CACNA2D1

Chr 7AR

calcium voltage-gated channel auxiliary subunit alpha2delta 1

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

NCBI Gene: 781 ENSG00000153956 OMIM: 114204

The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics, playing an important role in excitation-contraction coupling. Mutations cause autosomal recessive developmental and epileptic encephalopathy 110. This gene is highly constrained against loss-of-function variants (pLI >0.99), indicating that functional copies are essential for normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.241 OMIM phenotype

Clinical Summary— CACNA2D1

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Gene-Disease Validity (ClinGen)

short QT syndrome · ADDisputed

Disputed — evidence questions this relationship

2 total gene-disease associations curated

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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

4 unique Pathogenic / Likely Pathogenic· 408 VUS of 1144 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CACNA2D1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.15 (0.09–0.24)

0≤0.351.4

Missense OE?0.59 (0.54–0.64)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 11 / 74.4Missense obs/exp: 336 / 570.6Syn Z: 1.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCACNA2D1-related short QT syndromeOTHERAD

limitedCACNA2D1-related Brugada syndromeOTHERAD

limitedCACNA2D1-related neurodevelopmental disorderOTHERAR

This gene — mechanism propensity

0.3892th %ile

GOF

0.4678th %ile

LOF

0.64top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.24

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

1144 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic1

VUS408

Likely Benign555

Benign120

Conflicting36

Pathogenic

Likely Pathogenic

408

VUS

555

Likely Benign

120

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	0	0	3
Likely Pathogenic	1	0	0	0	1
VUS	19	341	42	6	408
Likely Benign	1	16	282	256	555
Benign	0	2	115	3	120
Conflicting	—				36
Total	23	360	439	265	1,123

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap CACNA2D1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →