CACNA2D1

Chr 7AR

calcium voltage-gated channel auxiliary subunit alpha2delta 1

Also known as: CACNA2, CACNL2A, CCHL2A, DEE110, LINC01112, lncRNA-N3

NCBI Gene: 781ENSG00000153956UniProt: P54289

The preproprotein encoded by this gene is cleaved into multiple chains that comprise the alpha-2 and delta subunits of the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. Mutations in this gene can cause cardiac deficiencies, including Brugada syndrome and short QT syndrome. Alternate splicing results in multiple transcript variants, some of which may lack the delta subunit portion. [provided by RefSeq, Nov 2014]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 110MIM #620149
AR
1175
ClinVar variants
15
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CACNA2D1
⚡
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.
📋
ClinVar Variants
15 Pathogenic / Likely Pathogenic· 184 VUS of 1175 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.24LOEUF
pLI 1.000
Z-score 6.81
OE 0.15 (0.09–0.24)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.49Z-score
OE missense 0.59 (0.54–0.64)
336 obs / 570.6 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.15 (0.09–0.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.54–0.64)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.90
0≤1.21.6
LoF obs/exp: 11 / 74.4Missense obs/exp: 336 / 570.6Syn Z: 1.08

ClinVar Variant Classifications

1175 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10
Likely Pathogenic5
VUS184
Likely Benign224
Benign37
Conflicting15
10
Pathogenic
5
Likely Pathogenic
184
VUS
224
Likely Benign
37
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
7
0
10
Likely Pathogenic
0
0
5
0
5
VUS
9
145
27
3
184
Likely Benign
0
8
109
107
224
Benign
0
1
33
3
37
Conflicting
—15
Total11155181113475

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

View in ClinVar →

Protein Context — Lollipop Plot

CACNA2D1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CACNA2D1-related short QT syndrome

disputed
ADUndeterminedUncertain
Cardiac
G2P ↗

CACNA2D1-related Brugada syndrome

disputed
ADUndeterminedUncertain
Cardiac
G2P ↗

CACNA2D1-related neurodevelopmental disorder

limited
ARUndeterminedDecreased Gene Product Level
Dev. Disorders
G2P ↗
missense variantframeshift variant NMD triggering

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 110

MIM #620149

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Calcium channelopathies and intellectual disability: a systematic review.
Kessi M et al.·Orphanet J Rare Dis
2021Review
Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.
Dahimene S et al.·Brain
2022Case report
Novel heterozygous mutation of CACNA2D1 gene in a Chinese family with arrhythmia.
Wang Q et al.·BMC Cardiovasc Disord
2024
Emerging therapeutic targets in the short QT syndrome.
Hancox JC et al.·Expert Opin Ther Targets
2018Review
miR‑107 promotes the erythroid differentiation of leukemia cells via the downregulation of Cacna2d1.
Ruan J et al.·Mol Med Rep
2015
AI-Driven Drug Target Screening Platform Identified Oncogene CACNA2D1 Activated by Enhancer Infestation in Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma.
Chung DL et al.·Int J Mol Sci
2025
Identification of novel fusion transcripts in multiple myeloma.
Lin M et al.·J Clin Pathol
2018
Pathophysiological Roles of Auxiliary Calcium Channel α(2)δ Subunits.
Hessenberger M et al.·Handb Exp Pharmacol
2023
"Benign" early repolarization versus malignant early abnormalities: clinical-electrocardiographic distinction and genetic basis.
Pérez-Riera AR et al.·Cardiol J
2012Review
Influence of the calcium voltage-gated channel auxiliary subunit (CACNA2D1) absence on intraocular pressure in mice.
Lankford L et al.·Exp Eye Res
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools