Sci
2025Cohort
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

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