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…

LOEUF 0.34

Clinical Summary— CACNA2D3

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.58) — some intolerance to loss-of-function variants.

📋

ClinVar Variants

192 VUS of 279 total submissions

Explore recent and relevant literature in Research Assistant →

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

ClinVar Variant Classifications

279 submitted variants in ClinVar

ClinVar

Classification Summary

VUS192

Likely Benign23

Benign13

192

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	190	1	0	192
Likely Benign	2	7	6	8	23
Benign	1	4	4	4	13
Total	4	201	11	12	228

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap CACNA2D3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →