CALM3 (Calmodulin 3)
A key calcium-binding messenger protein gene implicated in cardiac arrhythmias and neurodevelopmental disorders
Gene Information Card
| Symbol | CALM3 |
|---|---|
| Full Name | Calmodulin 3 (phosphorylase kinase, delta) |
| Gene Type | Protein coding |
| Chromosomal Location | 19q13.32 |
| NCBI Gene ID | 808 ncbi.nlm.nih.gov/gene/808 |
| Ensembl ID | ENSG00000160014 |
| UniProt ID | P0DP25 |
| OMIM ID | 114183 |
| HGNC ID | 1449 |
| Aliases | CALM2, CAMIII, PHKD, CALML2, CAM3 |
Description
CALM3 encodes calmodulin 3, a calcium-binding messenger protein that mediates calcium signaling by binding to and regulating numerous target proteins, including kinases, phosphatases, and ion channels. It is one of three calmodulin genes (CALM1, CALM2, CALM3) that produce identical calmodulin proteins but differ in their untranslated regions and tissue-specific expression. CALM3 is highly expressed in the brain and heart, and mutations are associated with severe cardiac arrhythmias such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), as well as neurodevelopmental disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Long QT syndrome 15 (LQTS15) | Missense mutations in CALM3 alter calcium binding affinity, disrupting calmodulin regulation of cardiac ion channels (e.g., L-type calcium channels, potassium channels), leading to prolonged QT interval and arrhythmia risk. | ClinVar, OMIM |
| Catecholaminergic polymorphic ventricular tachycardia 4 (CPVT4) | CALM3 mutations impair calmodulin binding to the ryanodine receptor (RyR2), causing aberrant calcium release from the sarcoplasmic reticulum during stress, triggering ventricular arrhythmias. | ClinVar, OMIM |
| Neurodevelopmental disorder with or without cardiac arrhythmia | De novo missense mutations in CALM3 disrupt neuronal calcium signaling, leading to intellectual disability, seizures, and variable cardiac involvement. | ClinVar, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebral cortex) | 45.2 | High |
| Heart (left ventricle) | 38.7 | High |
| Skeletal muscle | 32.1 | High |
| Liver | 12.4 | Medium |
| Kidney | 18.9 | Medium |
| Lung | 8.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 52.6 | High expression |
| HEK293 (embryonic kidney) | 41.3 | High expression |
| K562 (leukemia) | 22.1 | Medium expression |
| HepG2 (hepatocellular carcinoma) | 15.7 | Medium expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.97C>T (p.Arg33Cys) | Missense | Rare (0.001%) | Alters calcium binding affinity; associated with LQTS and CPVT |
| c.161G>A (p.Gly54Asp) | Missense | Rare (0.0005%) | Disrupts calmodulin structure; linked to neurodevelopmental disorder |
| c.293A>G (p.Asn98Ser) | Missense | Rare (0.0002%) | Impairs RyR2 regulation; causes CPVT |
| c.394C>T (p.Arg132Trp) | Missense | Rare (0.0001%) | Reduces calcium binding; associated with LQTS |
Mutation functional classification
Loss of Function (LOF)
CALM3 loss-of-function mutations (e.g., frameshift, nonsense) are extremely rare and not well characterized; complete loss is likely embryonic lethal due to essential calcium signaling roles.
Gain of Function (GOF)
Some missense mutations (e.g., p.Asn98Ser) may enhance calmodulin affinity for certain targets, leading to aberrant calcium channel modulation.
Dominant Negative (DN)
Most pathogenic CALM3 mutations act via dominant-negative mechanisms, where mutant calmodulin interferes with wild-type calmodulin function in regulating ion channels and calcium release channels.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Calcium signaling pathway (KEGG: hsa04020)
• Cardiac muscle contraction (KEGG: hsa04260)
• cGMP-PKG signaling pathway (KEGG: hsa04022)
• Alzheimer disease (KEGG: hsa05010)
Protein Summary
Calmodulin 3 is a 149-amino acid calcium-binding protein (17 kDa) composed of two globular domains each containing two EF-hand motifs. It undergoes a conformational change upon calcium binding, exposing hydrophobic patches that interact with over 300 target proteins. In the heart, calmodulin regulates L-type calcium channels (Cav1.2), ryanodine receptors (RyR2), and potassium channels (Kv7.1), making it critical for cardiac excitability and calcium homeostasis. In neurons, it modulates synaptic plasticity, neurotransmitter release, and gene expression. The protein is identical to that encoded by CALM1 and CALM2, but CALM3 expression is particularly enriched in the brain and heart.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CALM3 Knockout HEK293 Cell Line | EDJ-KQ1223 | Human | 808 | Details Get a Quote |
| CALM3 Knockout A-549 Cell Line | EDJ-KQ20551 | Human | 808 | Details Get a Quote |
| CALM3 Knockout HCT 116 Cell Line | EDJ-KQ20552 | Human | 808 | Details Get a Quote |
| CALM3 Knockout HeLa Cell Line | EDJ-KQ20553 | Human | 808 | Details Get a Quote |
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