CALM1

Summary

CALM1 (calmodulin 1, HGNC:1442) is a protein-coding gene on chromosome 14q32.11, encoding Calmodulin-1 (P0DP23). 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 encodes one of three calmodulin proteins which are members of the EF-hand calcium-binding protein family. Calcium-induced activation of calmodulin regulates and modulates the function of cardiac ion channels. Two pseudogenes have been identified on chromosome 7 and X. Multiple transcript variants encoding different isoforms have been found for this gene.A missense mutation in the CALM1 gene has been associated with ventricular tachycardia.

Source: NCBI Gene 801 — RefSeq curated summary.

At a glance

• Gene–disease (curated): long QT syndrome (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 199 total — 11 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006888

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1442
Approved symbol	CALM1
Name	calmodulin 1
Location	14q32.11
Locus type	gene with protein product
Status	Approved
Aliases	CAMI, PHKD, DD132, PHKD1
Ensembl gene	ENSG00000198668
Ensembl biotype	protein_coding
OMIM	114180
Entrez	801

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 8 protein_coding, 7 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000356978, ENST00000447653, ENST00000544280, ENST00000553422, ENST00000553542, ENST00000553630, ENST00000553964, ENST00000553995, ENST00000554296, ENST00000555132, ENST00000555267, ENST00000556721, ENST00000556757, ENST00000557020, ENST00000557123, ENST00000659177, ENST00000663135, ENST00000971957

RefSeq mRNA: 3 — MANE Select: NM_006888 NM_001363669, NM_001363670, NM_006888

CCDS: CCDS91917, CCDS9892

Canonical transcript exons

ENST00000356978 — 6 exons

Exon	Start	End
ENSE00001373724	90404689	90408268
ENSE00001405603	90397029	90397233
ENSE00003467186	90401259	90401402
ENSE00003595235	90400065	90400095
ENSE00003674133	90403862	90403968
ENSE00003683622	90404379	90404514

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 434.1255 / max 12487.6444, expressed in 1827 samples.

FANTOM5 promoters (23 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141012	407.4592	1827
141013	8.3252	1671
141017	4.8233	1233
141024	2.9910	908
141020	2.8935	982
141018	1.9681	585
141019	1.3151	649
141025	0.7456	249
141011	0.5746	279
141021	0.4061	200

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	99.94	gold quality
medial globus pallidus	UBERON:0002477	99.93	gold quality
parietal lobe	UBERON:0001872	99.92	gold quality
globus pallidus	UBERON:0001875	99.91	gold quality
postcentral gyrus	UBERON:0002581	99.91	gold quality
pons	UBERON:0000988	99.90	gold quality
frontal pole	UBERON:0002795	99.89	gold quality
orbitofrontal cortex	UBERON:0004167	99.88	gold quality
superior vestibular nucleus	UBERON:0007227	99.88	gold quality
paraflocculus	UBERON:0005351	99.87	gold quality
prefrontal cortex	UBERON:0000451	99.86	gold quality
lateral globus pallidus	UBERON:0002476	99.86	gold quality
entorhinal cortex	UBERON:0002728	99.86	gold quality
middle temporal gyrus	UBERON:0002771	99.86	gold quality
secondary oocyte	CL:0000655	99.85	gold quality
bronchial epithelial cell	CL:0002328	99.85	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.85	gold quality
occipital lobe	UBERON:0002021	99.84	gold quality
middle frontal gyrus	UBERON:0002702	99.84	gold quality
choroid plexus epithelium	UBERON:0003911	99.84	gold quality
medulla oblongata	UBERON:0001896	99.83	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.82	gold quality
substantia nigra pars compacta	UBERON:0001965	99.82	gold quality
ventral tegmental area	UBERON:0002691	99.82	gold quality
CA1 field of hippocampus	UBERON:0003881	99.82	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.82	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.82	gold quality
cerebellum	UBERON:0002037	99.81	gold quality
cerebellar hemisphere	UBERON:0002245	99.81	gold quality
corpus callosum	UBERON:0002336	99.81	gold quality

Single-cell (SCXA)

Detected in 35 experiment(s), a significant marker in 26.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	6787.76
E-MTAB-7316	yes	5727.85
E-HCAD-25	yes	5566.38
E-MTAB-11121	yes	5303.14
E-MTAB-10283	yes	3695.57
E-HCAD-35	yes	3555.74
E-HCAD-30	yes	3506.64
E-GEOD-180759	yes	3492.38
E-HCAD-24	yes	2797.30
E-HCAD-5	yes	1814.19
E-MTAB-6678	yes	1509.63
E-HCAD-4	yes	131.57
E-CURD-122	yes	60.70
E-CURD-88	yes	37.04
E-HCAD-6	yes	36.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CREM, E2F4, ESR1, FOS, HESX1, MEF2A, MYOG, NR3C2, PAX3, RELA, SP1, SP3, SPI1

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Microtubules have a role in stabilising the structure of the pericentriolar matrix, involving interaction with one or more proteins that are targets for binding of calmodulin (PMID:12006621)
• differential binding of calmodulin by RalA and RalB (PMID:12034722)
• calmodulin binds to a 35-aa segment in the C terminus of TRPV1, and disruption of the calmodulin-binding segment prevents TRPV1 desensitization (PMID:12808128)
• Calmodulin is a phospholipase C-beta interacting protein (PMID:12821674)
• the calcium binding dynamics of free calmodulin and CaM that is bound to other target proteins are altered by PEP-19 (PMID:14551202)
• CaM has a role in Fas-mediated apoptosis (PMID:14594800)
• CaM co-immunoprecipitates with EGF-activated and non-activated receptors (PMID:14960328)
• calmodulin has a role in ATP- augmented von Willebrand factor-dependent shear-induced platelet aggregation (PMID:15087444)
• It is suggested that calmodulin plays a significant role in cytokinesis including furrow formation and regression (PMID:15147735)
• calmodulin has a role in melatonin inhibition of estrogen receptor alpha (PMID:15229223)
• Calmodulin mediates Ca2+ sensitivity of Nav1.2 and Nav1.5 sodium channels (PMID:15316014)
• the majority of CaM nuclear entry occurs by facilitated mechanisms in all cell types examined, in part by a Ca2+-independent and in part by a Ca2+-dependent translocation mechanism (PMID:15522886)
• Ca(2+)-calmodulin assumes a novel conformation when it is part of a complex with the C-terminal tail of the Ca(V)1.2 alpha(1) subunit (PMID:15583004)
• transcriptional level of CALM1 is associated with susceptibility for hip OA (PMID:15746150)
• Calmodulin may be involved directly in SRY nuclear import during gonadal development, and disruption of SRY. (PMID:15746192)
• the Ral-CaM complex defines a multifaceted regulatory mechanism for PLC-delta1 activation (PMID:15817490)
• analysis of calmodulin and its interactions with ligands by circular dichroism (PMID:16013055)
• calmodulin and calcium regulate the binding of filamin A to actin filaments (PMID:16030015)
• CaM binds to the membrane-proximal EpoR cytoplasmic region and plays an essential role in activation of Jak2-mediated EpoR signaling (PMID:16084495)
• Ca2+/CaM has a role in regulating ubiquitination through direct interaction with TRE17 (PMID:16127172)
• Membrane trafficking at early steps of the basolateral endocytic pathway in HepG2 cells is regulated by an intricate interplay between calmodulin and PKC. (PMID:16154564)
• The high-resolution structure of the Ca(2+)/CaM-Ca(V)1.2 IQ domain complex was reported. (PMID:16299511)
• recruited CaM is used by the C terminus of AC8 to mediate Ca2+ stimulation (PMID:16613843)
• analysis of calcium/calmodulin binding to the pleckstrin homology domain of AKT1 (PMID:17580302)
• CaM was identified in the Fas-mediated death inducing signaling complex (DISC). The amount of CaM recruited into the DISC was increased after Fas-stimulation. (PMID:17654480)
• CaM affect cell morphology and motility through binding to stress fibers and regulate f-actin polymerization. (PMID:17884685)
• analysis of conformational changes of calmodulin upon Ca2+ binding (PMID:18178620)
• The CALM1 core promoter genotype is not a risk factor for knee osteoartrithis (KOA) etiology in Greek Caucasians on its own, but associated with the Asporin (ASPN) D14 or D15 risk allele, it could influence KOA susceptibility. (PMID:18452398)
• The present study suggests that the CALM1 core promoter polymorphism -16C/T is not a risk factor for knee osteoarthritis susceptibility in the Chinese Han population. (PMID:18940010)
• The interaction of calmodulin and HSP70 Heat-Shock Proteins was found in the nucleus during the S phase and regulated cell-cycle progression and cell apoptosis. (PMID:18989758)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• Data demonstrate that interaction between the antagonists and calmodulin (CaM) results in a differential inhibition of CaM-dependent proteins involved in Ca2+-signal regulation. (PMID:19133300)
• ZNF198-FGFR1 is associated with phosphorylation of several proteins including SSBP2, ABL, FLJ14235, CALM (calmodulin 1) and TRIM4 proteins. (PMID:19658100)
• Data show that that the prototypical CaM target sequence skMLCK, a fragment from skeletal muscle myosin light chain kinase, binds to CaM in a highly cooperative way, while only a lower degree of interdomain binding cooperativity emerges for CaMKK. (PMID:19667195)
• results provide a detailed picture of the MBP-CaM interaction, including a 3D model of the complex between full-length proteins (PMID:19855925)
• Data show that he calmodulin-CKII peptide system allows the study of photounbinding under different dissociation constants without changing the molecular system. (PMID:21124984)
• Thermodynamic and structural studies of Calmodulin (CaM)-Na(v)1.2(IQp) interactions show that apo and (Ca(2+))(4)-CaM adopt distinct conformations that both permit tight association with Na(v)1.2(IQp) during gating. (PMID:21439835)
• CALM1 is a functional target gene of the BACH1 transcription factor according to ChIP-seq and knockdown analysis in HEK 293 cells. (PMID:21555518)
• analysis of the intracellular loop 3 of the serotonin 5-HT(1A) receptor and its interaction with calmodulin by NMR (PMID:21640070)
• These results suggest that the association of CaM with L-selectin in the cell can be influenced by the membrane bilayer and that anionic lipids may modulate ectodomain shedding of transmembrane receptors. (PMID:21664913)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
mus_musculus	Calm1	ENSMUSG00000001175
rattus_norvegicus	Calm1	ENSRNOG00000072513
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), CALM2 (ENSG00000143933), 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), EFCAB2 (ENSG00000203666), EFCAB7 (ENSG00000203965), EFCAB9 (ENSG00000214360)

Protein

Protein identifiers

Calmodulin-1 — P0DP23 (reviewed: P0DP23)

All UniProt accessions (6): B4DJ51, G3V226, G3V361, G3V479, P0DP23, 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. Is a regulator of voltage-dependent L-type calcium channels. Mediates calcium-dependent inactivation of CACNA1C. Positively regulates calcium-activated potassium channel activity of KCNN2. Forms a potassium channel complex with KCNQ1 and regulates electrophysiological activity of the channel via calcium-binding. Acts as a sensor to modulate the endoplasmic reticulum contacts with other organelles mediated by VMP1:ATP2A2. (Microbial infection) Required for Legionella pneumophila SidJ glutamylase activity. (Microbial infection) Required for C.violaceum CopC and S.flexneri OspC3 arginine ADP-riboxanase activity.

Subunit / interactions. Homotetramer. 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. Interacts with alpha-synuclein/SNCA. Interacts with SLC9A1 in a calcium-dependent manner. In the absence of Ca(+2), interacts with GIMAP4 (via IQ domain). Interacts with SCN8A; the interaction modulates the inactivation rate of SCN8A. Interaction with KIF1A; the interaction is increased in presence of calcium and increases neuronal dense core vesicles motility. Interacts with KCNN3. Interacts with KCNQ1 (via C-terminus); forms a heterooctameric structure (with 4:4 KCNQ1:CALM stoichiometry) in a calcium-independent manner. Interacts with PIK3C3; the interaction modulates PIK3C3 kinase activity. Interacts with HINT1; interaction increases in the presence of calcium ions. Interacts with HINT3. Interacts with GARIN2; in mature sperm flagella. Interacts with IQUB. Interacts with SLC26A5 (via STAS domain); this interaction is calcium-dependent and the STAS domain interacts with only one lobe of CALM which is an elongated conformation. Ca(2+)-bound CALM1 binds CNGA1:CNGB1 channel (via CaM1 and CaM2 regions); this interaction modulates the affinity of the channel for cNMPs in response to intracellular Ca(2+) levels. Interacts with ITPR1; this interaction inhibits inositol 1,4,5 trisphosphate binding in both the presence and absence of calcium and 1,4,5 trisphosphate-induced calcium release in the presence of calcium. Component of the SIFI complex. Interacts with KCNN4; this interaction allows channel opening. Interacts with KCNN2; this interaction regulates the channel activity through calcium-binding. (Microbial infection) Interacts with Rubella virus protease/methyltransferase p150. (Microbial infection) Interacts with Legionella pneumophila glutamylase SidJ. (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. Cell projection. Cilium. Flagellum.

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

Disease relevance. Ventricular tachycardia, catecholaminergic polymorphic, 4 (CPVT4) [MIM:614916] 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. CPVT4 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4. Long QT syndrome 14 (LQT14) [MIM:616247] 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.

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.

Domain organisation. The N-terminal and C-terminal lobes of CALM bind to the C-terminus of KCNQ1 in a clamp-like conformation. Binding of CALM C-terminus to KCNQ1 is calcium-independent but is essential for assembly of the structure. Binding of CALM N-terminus to KCNQ1 is calcium-dependent and regulates electrophysiological activity of the channel. The C-lobe interacts with KCNN4 channels in a calcium-independent manner, whereas the N-lobe interacts with the S4-S5 linker of KCNN4 in a calcium-dependent manner playing a role as calcium sensor and gating the channel.

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

Similarity. Belongs to the calmodulin family.

RefSeq proteins (3): NP_001350598, NP_001350599, NP_008819* (*=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 (64 total): binding site 20, modified residue 11, helix 9, sequence variant 7, strand 7, domain 4, cross-link 2, initiator methionine 1, chain 1, region of interest 1, turn 1

Structure

Experimental structures (PDB)

337 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9MXD	X-RAY DIFFRACTION	1.17
7BF1	X-RAY DIFFRACTION	1.24
6XXX	X-RAY DIFFRACTION	1.25
4DJC	X-RAY DIFFRACTION	1.35
7BF2	X-RAY DIFFRACTION	1.43
2F3Y	X-RAY DIFFRACTION	1.45
2W73	X-RAY DIFFRACTION	1.45
4LZX	X-RAY DIFFRACTION	1.5
5V03	X-RAY DIFFRACTION	1.58
9MVW	X-RAY DIFFRACTION	1.58
2F3Z	X-RAY DIFFRACTION	1.6
6M7H	X-RAY DIFFRACTION	1.6
6DAD	X-RAY DIFFRACTION	1.65
6U3A	X-RAY DIFFRACTION	1.65
7KL5	X-RAY DIFFRACTION	1.65
7ZRQ	X-RAY DIFFRACTION	1.68
1CLL	X-RAY DIFFRACTION	1.7
1YR5	X-RAY DIFFRACTION	1.7
5DOW	X-RAY DIFFRACTION	1.7
5NIN	X-RAY DIFFRACTION	1.7
6U3B	X-RAY DIFFRACTION	1.7
7VUR	X-RAY DIFFRACTION	1.7
7VUS	X-RAY DIFFRACTION	1.7
7VUT	X-RAY DIFFRACTION	1.7
5K8Q	X-RAY DIFFRACTION	1.74
6U3D	X-RAY DIFFRACTION	1.75
3UCW	X-RAY DIFFRACTION	1.76
5V02	X-RAY DIFFRACTION	1.78
2Y4V	X-RAY DIFFRACTION	1.8
3UCY	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DP23-F1	85.22	0.43

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

144 pathways

ID	Pathway
R-HSA-111932	CaMK IV-mediated phosphorylation of CREB
R-HSA-111933	Calmodulin induced events
R-HSA-111957	Cam-PDE 1 activation
R-HSA-111997	CaM pathway
R-HSA-114608	Platelet degranulation
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-1474151	Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
R-HSA-163615	PKA activation
R-HSA-180024	DARPP-32 events
R-HSA-1855204	Synthesis of IP3 and IP4 in the cytosol
R-HSA-2025928	Calcineurin activates NFAT
R-HSA-203615	eNOS activation
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-2514859	Inactivation, recovery and regulation of the phototransduction cascade
R-HSA-2672351	Stimuli-sensing channels
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-4086398	Ca2+ pathway
R-HSA-418359	Reduction of cytosolic Ca++ levels
R-HSA-425561	Sodium/Calcium exchangers
R-HSA-438066	Unblocking of NMDA receptors, glutamate binding and activation
R-HSA-442720	CREB1 phosphorylation through the activation of Adenylate Cyclase
R-HSA-442729	CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde
R-HSA-442982	Ras activation upon Ca2+ influx through NMDA receptor
R-HSA-445355	Smooth Muscle Contraction
R-HSA-451308	Activation of Ca-permeable Kainate Receptor
R-HSA-5210891	Uptake and function of anthrax toxins
R-HSA-5218920	VEGFR2 mediated vascular permeability
R-HSA-5218921	VEGFR2 mediated cell proliferation
R-HSA-5576892	Phase 0 - rapid depolarisation
R-HSA-5578775	Ion homeostasis

MSigDB gene sets: 744 (showing top): BIOCARTA_GCR_PATHWAY, ELVIDGE_HYPOXIA_DN, GCM_MAP4K4, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_SEQUESTERING_OF_CALCIUM_ION, REACTOME_IONOTROPIC_ACTIVITY_OF_KAINATE_RECEPTORS, BIOCARTA_FMLP_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_CREB1_PHOSPHORYLATION_THROUGH_THE_ACTIVATION_OF_CAMKII_CAMKK_CAMKIV_CASCASDE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (27): 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), autophagosome membrane docking (GO:0016240), substantia nigra development (GO:0021762), regulation of cytokinesis (GO:0032465), cellular response to interferon-beta (GO:0035458), positive regulation of receptor signaling pathway via JAK-STAT (GO:0046427), 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), regulation of ryanodine-sensitive calcium-release channel activity (GO:0060314), negative regulation of ryanodine-sensitive calcium-release channel activity (GO:0060315), cellular response to type II interferon (GO:0071346), calcineurin-mediated signaling (GO:0097720), regulation of cardiac muscle cell action potential (GO:0098901), organelle localization by membrane tethering (GO:0140056), presynaptic endocytosis (GO:0140238), negative regulation of high voltage-gated calcium channel activity (GO:1901842), regulation of cell communication by electrical coupling involved in cardiac conduction (GO:1901844), negative regulation of calcium ion export across plasma membrane (GO:1905913), obsolete mitochondrion-endoplasmic reticulum membrane tethering (GO:1990456), cell surface receptor signaling pathway via JAK-STAT (GO:0007259)

GO Molecular Function (14): calcium channel regulator activity (GO:0005246), calcium ion binding (GO:0005509), 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), protein binding (GO:0005515), kinase activity (GO:0016301), metal ion binding (GO:0046872), transporter inhibitor activity (GO:0141110)

GO Cellular Component (27): spindle pole (GO:0000922), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), spindle microtubule (GO:0005876), plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), 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), cilium (GO:0005929), membrane (GO:0016020), motile cilium (GO:0031514), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-20 pathways:

Category	Pathways
Calmodulin induced events	2
CaM pathway	1
Ca-dependent events	1
DAG and IP3 signaling	1
Response to elevated platelet cytosolic Ca2+	1
Membrane Trafficking	1
Metabolism of cofactors	1
PKA-mediated phosphorylation of CREB	1
Opioid Signalling	1
Inositol phosphate metabolism	1
Downstream signaling events of B Cell Receptor (BCR)	1
Metabolism of nitric oxide: NOS3 activation and regulation	1
Mitochondrial biogenesis	1
The phototransduction cascade	1
Ion channel transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
regulation of heart contraction	2
regulation of release of sequestered calcium ion into cytosol	2
cellular response to cytokine stimulus	2
calcium-mediated signaling	2
ryanodine-sensitive calcium-release channel activity	2
calcium channel activity	2
protein binding	2
spindle	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 by sarcoplasmic reticulum	1
regulation of cardiac muscle contraction by calcium ion signaling	1
autophagosome maturation	1
organelle localization by membrane tethering	1
midbrain development	1
neural nucleus development	1
cytokinesis	1
regulation of cell cycle process	1
regulation of cell division	1
response to interferon-beta	1
cell surface receptor signaling pathway via JAK-STAT	1
regulation of receptor signaling pathway via JAK-STAT	1
positive regulation of receptor signaling pathway via STAT	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
regulation of transmembrane transporter activity	1
negative regulation of release of sequestered calcium ion into cytosol	1
regulation of ryanodine-sensitive calcium-release channel activity	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

25 interactions, top by confidence:

A	B	Type	Score
CALM1	IDH1	psi-mi:“MI:0407”(direct interaction)	0.650
IDH1	CALM1	psi-mi:“MI:0407”(direct interaction)	0.650
IDH1	CALM1	psi-mi:“MI:0915”(physical association)	0.650
CALM1	IQSEC2	psi-mi:“MI:0915”(physical association)	0.560
	CALM1	psi-mi:“MI:0407”(direct interaction)	0.440
TIFAB	DDX3X	psi-mi:“MI:0914”(association)	0.350
DISC1	NUDT21	psi-mi:“MI:0914”(association)	0.350
CTBP1	TAF15	psi-mi:“MI:0914”(association)	0.350
CTBP1	GSN	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POTEF	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
CALM1	MYO1C	psi-mi:“MI:0914”(association)	0.350
CAMK1D	CALM1	psi-mi:“MI:0914”(association)	0.350
PHKG2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
PPP3CC	MAP2K7	psi-mi:“MI:0914”(association)	0.350
SCN2B	RIMOC1	psi-mi:“MI:0914”(association)	0.350
UBR4	METTL15	psi-mi:“MI:0914”(association)	0.350
ATF1	MYO1C	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A2WN93, A2WNH1, A2Y609, A3E3H0, A3E4D8, A3E4F9, A4UHC0, A8I1Q0, O82018, O94739, O96102, P04353, P04464, P07463, P0DH95, P0DH96, P0DH97, P0DH98, P0DP23, P0DP27, P0DP28, P0DP30, P0DP31, P0DP35, P13868, P17928, P27161, P41040, P48976, P59220, P62151, P62162, P62163, P62199, P62200, P62201, P62202, P93087, P93171, Q03509

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

23 interactions.

A	Effect	B	Mechanism
CALM1	up-regulates	PPP3CA	binding
CALM1	up-regulates	PPP3CB	binding
CALM1	up-regulates	PPP3CC	binding
CALM1	up-regulates	CAMKK1	binding
EGFR	down-regulates	CALM1	phosphorylation
INSR	down-regulates	CALM1	phosphorylation
CALM1	“up-regulates activity”	NOS3	binding
CALM1	up-regulates	Calcineurin	binding
CALM1	“down-regulates activity”	SCN8A	binding
CCP110	“up-regulates activity”	CALM1	binding
CALM1	up-regulates	PP2B	binding
CALM1	up-regulates	CAMKK2	binding
calcium(2+)	up-regulates	CALM1	“chemical activation”
CALM1	up-regulates	EEF2K	binding
CALM1	“up-regulates activity”	GEM	binding
CALM1	“up-regulates activity”	KIF1A	binding
CSNK2A1	“down-regulates activity”	CALM1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	7
Uncertain significance	41
Likely benign	100
Benign	18

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1362982	NM_006888.6(CALM1):c.395A>G (p.Asp132Gly)	Pathogenic
183231	NM_006888.6(CALM1):c.426C>G (p.Phe142Leu)	Pathogenic
2100843	NM_006888.6(CALM1):c.286G>T (p.Asp96Tyr)	Pathogenic
426161	NM_006888.6(CALM1):c.424T>C (p.Phe142Leu)	Pathogenic
4785412	NM_006888.6(CALM1):c.270C>G (p.Phe90Leu)	Pathogenic
4787824	NM_006888.6(CALM1):c.389A>T (p.Asp130Val)	Pathogenic
639902	NM_006888.6(CALM1):c.394G>A (p.Asp132Asn)	Pathogenic
948239	NM_006888.6(CALM1):c.395A>T (p.Asp132Val)	Pathogenic
961658	NM_006888.6(CALM1):c.426C>A (p.Phe142Leu)	Pathogenic
974612	NM_006888.6(CALM1):c.422A>G (p.Glu141Gly)	Pathogenic
974613	NM_006888.6(CALM1):c.422A>T (p.Glu141Val)	Pathogenic
183232	NM_006888.6(CALM1):c.268T>C (p.Phe90Leu)	Likely pathogenic
3338336	NM_006888.6(CALM1):c.398G>T (p.Gly133Val)	Likely pathogenic
384090	NM_006888.6(CALM1):c.88A>C (p.Thr30Pro)	Likely pathogenic
388500	NM_006888.6(CALM1):c.313G>A (p.Glu105Lys)	Likely pathogenic
39757	NM_006888.6(CALM1):c.161A>T (p.Asn54Ile)	Likely pathogenic
418107	NM_006888.6(CALM1):c.419A>T (p.Glu140Val)	Likely pathogenic
542137	NM_006888.6(CALM1):c.398G>A (p.Gly133Glu)	Likely pathogenic

SpliceAI

897 predictions. Top by Δscore:

Variant	Effect	Δscore
14:90397152:G:GT	donor_gain	1.0000
14:90400060:TATA:T	acceptor_loss	1.0000
14:90400062:TA:T	acceptor_loss	1.0000
14:90400063:A:AG	acceptor_gain	1.0000
14:90400064:G:GC	acceptor_loss	1.0000
14:90400064:G:GG	acceptor_gain	1.0000
14:90401250:T:TA	acceptor_gain	1.0000
14:90401257:A:AG	acceptor_gain	1.0000
14:90401258:G:GG	acceptor_gain	1.0000
14:90401258:GA:G	acceptor_gain	1.0000
14:90401258:GAA:G	acceptor_gain	1.0000
14:90401258:GAAT:G	acceptor_gain	1.0000
14:90401258:GAATT:G	acceptor_gain	1.0000
14:90401375:GA:G	donor_gain	1.0000
14:90401387:G:GT	donor_gain	1.0000
14:90401399:GATG:G	donor_gain	1.0000
14:90401400:ATG:A	donor_gain	1.0000
14:90401400:ATGGT:A	donor_loss	1.0000
14:90401401:TG:T	donor_gain	1.0000
14:90401401:TGG:T	donor_loss	1.0000
14:90401402:GG:G	donor_gain	1.0000
14:90401402:GGTA:G	donor_loss	1.0000
14:90401403:G:GG	donor_gain	1.0000
14:90401404:T:A	donor_loss	1.0000
14:90403854:A:AG	acceptor_gain	1.0000
14:90403854:AATTC:A	acceptor_gain	1.0000
14:90403855:A:G	acceptor_gain	1.0000
14:90403857:TCGAG:T	acceptor_loss	1.0000
14:90403858:C:CA	acceptor_gain	1.0000
14:90403858:CGAG:C	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000309999 (14:90405231 G>A), RS1000358925 (14:90398325 A>C,G), RS1000384516 (14:90396016 T>C), RS1000619625 (14:90404785 C>A,T), RS1000700559 (14:90408359 G>A), RS1000752761 (14:90408091 C>T), RS1000871541 (14:90395099 T>G), RS1001025143 (14:90401041 G>T), RS1001270305 (14:90398019 C>T), RS1001700506 (14:90398357 C>T), RS1002204913 (14:90399165 AG>A), RS1002363400 (14:90406856 G>A), RS1002417158 (14:90406605 C>T), RS1002501062 (14:90398125 C>G,T), RS1002619809 (14:90399363 G>A)

Disease associations

OMIM: gene MIM:114180 | disease phenotypes: MIM:614916, MIM:616247, MIM:600996, MIM:604772

GenCC curated gene-disease

Disease	Classification	Inheritance
long QT syndrome 14	Definitive	Autosomal dominant
catecholaminergic polymorphic ventricular tachycardia 4	Strong	Autosomal dominant
catecholaminergic polymorphic ventricular tachycardia	Moderate	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): catecholaminergic polymorphic ventricular tachycardia 4 (MONDO:0013966), long QT syndrome 14 (MONDO:0014548), long QT syndrome (MONDO:0002442), catecholaminergic polymorphic ventricular tachycardia 1 (MONDO:0011484), catecholaminergic polymorphic ventricular tachycardia (MONDO:0017990)

Orphanet (3): Romano-Ward syndrome (Orphanet:101016), Catecholaminergic polymorphic ventricular tachycardia (Orphanet:3286), Congenital long QT syndrome (Orphanet:768)

HPO phenotypes

32 total (30 of 32 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:0001657	Prolonged QT interval
HP:0001663	Ventricular fibrillation
HP:0001664	Torsade de pointes
HP:0001688	Sinus bradycardia
HP:0001695	Cardiac arrest
HP:0001699	Sudden death
HP:0001962	Palpitations
HP:0002321	Vertigo
HP:0002900	Hypokalemia
HP:0003593	Infantile onset
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:0011463	Childhood onset
HP:0012266	T-wave alternans
HP:0012332	Abnormal autonomic nervous system physiology
HP:0012819	Myocarditis
HP:0031677	Polymorphic ventricular tachycardia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004097_2	Response to platinum-based neoadjuvant chemotherapy in cervical cancer	7.000000e-06
GCST009856_46	Leukocyte telomere length	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007943	response to platinum-based neoadjuvant chemotherapy

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
C563409	Arrhythmogenic Right Ventricular Dysplasia, Familial, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3885535 (PROTEIN-PROTEIN INTERACTION), CHEMBL6093 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 233,070 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL42	CLOZAPINE	4	37,581
CHEMBL422	TRIFLUOPERAZINE	4	20,044
CHEMBL643	PROMETHAZINE	4	36,306
CHEMBL71	CHLORPROMAZINE	4	45,827
CHEMBL449317	HESPERIDIN	3	18,753
CHEMBL50	QUERCETIN	3	74,559

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs12885713	Efficacy	3	cyclosporine	Psoriasis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12885713	CALM1	3	2.50	1	cyclosporine

ChEMBL bioactivities

18 potent at pChembl≥5 of 48 total, top 18 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	Kd	1	nM	CHEMBL3337496
7.75	Kd	18	nM	CHEMBL495235
7.74	Kd	18.25	nM	CHEMBL2408940
7.71	Kd	19.4	nM	CHEMBL2408939
6.96	Kd	110.4	nM	CHEMBL3752910
6.96	ED50	110.4	nM	CHEMBL3752910
6.67	Kd	212.5	nM	CHEMBL5653589
6.67	ED50	212.5	nM	CHEMBL5653589
6.07	Kd	850	nM	CHEMBL3798296
6.00	Kd	1000	nM	TRIFLUOPERAZINE
5.91	Kd	1240	nM	CHLORPROMAZINE
5.29	IC50	5170	nM	6-HYDROXYFLAVONE
5.26	IC50	5540	nM	CHEMBL515370
5.25	IC50	5620	nM	TAJIXANTHONE HYDRATE
5.14	IC50	7260	nM	CHLORPROMAZINE
5.10	IC50	8000	nM	CHLORPROMAZINE
5.03	IC50	9380	nM	CHEMBL66917
5.02	IC50	9590	nM	CHEMBL458017

PubChem BioAssay actives

53 with measured affinity, of 271 total; 17 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147980: Binding affinity to human CALM1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1104	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147980: Binding affinity to human CALM1 incubated for 45 mins by Kinobead based pull down assay	kd	0.2125	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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	9
Air Pollutants	affects cotreatment, increases abundance, increases expression, increases oxidation, affects expression (+1 more)	4
Ozone	increases oxidation, increases abundance, affects expression, affects cotreatment, increases expression	3
sodium arsenite	increases expression, increases abundance	2
cobaltous chloride	decreases expression	2
methacrylaldehyde	increases abundance, affects cotreatment, increases expression, increases oxidation	2
Acrolein	increases expression, increases oxidation, increases abundance, affects cotreatment	2
Arsenic	affects methylation, increases abundance, increases expression	2
Doxorubicin	affects expression, decreases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
methylselenic acid	increases expression	1
pyrogallol 1,3-dimethyl ether	increases expression, affects cotreatment, decreases expression, affects localization	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cupric oxide	increases expression	1
vanadyl sulfate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
deguelin	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
pyrimidifen	decreases expression	1

ChEMBL screening assays

23 unique, capped per target: 23 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3767036	Binding	Inhibition of human CaM/Src kinase SH2 domain interaction assessed as apparent association of CaM-Src kinase SH2 domain at 10 fold excess compound concentration by isothermal titration calorimetry	Identification of initial leads directed at the calmodulin-binding region on the Src-SH2 domain that exhibit anti-proliferation activity against pancreatic cancer. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4TV	CALM1-F142L iPSC c1	Induced pluripotent stem cell	Male
CVCL_A4TW	CALM1-F142L iPSC c2	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

74 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
NCT05122975	PHASE2	TERMINATED	Treatment of an Inherited Ventricular Arrhythmia
NCT06005428	PHASE2	TERMINATED	Effectiveness of CRD-4730 in Participants With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
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
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