CACNA2D2

Chr 3AR

calcium voltage-gated channel auxiliary subunit alpha2delta 2

Also known as: CACNA2D, CASVDD

NCBI Gene: 9254 ENSG00000007402 UniProt: Q9NY47 OMIM: 607082

The protein encodes the alpha-2/delta auxiliary subunit of voltage-dependent calcium channels, which undergoes post-translational cleavage and functions in channel assembly, membrane localization, and modulation of calcium currents and activation/inactivation kinetics. Autosomal recessive mutations cause early infantile epileptic encephalopathy with cerebellar atrophy, seizures, and variable developmental delay. The subunit serves as a receptor for the antiepileptic drug gabapentin.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Calcium channels mediate the entry of calcium ions into the cell upon membrane polarization. This gene encodes the alpha-2/delta subunit of the voltage-dependent calcium channel complex. The complex consists of the main channel-forming subunit alpha-1, and auxiliary subunits alpha-2/delta, beta, and gamma. The auxiliary subunits function in the assembly and membrane localization of the complex, and modulate calcium currents and channel activation/inactivation kinetics. The subunit encoded by this gene undergoes post-translational cleavage to yield the extracellular alpha2 peptide and a membrane-anchored delta polypeptide. This subunit is a receptor for the antiepileptic drug, gabapentin. Mutations in this gene are associated with early infantile epileptic encephalopathy. Single nucleotide polymorphisms in this gene are correlated with increased sensitivity to opioid drugs. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

OMIM ResearchGenerating clinical summary…

ARLOEUF 0.231 OMIM phenotype

Clinical Summary— CACNA2D2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

82 unique Pathogenic / Likely Pathogenic· 475 VUS of 1309 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 1.000

Z-score 6.89

OE 0.14 (0.08–0.23)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.00Z-score

OE missense 0.67 (0.61–0.72)

426 obs / 639.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.14 (0.08–0.23)

0≤0.351.4

Missense OE?0.67 (0.61–0.72)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 10 / 74.0Missense obs/exp: 426 / 639.5Syn Z: -0.38

ClinVar Variant Classifications

1309 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic51

Likely Pathogenic31

VUS475

Likely Benign676

Benign44

Conflicting17

Pathogenic

Likely Pathogenic

475

VUS

676

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	47	3	1	0	51
Likely Pathogenic	28	2	1	0	31
VUS	7	423	36	9	475
Likely Benign	1	8	343	324	676
Benign	0	3	35	6	44
Conflicting	—				17
Total	83	439	416	339	1,294

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

9 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap CACNA2D2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →