CACNA2D4

Chr 12AR

calcium voltage-gated channel auxiliary subunit alpha2delta 4

Also known as: RCD4

NCBI Gene: 93589 ENSG00000151062 UniProt: Q7Z3S7 OMIM: 608171

The alpha-2/delta-4 subunit regulates calcium current density and activation/inactivization kinetics of voltage-dependent calcium channels, which mediate calcium influx upon membrane depolarization. Biallelic mutations cause retinal cone dystrophy 4, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants, indicating intolerance to haploinsufficiency in the general population.

OMIM ResearchSummary from RefSeq, OMIM, 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…

Primary Disease Associations & Inheritance

Retinal cone dystrophy 4MIM #610478

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · CACNA2D4-related retinopathy · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.01

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.01LOEUF

pLI 0.000

Z-score 1.47

OE 0.82 (0.66–1.01)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.75Z-score

OE missense 0.92 (0.86–0.98)

628 obs / 683.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.82 (0.66–1.01)

0≤0.351.4

Missense OE?0.92 (0.86–0.98)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 60 / 73.6Missense obs/exp: 628 / 683.3Syn Z: 0.41

Background carrier burden — how many people carry a rare variant somewhere in CACNA2D4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 32

1,593 rare PASS variants

Rare truncating (LoF)

1 in 210

288 rare PASS variants

Rare synonymous (reference)

1 in 49

665 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CACNA2D4. 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 42	1 in 470
South Asian	~43k	1 in 31	1 in 190
Remaining (unassigned)	~30k	1 in 34	1 in 190
European (Finnish)	~27k	1 in 140	1 in 1,000
Admixed American	~22k	1 in 32	1 in 340
African / African American	~21k	1 in 28	1 in 220
East Asian	~20k	1 in 30	1 in 300
Ashkenazi Jewish	~13k	1 in 98	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 29	1 in 280

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): 37 of 38 coding exons well covered in gnomAD exomes; exon 30 marginal. Genomes: all 38.? see exons ↓