CALM2

Summary

CALM2 (calmodulin 2, HGNC:1445) is a protein-coding gene on chromosome 2p21, encoding Calmodulin-2 (P0DP24). Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding.

This gene is a member of the calmodulin gene family. There are three distinct calmodulin genes dispersed throughout the genome that encode the identical protein, but differ at the nucleotide level. Calmodulin is a calcium binding protein that plays a role in signaling pathways, cell cycle progression and proliferation. Several infants with severe forms of long-QT syndrome (LQTS) who displayed life-threatening ventricular arrhythmias together with delayed neurodevelopment and epilepsy were found to have mutations in either this gene or another member of the calmodulin gene family (PMID:23388215). Mutations in this gene have also been identified in patients with less severe forms of LQTS (PMID:24917665), while mutations in another calmodulin gene family member have been associated with catecholaminergic polymorphic ventricular tachycardia (CPVT)(PMID:23040497), a rare disorder thought to be the cause of a significant fraction of sudden cardiac deaths in young individuals. Pseudogenes of this gene are found on chromosomes 10, 13, and 17. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 805 — RefSeq curated summary.

At a glance

• Gene–disease (curated): long QT syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 241 total — 10 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 31
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001743

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1445
Approved symbol	CALM2
Name	calmodulin 2
Location	2p21
Locus type	gene with protein product
Status	Approved
Aliases	PHKD, PHKD2, CAMII
Ensembl gene	ENSG00000143933
Ensembl biotype	protein_coding
OMIM	114182
Entrez	805

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000272298, ENST00000409563, ENST00000432899, ENST00000456319, ENST00000460218, ENST00000482532, ENST00000484408, ENST00000489742, ENST00000652974, ENST00000655450, ENST00000655728, ENST00000656538, ENST00000668667, ENST00000670593, ENST00000921950, ENST00000946887, ENST00000946888

RefSeq mRNA: 4 — MANE Select: NM_001743 NM_001305624, NM_001305625, NM_001305626, NM_001743

CCDS: CCDS1832, CCDS92749

Canonical transcript exons

ENST00000272298 — 6 exons

Exon	Start	End
ENSE00001844794	47160084	47160804
ENSE00003488714	47170734	47170764
ENSE00003503613	47162519	47162662
ENSE00003539623	47162286	47162392
ENSE00003556131	47161723	47161858
ENSE00003845248	47176441	47176511

Expression profiles

Bgee: expression breadth ubiquitous, 310 present calls, max score 100.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 351.6139 / max 13495.3156, expressed in 1828 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28222	351.6139	1828

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	100.00	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.99	gold quality
orbitofrontal cortex	UBERON:0004167	99.97	gold quality
pons	UBERON:0000988	99.95	gold quality
germinal epithelium of ovary	UBERON:0001304	99.95	gold quality
occipital lobe	UBERON:0002021	99.95	gold quality
parietal pleura	UBERON:0002400	99.95	gold quality
visceral pleura	UBERON:0002401	99.95	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.95	gold quality
bronchial epithelial cell	CL:0002328	99.94	gold quality
prefrontal cortex	UBERON:0000451	99.94	gold quality
pleura	UBERON:0000977	99.94	gold quality
parietal lobe	UBERON:0001872	99.94	gold quality
primary visual cortex	UBERON:0002436	99.94	gold quality
entorhinal cortex	UBERON:0002728	99.94	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.93	gold quality
substantia nigra pars compacta	UBERON:0001965	99.93	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.93	gold quality
corpus callosum	UBERON:0002336	99.93	gold quality
lateral globus pallidus	UBERON:0002476	99.93	gold quality
postcentral gyrus	UBERON:0002581	99.93	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.93	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.93	gold quality
adult organism	UBERON:0007023	99.93	gold quality
superior vestibular nucleus	UBERON:0007227	99.93	gold quality
cranial nerve II	UBERON:0000941	99.92	gold quality
medulla oblongata	UBERON:0001896	99.92	gold quality
subthalamic nucleus	UBERON:0001906	99.92	gold quality
inferior vagus X ganglion	UBERON:0005363	99.92	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.92	gold quality

Single-cell (SCXA)

Detected in 41 experiment(s), a significant marker in 23.

Experiment	Marker?	Max mean expression
E-GEOD-98556	yes	13930.50
E-HCAD-25	yes	4147.94
E-HCAD-35	yes	2407.15
E-MTAB-8271	yes	604.76
E-MTAB-8142	yes	88.81
E-MTAB-10287	yes	80.60
E-HCAD-4	yes	75.37
E-MTAB-6701	yes	53.15
E-MTAB-7316	yes	48.61
E-HCAD-10	yes	39.78
E-GEOD-137537	yes	39.58
E-HCAD-1	yes	35.20
E-MTAB-8410	yes	32.95
E-HCAD-11	yes	32.80
E-CURD-88	yes	26.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

44 targeting CALM2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-1843	98.97	66.07	838
HSA-MIR-4802-5P	98.97	66.26	833
HSA-MIR-1304-5P	98.90	68.58	1054

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• P53 protein stimulates CAMII gene expression in 041 cells. (PMID:15225611)
• These results suggest that calmodulin plays a crucial role in the processes of Ca(2+)-induced neuronal cell death and the possibility that the blockage of calmodulin attenuates brain injury after cerebral ischemia. (PMID:16545345)
• These findings suggest that the CALM2 gene may be a genetic determinant of hip Osteoarthritis. (PMID:20198394)
• The 1.35 A structure of Ca(2+)-bound calmodulin in complex with the DIII-IV linker of Na(V)1.5 suggests that Ca(2+)/CaM destabilizes binding of the inactivation gate to its receptor, biasing inactivation toward more depolarized potentials. (PMID:22331908)
• CaM-2-ext interacts biochemically with the C-terminus of Ca(v)2.3 similar to the classical CaM-2 as shown by co-immunoprecipitation (PMID:22633975)
• Human calmodulin mutations disrupt calcium binding to the protein and are associated with cardiac arrest in early infancy. (PMID:23388215)
• 5 novel de novo CALM2 mutations in association with long-QT syndrome and exertioninduced arrhythmias.(p.N98S, p.N98I, p.D134H, p.D132E, p.Q136P) (PMID:24917665)
• the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive long QT syndrome, were determined. (PMID:26969752)
• Calmodulin 2 Mutation N98S Is Associated with Unexplained Cardiac Arrest in Infants Due to Low Clinical Penetrance Electrical Disorders. (PMID:27100291)
• Impaired Ca(2+)-dependent inactivation in human cardiomyocytes as the plausible mechanism for Long QT Syndrome associated with 2 novel CaM mutations. (PMID:27374306)
• Authors successfully recapitulated the disease phenotypes of LQT15 and revealed that inactivation of LTCC currents was impaired in CALM2-N98S hiPSC model. (PMID:28335032)
• Protein molecular diagnosis of autosomal dominant calmodulin mutations causing irregular heart rhythms has been presented. (PMID:29932249)
• Liver fibrosis caused by hepatitis C virus results in down-regulation of hepatic CALM2 expression. (PMID:30317608)
• Novel Association of a De Novo CALM2 Mutation With Long QT Syndrome and Hypertrophic Cardiomyopathy. (PMID:30354306)
• Prevalence and Phenotypic Correlations of Calmodulinopathy-Causative CALM1-3 Variants Detected in a Multicenter Molecular Autopsy Cohort of Sudden Unexplained Death Victims. (PMID:33191766)
• Targeting CALM2 Inhibits Hepatocellular Carcinoma Growth and Metastasis by Suppressing E2F5-mediated Cell Cycle Progression. (PMID:33788723)
• Circular RNA circ_0010729 Knockdown Attenuates Oxygen-Glucose Deprivation-Induced Human Cardiac Myocytes Injury by miR-338-3p/CALM2 Axis. (PMID:33951696)
• Calmodulinopathy in Japanese Children - Their Cardiac Phenotypes Are Severe and Show Early Onset in Fetal Life and Infancy. (PMID:37380439)
• microRNA-651-5p affects the proliferation, migration, and invasion of lung cancer cells by regulating Calmodulin 2 expression. (PMID:37470336)
• Calmodulin 2 expression is associated with poor prognosis in breast cancer. (PMID:38754328)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	calm2b	ENSDARG00000015050
mus_musculus	Calm2	ENSMUSG00000036438
rattus_norvegicus	Calm1	ENSRNOG00000030871
rattus_norvegicus	Calm2	ENSRNOG00000067086
drosophila_melanogaster	TpnC4	FBGN0033027
caenorhabditis_elegans		WBGENE00000285
caenorhabditis_elegans		WBGENE00000287
caenorhabditis_elegans	pat-10	WBGENE00003934
caenorhabditis_elegans		WBGENE00006583
caenorhabditis_elegans		WBGENE00008453
caenorhabditis_elegans	F35C12.3	WBGENE00009408
caenorhabditis_elegans		WBGENE00015264

Paralogs (20): CABP7 (ENSG00000100314), CABP5 (ENSG00000105507), CALML4 (ENSG00000129007), CETN2 (ENSG00000147400), CETN3 (ENSG00000153140), CABP1 (ENSG00000157782), CALM3 (ENSG00000160014), CABP2 (ENSG00000167791), CALML6 (ENSG00000169885), EFCAB3 (ENSG00000172421), EFCAB12 (ENSG00000172771), CABP4 (ENSG00000175544), CETN1 (ENSG00000177143), CALML3 (ENSG00000178363), CALML5 (ENSG00000178372), CALN1 (ENSG00000183166), CALM1 (ENSG00000198668), EFCAB2 (ENSG00000203666), EFCAB7 (ENSG00000203965), EFCAB9 (ENSG00000214360)

Protein

Protein identifiers

Calmodulin-2 — P0DP24 (reviewed: P0DP24)

All UniProt accessions (8): P0DP24, A0A590UJC0, A0A590UJE2, A0A590UJI2, B4DJ51, E7EMB3, F8WBR5, Q96HY3

UniProt curated annotations — full annotation on UniProt →

Function. Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Calcium-binding is required for the activation of calmodulin. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases, such as myosin light-chain kinases and calmodulin-dependent protein kinase type II (CaMK2), and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis. Mediates calcium-dependent inactivation of CACNA1C. Positively regulates calcium-activated potassium channel activity of KCNN2. (Microbial infection) Required for C.violaceum CopC and S.flexneri OspC3 arginine ADP-riboxanase activity.

Subunit / interactions. Interacts with MYO1C, MYO5A and RRAD. Interacts with MYO10. Interacts with CEP97, CCP110, TTN/titin and SRY. Interacts with USP6; the interaction is calcium dependent. Interacts with CDK5RAP2. Interacts with SCN5A. Interacts with RYR1. Interacts with FCHO1. Interacts with MIP in a 1:2 stoichiometry; the interaction with the cytoplasmic domains from two MIP subunits promotes MIP water channel closure. Interacts with ORAI1; this may play a role in the regulation of ORAI1-mediated calcium transport. Interacts with IQCF1. Interacts with SYT7. Interacts with CEACAM1 (via cytoplasmic domain); this interaction is in a calcium dependent manner and reduces homophilic cell adhesion through dissociation of dimer. Interacts with RYR2; regulates RYR2 calcium-release channel activity. Interacts with PCP4; regulates calmodulin calcium-binding. Interacts with the heterotetrameric KCNQ2 and KCNQ3 channel; the interaction is calcium-independent, constitutive and participates in the proper assembly of a functional heterotetrameric M channel. Component of the SIFI complex. (Microbial infection) Interacts with C.violaceum CopC. C.violaceum CopC interacts specifically with the apo form of calmodulin. (Microbial infection) Interacts with S.flexneri OspC1 and OspC3. S.flexneri OspC1 and OspC3 interact specifically with the apo form of calmodulin and prevents calcium-binding.

Subcellular location. Cytoplasm. Cytoskeleton. Spindle. Spindle pole. Microtubule organizing center. Centrosome.

Post-translational modifications. Ubiquitination results in a strongly decreased activity. Phosphorylation results in a decreased activity.

Disease relevance. Long QT syndrome 15 (LQT15) [MIM:616249] A form of long QT syndrome, a heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. The disease is caused by variants affecting the gene represented in this entry. Mutations in CALM2 are the cause of LQT15.

Activity regulation. (Microbial infection) Inactivated by S.flexneri OspC1 and OspC3 proteins, which specifically bind the apo-form of calmodulin, thereby preventing calcium-binding and activity.

Miscellaneous. This protein has four functional calcium-binding sites.

Similarity. Belongs to the calmodulin family.

RefSeq proteins (4): NP_001292553, NP_001292554, NP_001292555, NP_001734* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR050230	CALM/Myosin/TropC-like	Family

Pfam: PF13499

UniProt features (63 total): binding site 20, modified residue 11, sequence variant 8, helix 7, strand 6, domain 4, cross-link 2, initiator methionine 1, chain 1, sequence conflict 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
6XXF	X-RAY DIFFRACTION	1.7
5NIN	X-RAY DIFFRACTION	1.7
6Y4O	X-RAY DIFFRACTION	1.84
5J03	X-RAY DIFFRACTION	2
6SZ5	X-RAY DIFFRACTION	2.23
5WSV	X-RAY DIFFRACTION	2.33
3O77	X-RAY DIFFRACTION	2.35
8KA0	X-RAY DIFFRACTION	2.35
7MIR	ELECTRON MICROSCOPY	2.5
6PLM	X-RAY DIFFRACTION	2.59
3O78	X-RAY DIFFRACTION	2.6
5COC	X-RAY DIFFRACTION	2.67
6MUD	X-RAY DIFFRACTION	2.69
7MIS	ELECTRON MICROSCOPY	2.8
8KA1	X-RAY DIFFRACTION	2.82
8K9Z	X-RAY DIFFRACTION	2.9
7PPO	ELECTRON MICROSCOPY	2.91
5WSU	X-RAY DIFFRACTION	3
7PQE	ELECTRON MICROSCOPY	3.7
5VMS	ELECTRON MICROSCOPY	3.7
6S5T	ELECTRON MICROSCOPY	4.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DP24-F1	85.82	0.45

Functional residue map

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

Ligand- & substrate-binding residues (20): 27; 32; 57; 59; 61; 63; 68; 94; 96; 98; 100; 105 …

Post-translational modifications (13): 2, 22, 45, 82, 95, 100, 102, 111, 116, 116, 139, 22, 22

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9948001	CASP4 inflammasome assembly
R-HSA-9956593	Enterobacterial factors antagonize host defense

MSigDB gene sets: 557 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, ATF_B, BIOCARTA_GCR_PATHWAY, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_SEQUESTERING_OF_CALCIUM_ION, BIOCARTA_FMLP_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_CIRCULATORY_SYSTEM_PROCESS, MORF_UBE2I, GOBP_CELL_CYCLE_PHASE_TRANSITION, HSIAO_HOUSEKEEPING_GENES, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN

GO Biological Process (17): G2/M transition of mitotic cell cycle (GO:0000086), regulation of heart rate (GO:0002027), detection of calcium ion (GO:0005513), G protein-coupled receptor signaling pathway (GO:0007186), 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), substantia nigra development (GO:0021762), regulation of cytokinesis (GO:0032465), regulation of calcium-mediated signaling (GO:0050848), response to calcium ion (GO:0051592), regulation of cardiac muscle contraction (GO:0055117), long-term synaptic potentiation (GO:0060291), negative regulation of ryanodine-sensitive calcium-release channel activity (GO:0060315), calcineurin-mediated signaling (GO:0097720), presynaptic endocytosis (GO:0140238), regulation of cell communication by electrical coupling involved in cardiac conduction (GO:1901844), negative regulation of calcium ion export across plasma membrane (GO:1905913)

GO Molecular Function (15): calcium channel regulator activity (GO:0005246), calcium ion binding (GO:0005509), adenylate cyclase binding (GO:0008179), adenylate cyclase activator activity (GO:0010856), calcium channel inhibitor activity (GO:0019855), protein kinase binding (GO:0019901), titin binding (GO:0031432), protein serine/threonine kinase activator activity (GO:0043539), transmembrane transporter binding (GO:0044325), calcium-dependent protein binding (GO:0048306), protein phosphatase activator activity (GO:0072542), transporter inhibitor activity (GO:0141110), protein binding (GO:0005515), kinase activity (GO:0016301), metal ion binding (GO:0046872)

GO Cellular Component (21): spindle pole (GO:0000922), nucleus (GO:0005634), cytoplasm (GO:0005737), centrosome (GO:0005813), spindle microtubule (GO:0005876), plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), membrane (GO:0016020), sarcomere (GO:0030017), synaptic vesicle membrane (GO:0030672), vesicle (GO:0031982), protein-containing complex (GO:0032991), calcium channel complex (GO:0034704), myelin sheath (GO:0043209), calyx of Held (GO:0044305), sperm midpiece (GO:0097225), presynaptic cytosol (GO:0099523), catalytic complex (GO:1902494), mitochondrion (GO:0005739), spindle (GO:0005819), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Non-canonical inflammasome activation	1
Infection with Enterobacteria	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
regulation of heart contraction	2
calcium-mediated signaling	2
presynapse	2
calcium channel activity	2
protein binding	2
spindle	2
intracellular membrane-bounded organelle	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G2/M phase transition	1
regulation of biological quality	1
detection of chemical stimulus	1
response to calcium ion	1
G protein-coupled receptor activity	1
signal transduction	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
midbrain development	1
neural nucleus development	1
cytokinesis	1
regulation of cell cycle process	1
regulation of cell division	1
regulation of intracellular signal transduction	1
response to metal ion	1
regulation of striated muscle contraction	1
cardiac muscle contraction	1
regulation of synaptic plasticity	1
positive regulation of synaptic transmission	1
ryanodine-sensitive calcium-release channel activity	1
negative regulation of release of sequestered calcium ion into cytosol	1
regulation of ryanodine-sensitive calcium-release channel activity	1
negative regulation of calcium ion transmembrane transporter activity	1
endocytosis	1
establishment of localization in cell	1
vesicle-mediated transport in synapse	1
regulation of cell communication by electrical coupling	1
cell communication by electrical coupling involved in cardiac conduction	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

3 interactions, top by confidence:

A	B	Type	Score
CALM2	MYO1C	psi-mi:“MI:0914”(association)	0.350
UBR4	METTL15	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A2WN93, A2WNH1, A2Y609, A3E3H0, A3E4D8, A3E4F9, A4UHC0, A8CEP3, A8I1Q0, O96102, P02598, P04353, P04464, P07463, P0DP23, P0DP24, P0DP25, P0DP26, P0DP27, P0DP28, P0DP29, P0DP30, P0DP31, P0DP33, P0DP34, P0DP35, P17928, P27165, P27166, P62144, P62149, P62151, P62156, P62157, P62160, P62162, P62163, P62199, Q0JNL7, Q0JNS6

Diamond homologs: A2WN93, A2WNH1, A2Y609, A3E3H0, A3E4D8, A3E4F9, A4UHC0, A8CEP3, A8I1Q0, O16305, O82018, O94739, O96081, O96102, P02597, P02598, P02599, P04352, P04353, P04464, P05419, P07463, P0DH95, P0DH96, P0DH97, P0DH98, P0DP23, P0DP24, P0DP25, P0DP26, P0DP27, P0DP28, P0DP29, P0DP30, P0DP31, P0DP33, P11120, P13868, P15094, P17928

SIGNOR signaling

18 interactions.

A	Effect	B	Mechanism
calcium(2+)	up-regulates	CALM2	“chemical activation”
EGFR	down-regulates	CALM2	phosphorylation
INSR	down-regulates	CALM2	phosphorylation
CALM2	up-regulates	EEF2K	binding
CALM2	up-regulates	PPP3CB	binding
CALM2	“up-regulates activity”	NOS3	binding
CALM2	up-regulates	PPP3CC	binding
CALM2	up-regulates	PPP3CA	binding
CALM2	up-regulates	CAMKK1	binding
CALM2	up-regulates	CAMKK2	binding
CALM2	“down-regulates activity”	SCN8A	binding
CALM2	up-regulates	Calcineurin	binding
CCP110	“up-regulates activity”	CALM2	binding
CALM2	up-regulates	PP2B	binding
CALM2	“up-regulates activity”	GEM	binding
CALM2	“up-regulates activity”	KIF1A	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	7
Uncertain significance	73
Likely benign	119
Benign	13

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1327459	NM_001743.6(CALM2):c.340G>A (p.Gly114Arg)	Pathogenic
1398892	NM_001743.6(CALM2):c.388G>A (p.Asp130Asn)	Pathogenic
1456260	NM_001743.6(CALM2):c.394G>T (p.Asp132Tyr)	Pathogenic
183233	NM_001743.6(CALM2):c.287A>T (p.Asp96Val)	Pathogenic
488476	NM_001743.6(CALM2):c.414C>G (p.Asn138Lys)	Pathogenic
812710	NM_001743.6(CALM2):c.389A>G (p.Asp130Gly)	Pathogenic
955533	NM_001743.6(CALM2):c.395A>G (p.Asp132Gly)	Pathogenic
96720	NM_001743.6(CALM2):c.293A>G (p.Asn98Ser)	Pathogenic
96721	NM_001743.6(CALM2):c.293A>T (p.Asn98Ile)	Pathogenic
96722	NM_001743.6(CALM2):c.396T>G (p.Asp132Glu)	Pathogenic
1067140	NM_001743.6(CALM2):c.397G>A (p.Gly133Ser)	Likely pathogenic
1467722	NM_001743.6(CALM2):c.423G>C (p.Glu141Asp)	Likely pathogenic
2500174	NM_001743.6(CALM2):c.313G>C (p.Glu105Gln)	Likely pathogenic
2734184	NM_001743.6(CALM2):c.268T>C (p.Phe90Leu)	Likely pathogenic
448971	NM_001743.6(CALM2):c.400G>A (p.Asp134Asn)	Likely pathogenic
458191	NM_001743.6(CALM2):c.328A>T (p.Met110Leu)	Likely pathogenic
576319	NM_001743.6(CALM2):c.434T>G (p.Met145Arg)	Likely pathogenic

SpliceAI

947 predictions. Top by Δscore:

Variant	Effect	Δscore
2:47160756:A:C	donor_gain	1.0000
2:47161212:AAAAT:A	donor_gain	1.0000
2:47161719:TTAC:T	donor_loss	1.0000
2:47161720:TA:T	donor_loss	1.0000
2:47161720:TAC:T	donor_loss	1.0000
2:47161722:CCTT:C	donor_gain	1.0000
2:47161737:TG:T	donor_gain	1.0000
2:47161740:CCA:C	donor_gain	1.0000
2:47161742:A:AC	donor_gain	1.0000
2:47161761:T:TA	donor_gain	1.0000
2:47161762:C:A	donor_gain	1.0000
2:47161854:CCATC:C	acceptor_gain	1.0000
2:47161855:CATC:C	acceptor_gain	1.0000
2:47161855:CATCC:C	acceptor_gain	1.0000
2:47161857:TC:T	acceptor_gain	1.0000
2:47161858:CC:C	acceptor_gain	1.0000
2:47161858:CCTAG:C	acceptor_loss	1.0000
2:47161859:C:CA	acceptor_loss	1.0000
2:47161859:C:CC	acceptor_gain	1.0000
2:47161860:T:G	acceptor_loss	1.0000
2:47161863:C:CT	acceptor_gain	1.0000
2:47162281:CGTA:C	donor_loss	1.0000
2:47162282:GTAC:G	donor_loss	1.0000
2:47162283:TA:T	donor_loss	1.0000
2:47162285:C:CA	donor_loss	1.0000
2:47162388:ATTAC:A	acceptor_gain	1.0000
2:47162389:TTAC:T	acceptor_gain	1.0000
2:47162390:TAC:T	acceptor_gain	1.0000
2:47162391:AC:A	acceptor_gain	1.0000
2:47162391:ACCT:A	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000029816 (2:47178348 C>T), RS1000081939 (2:47177878 A>C,G), RS1000734024 (2:47166114 C>T), RS1000836388 (2:47169704 G>A), RS1000836539 (2:47170538 C>T), RS1000908613 (2:47170952 A>G), RS1001032103 (2:47175630 T>A), RS1001072456 (2:47174857 T>C), RS1001134894 (2:47176187 C>T), RS1001244029 (2:47178485 C>G), RS1001300482 (2:47177359 G>C), RS1001345170 (2:47164808 CAT>C), RS1001573215 (2:47168264 T>C), RS1001911709 (2:47169331 C>T), RS1001958249 (2:47169408 C>T)

Disease associations

OMIM: gene MIM:114182 | disease phenotypes: MIM:192500, MIM:616249

GenCC curated gene-disease

Disease	Classification	Inheritance
long QT syndrome 15	Definitive	Autosomal dominant
catecholaminergic polymorphic ventricular tachycardia	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
catecholaminergic polymorphic ventricular tachycardia	Moderate	AD
long QT syndrome	Definitive	AD

Mondo (5): long QT syndrome 1 (MONDO:0100316), long QT syndrome 15 (MONDO:0014550), multiple intestinal atresia (MONDO:0009465), long QT syndrome (MONDO:0002442), catecholaminergic polymorphic ventricular tachycardia (MONDO:0017990)

Orphanet (3): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768), Isolated multiple intestinal atresia (Orphanet:2300)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000365	Hearing impairment
HP:0001197	Abnormality of prenatal development or birth
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001645	Sudden cardiac death
HP:0001662	Bradycardia
HP:0001663	Ventricular fibrillation
HP:0001664	Torsade de pointes
HP:0001688	Sinus bradycardia
HP:0001695	Cardiac arrest
HP:0001962	Palpitations
HP:0002321	Vertigo
HP:0002900	Hypokalemia
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0004308	Ventricular arrhythmia
HP:0004755	Supraventricular tachycardia
HP:0004756	Ventricular tachycardia
HP:0005110	Atrial fibrillation
HP:0005135	Abnormal T-wave
HP:0005184	Prolonged QTc interval
HP:0006682	Premature ventricular contraction
HP:0011461	Fetal onset
HP:0011463	Childhood onset
HP:0012332	Abnormal autonomic nervous system physiology
HP:0030682	Left ventricular noncompaction
HP:0031677	Polymorphic ventricular tachycardia
HP:0034305	2:1 atrioventricular block
HP:0034306	Ventricular bigeminy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001066_16	Dialysis-related mortality	7.000000e-07

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C562441	Intestinal Atresia, Multiple (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296043 (SINGLE PROTEIN)

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

PubChem BioAssay actives

51 with measured affinity, of 267 total; 15 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3R)-2-[[(2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-3-hydroxypropanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxopentanoyl]amino]hexanoyl]amino]-3-hydroxybutanoyl]amino]acetyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoic acid	1179564: Binding affinity to calmodulin (unknown origin) by NMR analysis	kd	0.0010	uM
N-[3-(naphthalen-1-ylsulfonylamino)phenyl]naphthalene-1-sulfonamide	1799496: Fluorescence spectroscopy from Article 10.1016/j.chembiol.2004.11.007: “Enhanced ligand affinity for receptors in which components of the binding site are independently mobile.”	kd	0.0100	uM
N’-[(1R)-1-(3,4-dibutoxyphenyl)ethyl]-N-(3,3-diphenylpropyl)propane-1,3-diamine	404335: Binding affinity to calmodulin	kd	0.0180	uM
methyl (1R,12R,13R,17S,27S)-27-acetyloxy-5,7,12,20,22-pentahydroxy-24-methyl-9,18-dioxo-14-oxaheptacyclo[15.10.2.01,19.03,16.06,15.08,13.021,26]nonacosa-3,5,7,10,15,19,21(26),22,24,28-decaene-13-carboxylate	762906: Binding affinity to human calmodulin expressed in Escherichia coli using M124C-mBBr fluorescent biosensor by spectrofluorometer analysis	kd	0.0182	uM
methyl 2-[(1R,2S,12S)-2-acetyloxy-7,9,14,16-tetrahydroxy-5-methyl-11-oxopentacyclo[10.7.2.01,10.03,8.013,18]henicosa-3(8),4,6,9,13,15,17,20-octaene-15-carbonyl]-3,6-dihydroxybenzoate	762906: Binding affinity to human calmodulin expressed in Escherichia coli using M124C-mBBr fluorescent biosensor by spectrofluorometer analysis	kd	0.0194	uM
N-[4-(naphthalen-1-ylsulfonylamino)phenyl]naphthalene-1-sulfonamide	1799496: Fluorescence spectroscopy from Article 10.1016/j.chembiol.2004.11.007: “Enhanced ligand affinity for receptors in which components of the binding site are independently mobile.”	kd	0.0700	uM
N’-benzyl-N’-[2-[benzyl-[(3-methoxyphenyl)methyl]amino]ethyl]-N,N-dimethylethane-1,2-diamine	1297608: Binding affinity to CaM (unknown origin) by isothermal titration calorimetric analysis in presence of calcium2+	kd	0.8500	uM
Trifluoperazine	404335: Binding affinity to calmodulin	kd	1.0000	uM
Chlorpromazine	762906: Binding affinity to human calmodulin expressed in Escherichia coli using M124C-mBBr fluorescent biosensor by spectrofluorometer analysis	kd	1.2400	uM
6-hydroxy-2-phenylchromen-4-one	550024: Inhibition of human recombinant calmodulin assessed as inhibition of calmodulin-sensitive cAMP phosphodiesterase activation after 15 mins by spectrophotometric analysis	ic50	5.1700	uM
(1R,2S)-8-[(S)-[(2S)-3,3-dimethyloxiran-2-yl]-methoxymethyl]-1,11-dihydroxy-5-methyl-2-prop-1-en-2-yl-2,3-dihydro-1H-pyrano[3,2-a]xanthen-12-one	395887: Inhibition of recombinant calmodulin mediated bovine brain PDE1 activation assessed as effect on inorganic phosphate release by spectrophotometry	ic50	5.5400	uM
(1R,2S)-8-[(2S)-2,3-dihydroxy-3-methylbutyl]-1,11-dihydroxy-5-methyl-2-prop-1-en-2-yl-2,3-dihydro-1H-pyrano[3,2-a]xanthen-12-one;hydrate	395887: Inhibition of recombinant calmodulin mediated bovine brain PDE1 activation assessed as effect on inorganic phosphate release by spectrophotometry	ic50	5.6200	uM
methyl (2R)-2-(1H-indol-3-ylmethyl)-5-[4-[(E)-2-[4-[(4R)-4-(1H-indol-3-ylmethyl)-5-methoxy-2,5-dioxopentyl]phenyl]ethenyl]phenyl]-4-oxopentanoate	1799496: Fluorescence spectroscopy from Article 10.1016/j.chembiol.2004.11.007: “Enhanced ligand affinity for receptors in which components of the binding site are independently mobile.”	kd	9.0000	uM
3-methoxy-5-[2-(4-methoxyphenyl)ethyl]phenol	603866: Inhibition of Calmodulin-dependent PDE1 activity assessed as inorganic phosphate release after 30 min	ic50	9.3800	uM
(1R,2S)-8-[(2S)-2-chloro-3-hydroxy-3-methylbutyl]-1,11-dihydroxy-5-methyl-2-prop-1-en-2-yl-2,3-dihydro-1H-pyrano[3,2-a]xanthen-12-one;hydrate	395887: Inhibition of recombinant calmodulin mediated bovine brain PDE1 activation assessed as effect on inorganic phosphate release by spectrophotometry	ic50	9.5900	uM

CTD chemical–gene interactions

62 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	decreases expression, decreases reaction, increases abundance, affects cotreatment	4
Air Pollutants	affects cotreatment, decreases expression, increases abundance, affects expression	3
bisphenol A	affects expression, decreases expression	2
bisphenol S	decreases methylation, increases expression	2
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression	2
Valproic Acid	increases expression, decreases methylation	2
Okadaic Acid	decreases expression, increases expression, increases phosphorylation	2
dicrotophos	decreases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
uranyl acetate	affects expression	1
arsenite	increases methylation	1
methylparaben	decreases expression	1
3,3’-diindolylmethane	decreases expression, increases reaction	1
sodium arsenite	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
CGP 52608	increases reaction, affects binding	1
chloropicrin	increases expression	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
bromovanin	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
MT19c compound	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Afatinib	affects localization, affects reaction, affects response to substance, increases cleavage, affects expression	1
Glyphosate	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118592	Binding	Binding affinity to CALM2 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1M0	Abcam HeLa CALM2 KO	Cancer cell line	Female
CVCL_SG57	HAP1 CALM2 (-) 1	Cancer cell line	Male
CVCL_SG58	HAP1 CALM2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
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)
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT07148089	PHASE1	RECRUITING	A Study of SGT-501 Gene Therapy in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT01117454	Not specified	COMPLETED	Flecainide for Catecholaminergic Polymorphic Ventricular Tachycardia
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02927223	Not specified	COMPLETED	Atropine in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT04124237	Not specified	COMPLETED	Long Term Monitoring for Risk of Sudden Death
NCT04189822	Not specified	ENROLLING_BY_INVITATION	Hearts in Rhythm Organization (HiRO)National Registry and Bio Bank
NCT04650009	Not specified	COMPLETED	Physical Activity in Children With Inherited Cardiac Diseases
NCT04712136	Not specified	COMPLETED	Healthy-related Quality of Life and Physical Activity of Children With Cardiac Malformations
NCT05521451	Not specified	RECRUITING	Clinical Cohort Study - TRUST
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06546137	Not specified	RECRUITING	National Network for Cardiovascular Genomics: Advancing Cardiovascular Healthcare for Hereditary Diseases in Brazil’s Unified Health System Through a Multicenter Registry
NCT01745666	Not specified	UNKNOWN	Comparison Between Epinephrine and Exercise Test in QT Long Syndrome Patients
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.