CACNA1D

Chr 3ADAR

calcium voltage-gated channel subunit alpha1 D

Also known as: CACH3, CACN4, CACNL1A2, CCHL1A2, Cav1.3, PASNA, SANDD

NCBI Gene: 776 ENSG00000157388 UniProt: Q01668 OMIM: 114206

The CACNA1D protein forms the pore-forming alpha-1D subunit of voltage-dependent calcium channels that mediate calcium entry into excitable cells for muscle contraction, hormone/neurotransmitter release, and gene expression. Mutations cause primary aldosteronism with seizures and neurologic abnormalities, as well as sinoatrial node dysfunction and deafness, through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves gain-of-function mutations that alter normal calcium channel activity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

GOF/LOFmechanismAD/ARLOEUF 0.212 OMIM phenotypes

Clinical Summary— CACNA1D

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Gene-Disease Validity (ClinGen)

sinoatrial node dysfunction and deafness · ARModerate

Moderate evidence — consider for supplementary testing

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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Clinical Trials

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

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.21LOEUF

pLI 1.000

Z-score 8.67

OE 0.14 (0.10–0.21)

Highly constrained

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

Missense Constraint

4.58Z-score

OE missense 0.64 (0.60–0.67)

797 obs / 1253.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.14 (0.10–0.21)

0≤0.351.4

Missense OE0.64 (0.60–0.67)

0≤0.61.4

Synonymous OE1.02

0≤1.21.6

LoF obs/exp: 17 / 119.1Missense obs/exp: 797 / 1253.5Syn Z: -0.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCACNA1D-related sinoatrial node dysfunction and deafnessLOFAR

strongCACNA1D-related primary aldosteronism, seizures, and neurologic abnormalitiesGOFAD

Mechanism Note (variant-dependent)

GOFLOF— mechanism depends on specific variant

Cav1.3 (L-type). Monoallelic GOF variants cause increased calcium conductance (PASNA syndrome). Biallelic LOF variants cause SANDD syndrome. Mechanism depends on zygosity and variant.

References:PMID:27629093

0.5968th %ile

GOF

0.73top 25%

LOF

0.48top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOFLOEUF 0.21

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

GOFIdentification of an activating CACNA1D mutation in a second patient with congenital HH confirms the aetiological role of CACNA1D mutations in this disorder.PMID:28318089

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