CASQ2

Summary

CASQ2 (calsequestrin 2, HGNC:1513) is a protein-coding gene on chromosome 1p13.1, encoding Calsequestrin-2 (O14958). Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle.

The protein encoded by this gene specifies the cardiac muscle family member of the calsequestrin family. Calsequestrin is localized to the sarcoplasmic reticulum in cardiac and slow skeletal muscle cells. The protein is a calcium binding protein that stores calcium for muscle function. Mutations in this gene cause stress-induced polymorphic ventricular tachycardia, also referred to as catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2), a disease characterized by bidirectional ventricular tachycardia that may lead to cardiac arrest.

Source: NCBI Gene 845 — RefSeq curated summary.

At a glance

• Gene–disease (curated): catecholaminergic polymorphic ventricular tachycardia (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 31
• Clinical variants (ClinVar): 876 total — 36 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 27
• MANE Select transcript: NM_001232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1513
Approved symbol	CASQ2
Name	calsequestrin 2
Location	1p13.1
Locus type	gene with protein product
Status	Approved
Aliases	PDIB2
Ensembl gene	ENSG00000118729
Ensembl biotype	protein_coding
OMIM	114251
Entrez	845

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000261448, ENST00000488931, ENST00000713711, ENST00000713712, ENST00000713713, ENST00000713727, ENST00000713728, ENST00000713729, ENST00000850611, ENST00000850612, ENST00000874188, ENST00000874189

RefSeq mRNA: 1 — MANE Select: NM_001232 NM_001232

CCDS: CCDS884

Canonical transcript exons

ENST00000261448 — 11 exons

Exon	Start	End
ENSE00000800544	115738224	115738335
ENSE00000800545	115740728	115740828
ENSE00000800546	115744828	115744912
ENSE00001074019	115732901	115732974
ENSE00001074020	115702921	115702995
ENSE00001074027	115705192	115705292
ENSE00001957067	115768308	115768714
ENSE00003541303	115717840	115717894
ENSE00003569802	115726992	115727122
ENSE00003670364	115725508	115725553
ENSE00004282326	115700021	115701426

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 99.79.

FANTOM5 (CAGE): breadth broad, TPM avg 5.1790 / max 1112.6405, expressed in 185 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13987	3.1087	160
13988	0.8312	106
13989	0.6992	100
13986	0.2441	52
13990	0.1796	54
13983	0.0929	33
13985	0.0233	12

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.79	gold quality
left ventricle myocardium	UBERON:0006566	99.59	gold quality
myocardium	UBERON:0002349	99.53	gold quality
cardiac ventricle	UBERON:0002082	99.43	gold quality
heart left ventricle	UBERON:0002084	99.42	gold quality
cardiac atrium	UBERON:0002081	99.29	gold quality
right atrium auricular region	UBERON:0006631	99.29	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.26	gold quality
apex of heart	UBERON:0002098	98.95	gold quality
heart	UBERON:0000948	98.90	gold quality
vena cava	UBERON:0004087	98.70	gold quality
biceps brachii	UBERON:0001507	98.37	gold quality
popliteal artery	UBERON:0002250	98.36	gold quality
tibial artery	UBERON:0007610	98.36	gold quality
gluteal muscle	UBERON:0002000	98.28	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.20	gold quality
right coronary artery	UBERON:0001625	98.14	gold quality
diaphragm	UBERON:0001103	98.13	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.01	gold quality
triceps brachii	UBERON:0001509	97.99	gold quality
blood vessel layer	UBERON:0004797	97.97	gold quality
tibialis anterior	UBERON:0001385	97.91	gold quality
deltoid	UBERON:0001476	97.90	gold quality
saphenous vein	UBERON:0007318	97.90	gold quality
skeletal muscle tissue	UBERON:0001134	97.52	gold quality
quadriceps femoris	UBERON:0001377	97.48	gold quality
vastus lateralis	UBERON:0001379	97.46	gold quality
coronary artery	UBERON:0001621	96.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.91	gold quality
left coronary artery	UBERON:0001626	96.90	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

56 targeting CASQ2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-6513-5P	99.43	67.81	1071
HSA-MIR-4427	99.34	70.33	1854

Literature-anchored findings (GeneRIF, showing 40)

• missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel (PMID:11704930)
• calsequestrin 2 mutations causes severe forms of catecholaminergic polymorphic ventricular tachycardia (PMID:12386154)
• missense mutation in the CASQ2 gene is associated with autosomal-recessive CPVT(catecholamine-induced polymorphic ventricular tachycardia). (PMID:12732448)
• A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. (PMID:12858557)
• Intracellular Ca2+ cycling in normal heart relies on intricate interplay of CASQ2 with proteins of RyR2 channel complex, and disruption of these interactions can lead to cardiac arrhythmia. (PMID:16601229)
• CASQ2 mutations identified in polymorphic ventricular tachycardia create distinct abnormalities that lead to abnormal intracellular calcium regulation, thus facilitating the development of tachyarrhythmias. (PMID:16908766)
• CSQ was a highly phosphorylated protein with a glycan structure predictive of ER-retained proteins. (PMID:17045261)
• A variant was identified in CASQ2. (PMID:17655857)
• Data show that all three CPVT-related missense mutations lead to significant reduction in Ca2+-binding capacity and scattering experiments confirm that the linear polymerization behavior of CSQ is linked directly to its high-capacity Ca2+ binding. (PMID:17881003)
• analysis of how human and rat CASQ2 ventricular tachycardia-related mutations R33Q and L167H alter calcium sensitivity (PMID:18399795)
• study concludes CASQ2 in the sarcoplasmic reticulum (SR )determines magnitude & duration of Ca release from each SR terminal; 2 CPVT-inducing CASQ2 mutations lead to increased diastolic SR Ca release events and exhibit a similar CPVT disease phenotype (PMID:18469084)
• A novel mutation of F189L in the CASQ2 gene was identified in families with catecholaminergic polymorphic ventricular tachycardia. (PMID:18543230)
• REVIEW of Casq2 mutations that cause catecholaminergic polymorphic ventricular tachycardia and their effects on Casq2 function and Ca handling (PMID:18669926)
• Facilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression. (PMID:19357236)
• Data suggest that calsequestrin (CSQ)2 facilitates Ca(2+) release through RyR2 during systole, while CSQ1 curtails RyR1 opening to maintain Ca(2+) and allow repeated release/ graded activation with increased stimulation frequency. (PMID:19376574)
• Cardiac and fatal or near-fatal events were not rare in both catecholaminergic polymorphic ventricular tachycardia RYR2 and a CASQ2 mutation probands and affected family members during the long-term follow-up (PMID:19398665)
• up-regulation of casq2 gene in the thyroid of patients with Graves’ Hyperthyroidism may lead to the production of autoantibodies and sensitized T-lymphocytes, which cross-react with calsequestrin of patients who develop ophthalmopathy. (PMID:20039900)
• The human CASQ2 mutation K206N is associated with hyperglycosylation and altered cellular calcium handling. (PMID:20302875)
• A regulatory role of CASQ2 on cytosolic Ca(2+) and hERG channels which may contribute to the etiology of CPVT. (PMID:21063088)
• Catecholaminergic polymorphic ventricular tachycardia (CPTV) mutations modify CASQ2 behaviour, including folding, aggregation/polymerization and selectivity towards Ca2+. (PMID:21265816)
• Studies identified two phosphorylation sites, Ser(385) and Ser(393 in hCASQ2 by mass-spectroscopy. (PMID:21416293)
• Molecular analysis of the CASQ2 gene in 43 probands with Catecholaminergic polymorphic ventricular tachycardia were performed and eight mutations in five patients, were identified. (PMID:21618644)
• Common variations in or near CASQ2, GPD1L, and NOS1AP are associated with increased risk of sudden cardiac death in patients with coronary artery disease (PMID:21685173)
• Two causative genes of CPVT have been identified: RYR2, encoding the cardiac ryanodine receptor (RyR2) Ca(2+) release channel, and CASQ2, encoding cardiac calsequestrin. Their mutation have been found in 60% of patients with CPVT. (PMID:21872879)
• Aspartate to histidine casq2 mutation causes arrhythmia in cardiomyocytes generated from catecholaminergic polymorphic ventricular tachycardia patients. (PMID:22050625)
• Ca(2+) and JNT-dependent disassembly of the CSQ2 polymer (PMID:22123818)
• A review of the physiology of Casq2 in cardiac Ca2+ handling and discuss pathophysiological mechanisms that lead to catecholaminergic polymorphic ventricular tachycardia caused by CASQ2 mutations. (PMID:22421959)
• patients with CASQ2-associated CPVT should be recommended to receive ICDs to prevent sudden death when medical therapy is not effective. (PMID:22481011)
• In a consanguineous family, a novel homozygous CASQ2 mutation (p.L77P) was identified in a child with CPVT who required implantation of a cardioverter defibrillator due to episodes of syncope while on medical therapy (PMID:22650415)
• Genetic background of catecholaminergic polymorphic ventricular tachycardia in Japan. (PMID:23595086)
• The sarcoplasmic reticulum calcium content in human type II fibres is primarily determined by the CSQ1 abundance, and in type I fibres, by the combined amounts of both CSQ1 and CSQ2. (PMID:24127619)
• We observed association between a CASQ2 polymorphism and SCA due to VA in patients with CAD adjusting for CHF and independent associations between CASQ2 SNPs and CHF adjusting for SCA. (PMID:24444446)
• Mutations in the MYBPC3 and CASQ2 genes and six combinations between loci in the MYBPC3, MYH7 and CASQ2 genes were responsible for cardiomyopathy risk in a studied cohort. (PMID:25892673)
• induced Pluripotent Stem Cell-derived cardiomyocytes are useful for investigating the similarities/differences in the pathophysiological consequences of RyR2 versus CASQ2 mutations underlying Catecholaminergic polymorphic ventricular tachycardia. (PMID:26153920)
• We show for the first time a heterozygous CASQ2 variant causing autosomal dominant CPVT in a large family with a severe phenotype. (PMID:27157848)
• a direct interaction exists between RyR2 and CSQ2, is reported. (PMID:27609834)
• CASQ2 variants are associated with catecholaminergic polymorphic ventricular tachycardia. (PMID:31482657)
• Catecholaminergic Polymorphic Ventricular Tachycardia. (PMID:31934898)
• Association of T66A polymorphism in CASQ2 with PR interval in a Chinese population.", trans “Assoziation des T66A-Polymorphismus im CASQ2-Gen mit dem PR-Intervall in einer chinesischen Population. (PMID:32291483)
• An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia. (PMID:32693635)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	casq2	ENSDARG00000008982
mus_musculus	Casq2	ENSMUSG00000027861
rattus_norvegicus	Casq2	ENSRNOG00000016243
caenorhabditis_elegans		WBGENE00000822

Paralogs (1): CASQ1 (ENSG00000143318)

Protein

Protein identifiers

Calsequestrin-2 — O14958 (reviewed: O14958)

Alternative names: Calsequestrin, cardiac muscle isoform

All UniProt accessions (8): A0AA34QVH1, A0AAQ5BGQ8, A0AAQ5BGR1, A0AAQ5BGR3, A0AAQ5BGR5, A0AAQ5BGS1, A0AAQ5BGT6, O14958

UniProt curated annotations — full annotation on UniProt →

Function. Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle. Calcium ions are bound by clusters of acidic residues at the protein surface, especially at the interface between subunits. Can bind around 60 Ca(2+) ions. Regulates the release of lumenal Ca(2+) via the calcium release channel RYR2; this plays an important role in triggering muscle contraction. Plays a role in excitation-contraction coupling in the heart and in regulating the rate of heart beats.

Subunit / interactions. Monomer, homodimer and homooligomer. Mostly monomeric in the absence of calcium. Forms higher oligomers in a calcium-dependent manner. Dimers associate to form tetramers, that then form linear homomer chains. Interacts with ASPH and TRDN.

Subcellular location. Sarcoplasmic reticulum lumen.

Post-translational modifications. Phosphorylation in the C-terminus, probably by CK2, moderately increases calcium buffering capacity. N-glycosylated.

Disease relevance. Ventricular tachycardia, catecholaminergic polymorphic, 2 (CPVT2) [MIM:611938] An arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress. CPVT2 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the calsequestrin family.

Isoforms (2)

UniProt ID	Names	Canonical?
O14958-1	1	yes
O14958-2	2

RefSeq proteins (1): NP_001223* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001393	Calsequestrin	Family
IPR018233	Calsequestrin_CS	Conserved_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR041858	Calsequestrin_middle_dom	Domain
IPR041859	Calsequestrin_N	Domain
IPR041860	Calsequestrin_C	Domain

Pfam: PF01216

UniProt features (52 total): strand 15, helix 12, sequence variant 8, turn 6, modified residue 3, sequence conflict 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6OWV	X-RAY DIFFRACTION	1.88
7F05	X-RAY DIFFRACTION	2.3
2VAF	X-RAY DIFFRACTION	3.8
6OWW	X-RAY DIFFRACTION	3.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14958-F1	90.63	0.84

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 282, 385, 393

Glycosylation sites (1): 335

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-5578775	Ion homeostasis
R-HSA-382551	Transport of small molecules
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction
R-HSA-983712	Ion channel transport

MSigDB gene sets: 290 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CIRCULATORY_SYSTEM_PROCESS, LFA1_Q6, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, TGACCTY_ERR1_Q2, MEF2_02, MODULE_329, AAAYRNCTG_UNKNOWN, GNF2_MYL3, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CONTRACTION_BY_REGULATION_OF_THE_RELEASE_OF_SEQUESTERED_CALCIUM_ION, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING

GO Biological Process (16): regulation of heart rate (GO:0002027), detection of calcium ion (GO:0005513), intracellular calcium ion homeostasis (GO:0006874), striated muscle contraction (GO:0006941), regulation of cell communication by electrical coupling (GO:0010649), regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0010880), regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion (GO:0010881), negative regulation of potassium ion transport (GO:0043267), obsolete sequestering of calcium ion (GO:0051208), protein polymerization (GO:0051258), cardiac muscle contraction (GO:0060048), regulation of membrane repolarization (GO:0060306), cellular response to caffeine (GO:0071313), Purkinje myocyte to ventricular cardiac muscle cell signaling (GO:0086029), regulation of membrane repolarization during ventricular cardiac muscle cell action potential (GO:1905024), regulation of release of sequestered calcium ion into cytosol (GO:0051279)

GO Molecular Function (6): calcium ion binding (GO:0005509), protein homodimerization activity (GO:0042803), calcium-dependent protein binding (GO:0048306), calcium ion sequestering activity (GO:0140314), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): cytoplasm (GO:0005737), junctional sarcoplasmic reticulum membrane (GO:0014701), sarcoplasmic reticulum (GO:0016529), Z disc (GO:0030018), sarcoplasmic reticulum membrane (GO:0033017), sarcoplasmic reticulum lumen (GO:0033018), calcium channel complex (GO:0034704)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Ion channel transport	1
Cardiac conduction	1
Muscle contraction	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
calcium ion binding	2
cellular anatomical structure	2
sarcoplasmic reticulum	2
regulation of heart contraction	1
regulation of biological quality	1
detection of chemical stimulus	1
response to calcium ion	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
muscle contraction	1
cell communication by electrical coupling	1
regulation of cell communication	1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of release of sequestered calcium ion into cytosol	1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of cardiac muscle contraction by calcium ion signaling	1
potassium ion transport	1
regulation of potassium ion transport	1
negative regulation of monoatomic ion transport	1
protein-containing complex assembly	1
striated muscle contraction	1
heart contraction	1
regulation of membrane potential	1
regulation of biological process	1
membrane repolarization	1
response to caffeine	1
cellular response to alkaloid	1
cellular response to purine-containing compound	1
cell-cell signaling	1
Purkinje myocyte to ventricular cardiac muscle cell communication	1
regulation of ventricular cardiac muscle cell membrane repolarization	1
membrane repolarization during ventricular cardiac muscle cell action potential	1
regulation of membrane repolarization during cardiac muscle cell action potential	1
release of sequestered calcium ion into cytosol	1
regulation of calcium ion transmembrane transport	1
metal ion binding	1
identical protein binding	1
protein dimerization activity	1
protein binding	1
metal ion sequestering activity	1

Protein interactions and networks

STRING

1817 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASQ2	RYR2	Q92736	987
CASQ2	TRDN	Q13061	985
CASQ2	ASPH	Q12797	980
CASQ2	FKBP1B	P68106	864
CASQ2	CACNA1C	Q13936	754
CASQ2	KCNJ2	P48049	738
CASQ2	CALM1	P02593	723
CASQ2	SCN5A	Q14524	699
CASQ2	A0A590UK56	A0A590UK56	697
CASQ2	MYL7	Q01449	656
CASQ2	ATP2A2	P16614	650
CASQ2	NPR1	P16066	649
CASQ2	KCNH2	Q12809	646
CASQ2	CALML3	P27482	635
CASQ2	CALR	P27797	631

IntAct

20 interactions, top by confidence:

A	B	Type	Score
BYSL	CASQ2	psi-mi:“MI:0915”(physical association)	0.560
CASQ2	BYSL	psi-mi:“MI:0915”(physical association)	0.560
CASQ2	PES1	psi-mi:“MI:0914”(association)	0.530
CASQ2	CASQ2	psi-mi:“MI:0407”(direct interaction)	0.440
CASQ2	DNAJC3	psi-mi:“MI:0915”(physical association)	0.400
CASQ2	H1-5	psi-mi:“MI:0915”(physical association)	0.400
CASQ2	H1-2	psi-mi:“MI:0915”(physical association)	0.400
CASQ2	H1-1	psi-mi:“MI:0915”(physical association)	0.400
CASQ2	RPL10A	psi-mi:“MI:0915”(physical association)	0.400
CASQ2	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
CASQ2	MYH9	psi-mi:“MI:0915”(physical association)	0.400
CASQ2	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
CASQ2	ERI2	psi-mi:“MI:0915”(physical association)	0.400
CASQ2	PLEC	psi-mi:“MI:0915”(physical association)	0.400
CASQ2	H3-4	psi-mi:“MI:0915”(physical association)	0.400
CFTR	CASQ2	psi-mi:“MI:0915”(physical association)	0.370
CASQ2	TSNARE1	psi-mi:“MI:0914”(association)	0.350
CASQ2	KCNN4	psi-mi:“MI:0914”(association)	0.350

BioGRID (140): ACTA2 (Affinity Capture-MS), ZFP91 (Affinity Capture-MS), GTF3C2 (Affinity Capture-MS), CBX6 (Affinity Capture-MS), CUL7 (Affinity Capture-MS), GTPBP6 (Affinity Capture-MS), PPP1R9A (Affinity Capture-MS), PPP1R9B (Affinity Capture-MS), GTF3C3 (Affinity Capture-MS), ZBTB21 (Affinity Capture-MS), GTF3C1 (Affinity Capture-MS), WDR12 (Affinity Capture-MS), PRDM10 (Affinity Capture-MS), OBSL1 (Affinity Capture-MS), EPB41L5 (Affinity Capture-MS)

ESM2 similar proteins: A0A8M1N5Y4, A5PMF7, O09161, O09165, O14958, O18934, O77560, O80977, P07221, P08003, P12637, P13667, P19204, P19633, P20942, P24643, P27824, P31231, P31235, P31415, P35564, P35565, P38659, P51868, P81628, P93026, P93484, Q01H84, Q0JD42, Q14554, Q29RV1, Q2KIL5, Q56ZQ3, Q5FVM7, Q5I0H9, Q5R440, Q5RAN9, Q5RCM7, Q5WA72, Q5ZKZ4

Diamond homologs: O09161, O09165, O14958, O18934, P07221, P12637, P19204, P19633, P31231, P31235, P31236, P31415, P51868, Q5RAN9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CSNK2A1	unknown	CASQ2	phosphorylation
CSNK2A2	unknown	CASQ2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
nucleosome assembly	6	56.2×	8e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

876 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	26
Uncertain significance	340
Likely benign	334
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1033372	NM_001232.4(CASQ2):c.737+2T>A	Pathogenic
1425730	NM_001232.4(CASQ2):c.988C>T (p.Gln330Ter)	Pathogenic
1455404	NC_000001.10:g.(?116269603)(116269753_?)del	Pathogenic
1457736	NM_001232.4(CASQ2):c.1014+1G>A	Pathogenic
17610	NM_001232.4(CASQ2):c.919G>C (p.Asp307His)	Pathogenic
17611	NM_001232.4(CASQ2):c.339_354del (p.Ser113fs)	Pathogenic
17612	NM_001232.4(CASQ2):c.500T>A (p.Leu167His)	Pathogenic
1784131	NM_001232.4(CASQ2):c.199C>T (p.Gln67Ter)	Pathogenic
190754	NM_001232.4(CASQ2):c.204del (p.Lys68fs)	Pathogenic
190758	NM_001232.4(CASQ2):c.1017dup (p.Asp340Ter)	Pathogenic
2565185	NM_001232.4(CASQ2):c.1028G>A (p.Trp343Ter)	Pathogenic
2704628	NM_001232.4(CASQ2):c.31del (p.Ile11fs)	Pathogenic
2717451	NM_001232.4(CASQ2):c.1082G>A (p.Trp361Ter)	Pathogenic
2744443	NM_001232.4(CASQ2):c.414_415del (p.Leu139fs)	Pathogenic
2770074	NM_001232.4(CASQ2):c.754del (p.Leu252fs)	Pathogenic
2794330	NM_001232.4(CASQ2):c.846C>A (p.Tyr282Ter)	Pathogenic
2806492	NM_001232.4(CASQ2):c.205C>T (p.Gln69Ter)	Pathogenic
2811031	NM_001232.4(CASQ2):c.3G>A (p.Met1Ile)	Pathogenic
2822271	NM_001232.4(CASQ2):c.781del (p.Trp261fs)	Pathogenic
2865838	NM_001232.4(CASQ2):c.537C>A (p.Tyr179Ter)	Pathogenic
2914975	NM_001232.4(CASQ2):c.244C>T (p.Gln82Ter)	Pathogenic
3236407	NM_001232.4(CASQ2):c.320-2A>G	Pathogenic
3247739	NC_000001.10:g.(?116243862)(116244067_?)del	Pathogenic
3247740	NC_000001.10:g.(?116287429)(116287553_?)del	Pathogenic
3623127	NM_001232.4(CASQ2):c.582del (p.Lys194fs)	Pathogenic
3638681	NM_001232.4(CASQ2):c.591del (p.Thr198fs)	Pathogenic
3676998	NM_001232.4(CASQ2):c.421-2A>T	Pathogenic
3688556	NM_001232.4(CASQ2):c.45del (p.Ser16fs)	Pathogenic
3722580	NM_001232.4(CASQ2):c.172G>T (p.Glu58Ter)	Pathogenic
3722584	NM_001232.4(CASQ2):c.843_847del (p.Tyr282fs)	Pathogenic

SpliceAI

1271 predictions. Top by Δscore:

Variant	Effect	Δscore
1:115701422:TCAGC:T	acceptor_gain	1.0000
1:115701423:CAGC:C	acceptor_gain	1.0000
1:115701423:CAGCC:C	acceptor_gain	1.0000
1:115701425:GC:G	acceptor_gain	1.0000
1:115701426:CC:C	acceptor_gain	1.0000
1:115701426:CCTG:C	acceptor_loss	1.0000
1:115701427:C:CC	acceptor_gain	1.0000
1:115701428:T:G	acceptor_loss	1.0000
1:115701430:C:CT	acceptor_gain	1.0000
1:115701431:A:T	acceptor_gain	1.0000
1:115701432:G:C	acceptor_gain	1.0000
1:115701432:G:GC	acceptor_gain	1.0000
1:115702919:A:AC	donor_gain	1.0000
1:115702920:C:CC	donor_gain	1.0000
1:115702920:CAT:C	donor_gain	1.0000
1:115702991:ACGAG:A	acceptor_gain	1.0000
1:115702992:CGAG:C	acceptor_gain	1.0000
1:115702992:CGAGC:C	acceptor_gain	1.0000
1:115702993:GAG:G	acceptor_gain	1.0000
1:115702994:AG:A	acceptor_gain	1.0000
1:115702995:GC:G	acceptor_loss	1.0000
1:115702996:C:CC	acceptor_gain	1.0000
1:115702997:T:A	acceptor_loss	1.0000
1:115703000:A:T	acceptor_gain	1.0000
1:115705187:CTCA:C	donor_loss	1.0000
1:115705188:TCACC:T	donor_loss	1.0000
1:115705189:CA:C	donor_loss	1.0000
1:115705190:A:AC	donor_gain	1.0000
1:115705191:C:CC	donor_gain	1.0000
1:115705288:GCCAT:G	acceptor_gain	1.0000

AlphaMissense

2713 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:115701414:A:G	W343R	0.998
1:115701414:A:T	W343R	0.998
1:115701368:A:G	L358P	0.997
1:115701412:C:A	W343C	0.997
1:115701412:C:G	W343C	0.997
1:115702940:C:T	G332E	0.997
1:115702941:C:A	G332W	0.997
1:115702983:A:G	W318R	0.997
1:115702983:A:T	W318R	0.997
1:115705268:A:G	L288P	0.997
1:115725508:C:A	W261C	0.997
1:115725508:C:G	W261C	0.997
1:115732951:C:G	A186P	0.997
1:115701360:A:G	W361R	0.996
1:115701360:A:T	W361R	0.996
1:115705218:A:G	W305R	0.996
1:115705218:A:T	W305R	0.996
1:115725510:A:G	W261R	0.996
1:115725510:A:T	W261R	0.996
1:115732950:G:T	A186D	0.996
1:115701358:C:A	W361C	0.995
1:115701358:C:G	W361C	0.995
1:115717860:A:G	F273S	0.995
1:115717863:G:T	A272D	0.995
1:115738250:C:T	G169D	0.995
1:115705229:A:G	L301P	0.994
1:115705256:G:T	A292D	0.994
1:115705257:C:G	A292P	0.994
1:115717859:A:C	F273L	0.994
1:115717859:A:T	F273L	0.994

dbSNP variants (sampled 300 via entrez): RS1000011824 (1:115705780 G>C), RS1000020119 (1:115763516 C>T), RS1000047838 (1:115747878 G>C), RS1000057740 (1:115725715 C>T), RS1000073771 (1:115742672 G>C), RS1000074228 (1:115763325 G>T), RS1000127829 (1:115726501 A>G), RS1000159920 (1:115766245 T>G), RS1000195399 (1:115770479 A>C), RS1000217517 (1:115702470 A>G), RS1000307271 (1:115700012 T>C), RS1000375670 (1:115699933 T>C), RS1000386818 (1:115737595 C>T), RS1000411084 (1:115738014 G>A), RS1000469351 (1:115705767 T>G)

Disease associations

OMIM: gene MIM:114251 | disease phenotypes: MIM:600996, MIM:604772, MIM:611938, MIM:113900, MIM:194200, MIM:115080

GenCC curated gene-disease

Disease	Classification	Inheritance
catecholaminergic polymorphic ventricular tachycardia 2	Definitive	Autosomal recessive
catecholaminergic polymorphic ventricular tachycardia	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Disputed	AD
catecholaminergic polymorphic ventricular tachycardia	Definitive	AR
catecholaminergic polymorphic ventricular tachycardia	Moderate	AD

Mondo (11): catecholaminergic polymorphic ventricular tachycardia 1 (MONDO:0011484), catecholaminergic polymorphic ventricular tachycardia 2 (MONDO:0012762), cardiomyopathy (MONDO:0004994), polymorphic ventricular tachycardia (MONDO:0020575), progressive familial heart block (MONDO:0019490), catecholaminergic polymorphic ventricular tachycardia (MONDO:0017990), long QT syndrome (MONDO:0002442), cardiac rhythm disease (MONDO:0007263), dilated cardiomyopathy (MONDO:0005021), Wolff-Parkinson-White syndrome (MONDO:0008685), cardiac conduction defect (MONDO:0100042)

Orphanet (5): Catecholaminergic polymorphic ventricular tachycardia (Orphanet:3286), Rare cardiomyopathy (Orphanet:167848), Hereditary progressive cardiac conduction defect (Orphanet:871), Dilated cardiomyopathy (Orphanet:217604), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

27 total (28 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001644	Dilated cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001662	Bradycardia
HP:0001663	Ventricular fibrillation
HP:0001678	Atrioventricular block
HP:0001695	Cardiac arrest
HP:0001699	Sudden death
HP:0001962	Palpitations
HP:0002321	Vertigo
HP:0003621	Juvenile onset
HP:0004755	Supraventricular tachycardia
HP:0004756	Ventricular tachycardia
HP:0004757	Paroxysmal atrial fibrillation
HP:0004758	Effort-induced polymorphic ventricular tachycardia
HP:0005110	Atrial fibrillation
HP:0006673	Reduced systolic function
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0011704	Sick sinus syndrome
HP:0025478	Atrial standstill
HP:0031677	Polymorphic ventricular tachycardia
HP:0034039	Ventricular couplet
HP:0034040	Bidirectional ventricular tachycardia
HP:0001716	Wolff-Parkinson-White syndrome

GWAS associations

31 associations (top):

Study	Trait	p-value
GCST003598_21	QRS duration	8.000000e-09
GCST003598_48	QRS duration	3.000000e-08
GCST003844_35	QRS duration	7.000000e-09
GCST006061_76	Atrial fibrillation	5.000000e-16
GCST006061_77	Atrial fibrillation	3.000000e-15
GCST006414_106	Atrial fibrillation	5.000000e-13
GCST007103_2	QRS duration	2.000000e-11
GCST007104_2	QRS duration	2.000000e-18
GCST007269_17	Pulse pressure	2.000000e-12
GCST010796_2624	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-10
GCST010796_2625	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-11
GCST010796_2626	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-12
GCST010796_2627	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-15
GCST010796_2628	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-16
GCST010796_2629	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-18
GCST010796_2630	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-19
GCST010796_2631	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-20
GCST010796_2632	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-22
GCST010796_2633	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-24
GCST010796_2634	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-25
GCST010796_2635	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-25
GCST010796_2636	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-26
GCST010796_2637	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-26
GCST010796_2638	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-25
GCST010796_2639	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-23
GCST010796_2640	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-20
GCST010796_2641	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-16
GCST010796_2642	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-12
GCST010796_2643	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-27
GCST011214_2	Left ventricle wall thickness	3.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005054	QRS complex
EFO:0005763	pulse pressure measurement
EFO:0004327	electrocardiography
EFO:0008205	left ventricular structural measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C563409	Arrhythmogenic Right Ventricular Dysplasia, Familial, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, increases methylation	4
Doxorubicin	decreases expression	3
Nickel	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
2,7-dihydroxynaphthalene	decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
incobotulinumtoxinA	decreases expression	1
Sunitinib	decreases expression	1
Amphotericin B	increases expression	1
Arsenic	affects methylation	1
Bleomycin	increases expression	1
Dexamethasone	affects expression	1
Estradiol	affects binding, increases expression	1
Etoposide	decreases expression	1
Triclosan	decreases expression	1
Cyclosporine	increases methylation	1

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C6P2	CIAUi003-A-1	Induced pluripotent stem cell	Female
CVCL_E4JF	UMGi158-B	Induced pluripotent stem cell	Female
CVCL_WM06	CIAUi003-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

313 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT06658899	PHASE2	RECRUITING	A Phase 2 Study of CRD-4730 in CPVT
NCT07263139	PHASE2	RECRUITING	Safety, Tolerability, and Exploratory Efficacy of AGP100 in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT05122975	PHASE2	TERMINATED	Treatment of an Inherited Ventricular Arrhythmia