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CACNA2D2
calcium voltage-gated channel auxiliary subunit alpha2delta 2
CACNA2D2 encodes an auxiliary subunit of voltage-gated calcium channels, playing a critical role in regulating neuronal excitability and synaptic transmission. The CACNA2D2 gene provides instructions for making the alpha2delta-2 subunit, which modulates the function of voltage-gated calcium channels in the nervous system.
CACNA2D2 is located on the short (p) arm of chromosome 3, at band 3p21.31. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 3 in the library →Overview
CACNA2D2 is located on chromosome 3 and encodes the alpha2delta-2 auxiliary subunit of voltage-gated calcium channels. These channels are essential for controlling the flow of calcium ions into nerve cells, a process that underlies neuronal communication and excitability throughout the central nervous system.
The alpha2delta-2 subunit does not form the channel pore itself but instead associates with the main channel-forming subunit to modulate channel trafficking, voltage sensitivity, and current amplitude. Disruption of CACNA2D2 function can therefore impair normal calcium signalling in neurons, contributing to abnormal electrical activity in the brain. The gene is particularly relevant to neurogenetics, with variants linked to epilepsy and movement disorders.
What the gene does
The alpha2delta-2 protein functions as a regulatory component of voltage-gated calcium channels, which mediate calcium entry into cells in response to changes in membrane potential. By associating with the main pore-forming alpha1 subunit, alpha2delta-2 influences several key properties of the channel complex. It promotes proper trafficking of calcium channels to the cell membrane, enhances channel opening in response to voltage changes, and increases the magnitude of calcium currents.
In the nervous system, alpha2delta-2 is expressed predominantly in the brain and spinal cord, where it contributes to synaptic transmission and neuronal excitability. Calcium influx through voltage-gated channels triggers neurotransmitter release at synapses and shapes the electrical signals that propagate along nerve fibres. The modulatory role of alpha2delta-2 means that even subtle changes in its activity can have significant effects on network-level brain function, particularly in regions involved in motor control and seizure susceptibility.
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Chromosome location
CACNA2D2 is located on the short arm of chromosome 3 at position 3p21.31. This chromosomal region contains numerous genes involved in neurological and developmental functions. The gene spans a substantial genomic interval and produces a protein of 1150 amino acids through the coordinated expression of multiple exons.
Protein structure
The alpha2delta-2 protein comprises 1150 amino acids and contains several well-characterised functional domains, including those established through current structural annotations. These domain boundaries may vary slightly between databases as structural knowledge evolves. The N-terminal region includes a disordered segment spanning amino acids 1 to 41, which may serve regulatory or structural flexibility functions. A von Willebrand factor type A domain (VWFA) is present between amino acids 291 and 469, incorporating a MIDAS-like motif at positions 297 to 301 that is thought to participate in metal ion coordination and protein-protein interactions. Additionally, a Cache domain extends from amino acids 485 to 574, a structural module typically involved in binding small molecules or mediating protein associations. These domains collectively enable the alpha2delta-2 subunit to interact with calcium channel complexes and modulate their function at the cell membrane.
Key variants
Pathogenic variants in CACNA2D2 are typically inherited in an autosomal recessive manner, meaning that two altered copies of the gene are generally required for clinical manifestations. When both parents carry one altered copy, each pregnancy has a 25% (1 in 4) chance of the child inheriting both variants and being affected. Variants that disrupt protein function or stability can impair the ability of voltage-gated calcium channels to operate normally, leading to altered neuronal excitability. The spectrum of reported variants includes missense changes, truncating mutations, and deletions affecting critical functional domains.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1555C>T | p.Gln519Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebellar atrophy with seizures and variable developmental delay |
c.97_103dup | p.Arg35fs | Pathogenic/Likely pathogenic | ★★☆☆ | Early-infantile DEE |
c.1017del | p.Ser340fs | Pathogenic | ★☆☆☆ | Early-infantile DEE |
c.107_177del | p.Pro36fs | Pathogenic | ★☆☆☆ | Early-infantile DEE |
c.1126G>T | p.Glu376Ter | Pathogenic | ★☆☆☆ | Cerebellar atrophy with seizures and variable developmental delay |
c.1162_1165del | p.Thr388fs | Pathogenic | ★☆☆☆ | Early-infantile DEE |
c.1269_1270del | p.Phe424fs | Pathogenic | ★☆☆☆ | Early-infantile DEE |
c.1293del | p.His431fs | Pathogenic | ★☆☆☆ | Early-infantile DEE |
c.1298_1299del | p.Asn432_Tyr433insTer | Pathogenic | ★☆☆☆ | Early-infantile DEE |
c.1324del | p.Ala442fs | Pathogenic | ★☆☆☆ | Early-infantile DEE |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in CACNA2D2 have been associated with neurological conditions characterised by abnormal brain electrical activity and motor dysfunction. Evidence linking CACNA2D2 to these conditions continues to develop, with pathogenic variants reported in a growing number of families. Evidence suggests that loss of alpha2delta-2 function can contribute to epilepsy, particularly early-onset or syndromic forms that may include additional developmental or neurological features. Some individuals with CACNA2D2 variants have also presented with ataxia, a movement disorder characterised by impaired coordination and balance, reflecting the gene's role in cerebellar and motor pathway function. The clinical presentation can vary depending on the nature and location of the genetic variant.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic CACNA2D2 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
CACNA2D2 is included on several NHS Genomic Medicine Service gene panels, reflecting its clinical relevance for diagnosing inherited neurological disorders. The gene holds green classification status on the Early Onset or Syndromic Epilepsy panel (R59) and is also listed with green status on the Hereditary Ataxia panel, underscoring the gene's association with movement disorders involving cerebellar dysfunction. These panel memberships mean that CACNA2D2 is routinely analysed in UK clinical diagnostic pathways for individuals presenting with unexplained epilepsy or ataxia.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the CACNA2D2 gene do?
CACNA2D2 encodes an auxiliary subunit that modulates voltage-gated calcium channels in the nervous system. The protein regulates how these channels traffic to the cell surface, respond to voltage changes, and conduct calcium ions into neurons, thereby influencing neuronal excitability and synaptic transmission.
How are CACNA2D2 variants inherited?
Variants in CACNA2D2 are typically inherited in an autosomal recessive pattern. This means an individual generally needs to inherit an altered copy of the gene from both parents to develop associated neurological conditions.
Is genetic testing for CACNA2D2 available on the NHS?
Yes, CACNA2D2 is analysed as part of NHS Genomic Medicine Service panels for early-onset or syndromic epilepsy and hereditary ataxia. Testing is arranged by specialist clinicians when an individual's symptoms suggest a genetic cause within these categories.