CACNA2D3

Chr 3

calcium voltage-gated channel auxiliary subunit alpha2delta 3

Also known as: HSA272268

NCBI Gene: 55799 ENSG00000157445 UniProt: Q8IZS8 OMIM: 606399

The alpha-2/delta-3 subunit regulates calcium current density and activation/inactivation kinetics of voltage-dependent calcium channels, specifically P/Q-type, N-type, and L-type calcium channels in the nervous system. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and developmental regression. This gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

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P/LP missense

0.34

LOEUF· LoF intol.

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Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.578

Z-score 5.99

OE 0.22 (0.14–0.34)

Highly constrained

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

Missense Constraint?

1.86Z-score

OE missense 0.78 (0.72–0.84)

451 obs / 576.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.14–0.34)

0≤0.351.4

Missense OE?0.78 (0.72–0.84)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 15 / 68.5Missense obs/exp: 451 / 576.9Syn Z: -0.08

Background carrier burden — how many people carry a rare variant somewhere in CACNA2D3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 56

1,297 rare PASS variants

Rare truncating (LoF)

1 in 1,700

152 rare PASS variants

Rare synonymous (reference)

1 in 88

575 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CACNA2D3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 60	1 in 1,800
South Asian	~43k	1 in 45	1 in 740
Remaining (unassigned)	~30k	1 in 44	1 in 840
European (Finnish)	~27k	1 in 160	1 in 2,900
Admixed American	~22k	1 in 48	1 in 760
African / African American	~21k	1 in 46	1 in 1,600
East Asian	~20k	1 in 52	1 in 1,400
Ashkenazi Jewish	~13k	1 in 190	≈ 1 in 4,200
Middle Eastern	~2,884	1 in 44	1 in 570

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 32 of 38 coding exons well covered in gnomAD exomes; exons 1, 3, 17, 19, 30, 33 marginal. Genomes: 37 of 38 (exon 1 below).? see exons ↓