CALM3

Summary

CALM3 (calmodulin 3, HGNC:1449) is a protein-coding gene on chromosome 19q13.32, encoding Calmodulin-3 (P0DP25). 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 a member of a family of proteins that binds calcium and functions as a enzymatic co-factor. Activity of this protein is important in the regulation of the cell cycle and cytokinesis. Multiple alternatively spliced transcript variants have been observed at this gene.

Source: NCBI Gene 808 — RefSeq curated summary.

At a glance

• Gene–disease (curated): long QT syndrome (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 218 total — 7 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 28
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005184

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1449
Approved symbol	CALM3
Name	calmodulin 3
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	PHKD, PHKD3
Ensembl gene	ENSG00000160014
Ensembl biotype	protein_coding
OMIM	114183
Entrez	808

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000291295, ENST00000391918, ENST00000477244, ENST00000482455, ENST00000486500, ENST00000594523, ENST00000595072, ENST00000596362, ENST00000597743, ENST00000597868, ENST00000598871, ENST00000599839, ENST00000602169, ENST00000866714, ENST00000866715, ENST00000866716, ENST00000866717, ENST00000866718, ENST00000952656

RefSeq mRNA: 7 — MANE Select: NM_005184 NM_001329921, NM_001329922, NM_001329923, NM_001329924, NM_001329925, NM_001329926, NM_005184

CCDS: CCDS33061, CCDS86782, CCDS86783

Canonical transcript exons

ENST00000291295 — 6 exons

Exon	Start	End
ENSE00001855834	46609125	46610782
ENSE00003204091	46601330	46601437
ENSE00003464444	46605827	46605857
ENSE00003557822	46608846	46608981
ENSE00003615243	46608482	46608588
ENSE00003656618	46608197	46608340

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 276.3318 / max 3129.0879, expressed in 1828 samples.

FANTOM5 promoters (27 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176558	195.8773	1827
176557	52.4184	1822
176575	5.6824	1497
176591	3.7516	1378
176586	2.5725	1166
176587	2.1923	1081
176588	1.5135	820
176590	1.4479	776
176581	1.0851	613
176584	1.0378	531

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	99.84	gold quality
right frontal lobe	UBERON:0002810	99.82	gold quality
left testis	UBERON:0004533	99.77	gold quality
right testis	UBERON:0004534	99.74	gold quality
cortical plate	UBERON:0005343	99.68	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.66	gold quality
nucleus accumbens	UBERON:0001882	99.65	gold quality
cerebellar hemisphere	UBERON:0002245	99.65	gold quality
cerebellar cortex	UBERON:0002129	99.64	gold quality
amygdala	UBERON:0001876	99.61	gold quality
cingulate cortex	UBERON:0003027	99.56	gold quality
anterior cingulate cortex	UBERON:0009835	99.54	gold quality
frontal cortex	UBERON:0001870	99.44	gold quality
frontal lobe	UBERON:0016525	99.44	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.43	gold quality
ganglionic eminence	UBERON:0004023	99.42	gold quality
caudate nucleus	UBERON:0001873	99.41	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.38	gold quality
monocyte	CL:0000576	99.27	gold quality
putamen	UBERON:0001874	99.25	gold quality
neocortex	UBERON:0001950	99.24	gold quality
cerebellum	UBERON:0002037	99.24	gold quality
ventricular zone	UBERON:0003053	99.23	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.19	gold quality
parietal lobe	UBERON:0001872	99.15	gold quality
orbitofrontal cortex	UBERON:0004167	99.14	gold quality
pons	UBERON:0000988	99.12	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.12	gold quality
right coronary artery	UBERON:0001625	99.11	gold quality
popliteal artery	UBERON:0002250	99.09	gold quality

Single-cell (SCXA)

Detected in 20 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	1963.93
E-GEOD-111727	yes	475.29
E-GEOD-81383	yes	152.15
E-MTAB-6701	yes	48.75
E-HCAD-4	yes	39.62
E-GEOD-134144	yes	32.60
E-CURD-46	yes	24.04
E-HCAD-1	yes	24.00
E-CURD-122	yes	23.58
E-MTAB-9221	yes	23.23
E-HCAD-5	yes	16.96
E-MTAB-7316	yes	15.21
E-CURD-114	yes	11.07
E-MTAB-10553	yes	8.96
E-CURD-88	yes	5.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 16)

• The rat and mouse 3’-UTR region had an identity of approximately 80% with the human. Three common polyadenylation signals in the 3’-UTR may account for the multiple CaM III transcripts. (PMID:11710561)
• These findings demonstrate that physical interaction of CaM with recombinant and native 5-HT(2C) receptors is critical for G protein-independent, arrestin-dependent receptor signaling. (PMID:18768750)
• data suggest that the -34T>A CALM3 polymorphism is a modifier gene for Familial Hypertrophy Cardiomyopathy, potentially by affecting expression level of CALM3 and therefore Ca(2+)-handling and development of hypertrophy. (PMID:19429631)
• Differentiation paralleled the activation of Wnt5/Calmodulin signalling by autocrine/paracrine intense secretion of Wnt5a and Wnt5b (PMID:21980498)
• the association of EGFR, CALM3 and SMARCD1 gene polymorphisms with bone mineral density in white women, as conducted. (PMID:25396734)
• CALM3 had the highest ranking in the 1629-gene LQTS nodal network of the 7 genes identified through our filtering process. (PMID:25460178)
• the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive long QT syndrome, were determined. (PMID:26969752)
• We discovered a novel CPVT mutation in the CALM3 gene that shares functional characteristics with established CPVT-associated mutations in CALM1. A small proportion of A103V-CaM is sufficient to evoke arrhythmogenic Ca disturbances via ryanodine receptor 2 dysregulation, which explains the autosomal dominant inheritance. (PMID:27516456)
• results suggest that ACE2, TNNI3K and CALM3 polymorphisms are associated with increased risk of hypertrophic cardiomyopathies and dilated cardiomyopathies and may act as disease modifiers of these diseases. (PMID:28744816)
• Study identified the structure and function of Ca2+-dependent interaction of CaM with the inactivation gate (IG) of NaV1.5 channels. Models of full-length NaV1.5 suggest that CaM binding to the IG directly modulates its function by destabilizing the inactivated state, which would promote resetting of the IG after channels close. (PMID:29606593)
• Protein molecular diagnosis of autosomal dominant calmodulin mutations causing irregular heart rhythms has been presented. (PMID:29932249)
• Novel CALM3-E141K and CALM1-E141V are associated with congenital arrhythmia susceptibility. (PMID:31454269)
• Prevalence and Phenotypic Correlations of Calmodulinopathy-Causative CALM1-3 Variants Detected in a Multicenter Molecular Autopsy Cohort of Sudden Unexplained Death Victims. (PMID:33191766)
• Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family. (PMID:35225649)
• Calmodulinopathy in Japanese Children - Their Cardiac Phenotypes Are Severe and Show Early Onset in Fetal Life and Infancy. (PMID:37380439)
• CALM3 affects the prognosis of leukemia and hemorrhoids. (PMID:37932969)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	calm1a	ENSDARG00000021811
danio_rerio	calm1b	ENSDARG00000034187
mus_musculus	Calm3	ENSMUSG00000019370
rattus_norvegicus	Calm3	ENSRNOG00000016770
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), 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-3 — P0DP25 (reviewed: P0DP25)

All UniProt accessions (5): P0DP25, A0A590UJD7, B4DJ51, M0QZ52, 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. (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. Ventricular tachycardia, catecholaminergic polymorphic, 6 (CPVT6) [MIM:618782] 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. CPVT6 inheritance is autosomal dominant. The disease may be caused by variants affecting the gene represented in this entry. Long QT syndrome 16 (LQT16) [MIM:618782] An autosomal dominant 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.

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

Similarity. Belongs to the calmodulin family.

RefSeq proteins (7): NP_001316850, NP_001316851, NP_001316852, NP_001316853, NP_001316854, NP_001316855, NP_005175* (*=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 (58 total): binding site 20, modified residue 11, helix 8, strand 7, domain 4, sequence variant 3, cross-link 2, initiator methionine 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
6K67	X-RAY DIFFRACTION	1.95
5J03	X-RAY DIFFRACTION	2
7BYL	ELECTRON MICROSCOPY	2.5
7XNN	ELECTRON MICROSCOPY	2.5
7XNK	ELECTRON MICROSCOPY	2.6
5COC	X-RAY DIFFRACTION	2.67
7VNP	ELECTRON MICROSCOPY	2.79
7VNR	ELECTRON MICROSCOPY	2.8
9LJ5	ELECTRON MICROSCOPY	2.9
7VNQ	ELECTRON MICROSCOPY	2.96
7BYM	ELECTRON MICROSCOPY	3.1
7XNL	ELECTRON MICROSCOPY	3.1
9IXY	ELECTRON MICROSCOPY	3.1
9LIZ	ELECTRON MICROSCOPY	3.1
9LJ1	ELECTRON MICROSCOPY	3.2
7BYN	ELECTRON MICROSCOPY	3.3
8Z5P	ELECTRON MICROSCOPY	3.41
7XNI	ELECTRON MICROSCOPY	3.5
8Z5R	ELECTRON MICROSCOPY	3.52
7CR3	ELECTRON MICROSCOPY	3.6
8Z5M	ELECTRON MICROSCOPY	3.66
7CR7	ELECTRON MICROSCOPY	3.7
8Z5T	ELECTRON MICROSCOPY	3.74
7CR4	ELECTRON MICROSCOPY	3.9
8Z5Q	ELECTRON MICROSCOPY	4.24
8BD2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DP25-F1	85.45	0.45

Antibody-complex structures (SAbDab): 1 — 6K67

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: 567 (showing top): BIOCARTA_GCR_PATHWAY, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, BIOCARTA_FMLP_PATHWAY, ACTACCT_MIR196A_MIR196B, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, TGCGCANK_UNKNOWN, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_AMINE, PAL_PRMT5_TARGETS_UP, GOBP_RESPONSE_TO_CORTICOSTEROID

GO Biological Process (24): G2/M transition of mitotic cell cycle (GO:0000086), response to amphetamine (GO:0001975), 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 corticosterone (GO:0051412), response to calcium ion (GO:0051592), regulation of cardiac muscle contraction (GO:0055117), long-term synaptic potentiation (GO:0060291), obsolete establishment of protein localization to mitochondrial membrane (GO:0090151), calcineurin-mediated signaling (GO:0097720), regulation of cardiac muscle cell action potential (GO:0098901), presynaptic endocytosis (GO:0140238), regulation of synaptic vesicle endocytosis (GO:1900242), 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), regulation of synaptic vesicle exocytosis (GO:2000300), establishment of protein localization to membrane (GO:0090150)

GO Molecular Function (19): calcium channel regulator activity (GO:0005246), calcium ion binding (GO:0005509), adenylate cyclase binding (GO:0008179), adenylate cyclase activator activity (GO:0010856), protein kinase binding (GO:0019901), protein domain specific binding (GO:0019904), nitric-oxide synthase regulator activity (GO:0030235), titin binding (GO:0031432), type 3 metabotropic glutamate receptor binding (GO:0031800), protein serine/threonine kinase activator activity (GO:0043539), phosphatidylinositol 3-kinase binding (GO:0043548), transmembrane transporter binding (GO:0044325), calcium-dependent protein binding (GO:0048306), nitric-oxide synthase binding (GO:0050998), 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 (26): 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), sarcomere (GO:0030017), growth cone (GO:0030426), synaptic vesicle membrane (GO:0030672), mitochondrial membrane (GO:0031966), 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), Schaffer collateral - CA1 synapse (GO:0098685), presynaptic cytosol (GO:0099523), postsynaptic cytosol (GO:0099524), catalytic complex (GO:1902494), mitochondrion (GO:0005739), spindle (GO:0005819), cytoskeleton (GO:0005856), membrane (GO:0016020), organelle (GO:0043226)

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	5
protein binding	4
regulation of heart contraction	2
calcium-mediated signaling	2
presynapse	2
enzyme binding	2
spindle	2
cytosol	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G2/M phase transition	1
response to amine	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 glucocorticoid	1
response to mineralocorticoid	1
response to alcohol	1
response to ketone	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
cardiac muscle cell action potential	1
regulation of action potential	1
endocytosis	1
establishment of localization in cell	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

15 interactions, top by confidence:

A	B	Type	Score
MYO6	GIPC1	psi-mi:“MI:0914”(association)	0.690
RAC1	COX6C	psi-mi:“MI:0914”(association)	0.640
MYO1C	CALM3	psi-mi:“MI:0915”(physical association)	0.500
CALM3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CAPZB	ENAH	psi-mi:“MI:0914”(association)	0.350
CDC42	PPP1R12A	psi-mi:“MI:0914”(association)	0.350
MYL6	CALM3	psi-mi:“MI:0914”(association)	0.350
MYL6B	CALM3	psi-mi:“MI:0914”(association)	0.350
MYO1B	MYO1C	psi-mi:“MI:0914”(association)	0.350
MYO1E	MYO1C	psi-mi:“MI:0914”(association)	0.350
MYO9B	PPM1G	psi-mi:“MI:0914”(association)	0.350
PHKG2	PRPF40A	psi-mi:“MI:0914”(association)	0.350
VAPA	ESYT2	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	CALM3	“chemical activation”
EGFR	down-regulates	CALM3	phosphorylation
INSR	down-regulates	CALM3	phosphorylation
CALM3	up-regulates	EEF2K	binding
CALM3	up-regulates	PPP3CB	binding
CALM3	“up-regulates activity”	NOS3	binding
CALM3	up-regulates	PPP3CC	binding
CALM3	up-regulates	PPP3CA	binding
CALM3	up-regulates	CAMKK1	binding
CALM3	up-regulates	CAMKK2	binding
CALM3	“down-regulates activity”	SCN8A	binding
CALM3	up-regulates	Calcineurin	binding
CCP110	“up-regulates activity”	CALM3	binding
CALM3	up-regulates	PP2B	binding
CALM3	“up-regulates activity”	GEM	binding
CALM3	“up-regulates activity”	KIF1A	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by Rho GTPases	6	11.4×	3e-04
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	6	11.2×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
actin filament organization	6	32.4×	3e-06
endocytosis	6	26.0×	6e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	2
Uncertain significance	55
Likely benign	124
Benign	13

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1358003	NM_005184.4(CALM3):c.390C>G (p.Asp130Glu)	Pathogenic
2138308	NM_005184.4(CALM3):c.426T>G (p.Phe142Leu)	Pathogenic
409870	NM_005184.4(CALM3):c.286G>C (p.Asp96His)	Pathogenic
409871	NM_005184.4(CALM3):c.281A>C (p.Asp94Ala)	Pathogenic
812676	NM_005184.4(CALM3):c.389A>G (p.Asp130Gly)	Pathogenic
812677	A103V	Pathogenic
812678	NM_005184.4(CALM3):c.421G>A (p.Glu141Lys)	Pathogenic
389576	NM_005184.4(CALM3):c.395A>G (p.Asp132Gly)	Likely pathogenic
458198	NM_005184.4(CALM3):c.422A>G (p.Glu141Gly)	Likely pathogenic

SpliceAI

778 predictions. Top by Δscore:

Variant	Effect	Δscore
19:46601436:TGGT:T	donor_loss	1.0000
19:46601438:G:GA	donor_loss	1.0000
19:46605825:A:AG	acceptor_gain	1.0000
19:46605826:G:GG	acceptor_gain	1.0000
19:46608195:A:AG	acceptor_gain	1.0000
19:46608195:A:C	acceptor_loss	1.0000
19:46608196:G:GA	acceptor_gain	1.0000
19:46608196:GA:G	acceptor_gain	1.0000
19:46608196:GAGT:G	acceptor_gain	1.0000
19:46608196:GAGTT:G	acceptor_gain	1.0000
19:46608313:GA:G	donor_gain	1.0000
19:46608337:GATG:G	donor_gain	1.0000
19:46608473:A:AG	acceptor_gain	1.0000
19:46608474:C:G	acceptor_gain	1.0000
19:46608478:CCAGG:C	acceptor_loss	1.0000
19:46608479:CA:C	acceptor_loss	1.0000
19:46608480:A:AG	acceptor_gain	1.0000
19:46608480:A:T	acceptor_loss	1.0000
19:46608480:AG:A	acceptor_gain	1.0000
19:46608480:AGG:A	acceptor_gain	1.0000
19:46608481:G:A	acceptor_gain	1.0000
19:46608481:G:GT	acceptor_gain	1.0000
19:46608481:GGG:G	acceptor_gain	1.0000
19:46608481:GGGA:G	acceptor_gain	1.0000
19:46608481:GGGAA:G	acceptor_gain	1.0000
19:46608589:G:GG	donor_gain	1.0000
19:46608589:GTA:G	donor_loss	1.0000
19:46608590:T:A	donor_loss	1.0000
19:46608804:C:A	acceptor_gain	1.0000
19:46608842:CCAG:C	acceptor_loss	1.0000

AlphaMissense

1015 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:46608508:T:C	F69L	1.000
19:46608510:C:A	F69L	1.000
19:46608510:C:G	F69L	1.000
19:46608877:T:C	L106P	1.000
19:46608211:T:C	F17L	0.999
19:46608213:C:A	F17L	0.999
19:46608213:C:G	F17L	0.999
19:46608220:T:C	F20L	0.999
19:46608222:T:A	F20L	0.999
19:46608222:T:G	F20L	0.999
19:46608245:T:A	I28N	0.999
19:46608260:T:C	L33S	0.999
19:46608262:G:T	G34W	0.999
19:46608263:G:A	G34E	0.999
19:46608276:A:C	R38S	0.999
19:46608276:A:T	R38S	0.999
19:46608277:T:C	S39P	0.999
19:46608284:G:T	G41V	0.999
19:46608308:T:C	L49P	0.999
19:46608509:T:C	F69S	0.999
19:46608512:T:C	L70P	0.999
19:46608571:T:C	F90L	0.999
19:46608573:C:A	F90L	0.999
19:46608573:C:G	F90L	0.999
19:46608580:T:C	F93L	0.999
19:46608582:T:A	F93L	0.999
19:46608582:T:G	F93L	0.999
19:46608862:T:A	I101N	0.999
19:46608900:G:A	G114R	0.999
19:46608900:G:C	G114R	0.999

dbSNP variants (sampled 300 via entrez): RS1000080684 (19:46609987 G>C), RS1000300672 (19:46604132 G>T), RS1000590419 (19:46610055 C>A,T), RS1000678404 (19:46599488 A>G), RS1000709018 (19:46599742 C>A), RS1000976232 (19:46600663 C>T), RS1000985622 (19:46606143 A>T), RS1001080500 (19:46605847 G>A,C), RS1001171777 (19:46609529 G>A,C), RS1001204545 (19:46609771 G>A,C), RS1001654194 (19:46603438 C>A,T), RS1001769817 (19:46603988 G>A), RS1001907027 (19:46599153 T>A,C,G), RS1001992632 (19:46604965 C>T), RS1002103511 (19:46610251 G>A,C)

Disease associations

OMIM: gene MIM:114183 | disease phenotypes: MIM:192500, MIM:618782, MIM:236670

GenCC curated gene-disease

Disease	Classification	Inheritance
familial long QT syndrome	Definitive	Autosomal dominant
long QT syndrome 16	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 (6): long QT syndrome 1 (MONDO:0100316), familial long QT syndrome (MONDO:0019171), long QT syndrome 16 (MONDO:0032915), ventricular tachycardia, catecholaminergic polymorphic 6 (MONDO:0800374), muscular dystrophy-dystroglycanopathy, type A (MONDO:0000171), catecholaminergic polymorphic ventricular tachycardia (MONDO:0017990)

Orphanet (3): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768), Walker-Warburg syndrome (Orphanet:899)

HPO phenotypes

28 total (28 of 28 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:0003577	Congenital 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:0011648	Patent ductus arteriosus after birth at term
HP:0011682	Perimembranous ventricular septal defect
HP:0011706	Second degree atrioventricular block
HP:0012266	T-wave alternans
HP:0012332	Abnormal autonomic nervous system physiology
HP:0031677	Polymorphic ventricular tachycardia
HP:0500018	Abnormal cardiac exercise stress test

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001728_17	Ulcerative colitis	2.000000e-09
GCST004132_48	Crohn’s disease	4.000000e-07
GCST90002387_57	Immature fraction of reticulocytes	2.000000e-33

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D058494	Walker-Warburg Syndrome	C10.500.507.450.499.249.500; C11.270.881; C16.131.666.507.450.499.249.500; C16.320.577.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, affects expression, decreases expression	3
Valproic Acid	affects expression, increases expression	3
cobaltous chloride	decreases expression	2
chloropicrin	decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Rotenone	decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
pirinixic acid	decreases expression, increases activity, affects binding	1
bisphenol A	affects expression	1
arsenite	increases methylation	1
afimoxifene	decreases response to substance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
pentabromodiphenyl ether	decreases expression	1
deguelin	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	increases expression	1
Glyphosate	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Aspirin	increases expression	1
Benzo(a)pyrene	affects methylation	1
Calcium Chloride	decreases activity, decreases reaction, affects binding	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2TC	Abcam HEK293T CALM3 KO	Transformed cell line	Female
CVCL_SG59	HAP1 CALM3 (-) 1	Cancer cell line	Male
CVCL_SG60	HAP1 CALM3 (-) 2	Cancer cell line	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
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
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry