CACNA1A

Chr 19AD

calcium voltage-gated channel subunit alpha1 A

ENSG00000141837 UniProt: O00555 OMIM: 601011

The CACNA1A gene encodes the alpha-1A subunit of voltage-dependent calcium channels that mediate calcium entry into neurons and regulate neurotransmitter release. Mutations cause autosomal dominant disorders including familial hemiplegic migraine, episodic ataxia type 2, spinocerebellar ataxia 6 (from CAG repeat expansions), and developmental and epileptic encephalopathy 42. The gene is highly intolerant to loss-of-function variants, and mutations can cause disease through multiple mechanisms depending on the specific variant type.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the 'high-voltage activated' (HVA) group and are specifically blocked by the spider omega-agatoxin-IVA (AC P54282) (By similarity). They are however insensitive to dihydropyridines (DHP)

OMIM ResearchGenerating clinical summary…

GOF/LOFmechanismADLOEUF 0.135 OMIM phenotypes

Clinical Summary— CACNA1A

⚡

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.

💊

Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 9.27

OE 0.08 (0.04–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.78Z-score

OE missense 0.58 (0.54–0.61)

844 obs / 1467.6 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.08 (0.04–0.13)

0≤0.351.4

Missense OE?0.58 (0.54–0.61)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 9 / 117.4Missense obs/exp: 844 / 1467.6Syn Z: -0.26

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCACNA1A-related epileptic encephalopathyOTHERAD

Mechanism Note (variant-dependent)

GOFLOF— mechanism depends on specific variant

Cav2.1 mechanism is phenotype-dependent. FHM1 variants are GOF (enhanced P/Q-type current). EA2 variants are LOF (reduced current). SCA6 involves polyglutamine expansion. G2P classifies as undetermined.12

This gene — mechanism propensity

0.5575th %ile

GOF

0.74top 25%

LOF

0.58top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.13 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOFprediction above median · 1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNExpression studies provided direct evidence that this mutation impairs Ca(2+) channel function. Mutant/wild-type co-expression studies indicated a dominant negative effect.2

GOFEA2 typically results from nonsense mutations in the CACNA1A gene that encodes the alpha1A (Cav2.1) subunit of the P/Q-type calcium (Ca2+) channel.3

LOFThese data have implications for EA2 in humans, suggesting a haploinsufficiency mechanism at least for some of the CACNA1A mutations leading to a premature stop codon.4

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

References