CACNA1D

Chr 3

calcium voltage-gated channel subunit alpha1 D

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

NCBI Gene: 776ENSG00000157388UniProt: Q01668

Voltage-dependent calcium channels 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, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, namely alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1D subunit. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

Primary Disease Associations & Inheritance

UniProtSinoatrial node dysfunction and deafness
UniProtPrimary aldosteronism, seizures, and neurologic abnormalities
770
ClinVar variants
6
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— CACNA1D
🧬
Gene-Disease Validity (ClinGen)
sinoatrial node dysfunction and deafness · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

⚡
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
6 Pathogenic / Likely Pathogenic· 452 VUS of 770 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.
0.21LOEUF
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?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.
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?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.0.14 (0.10–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.60–0.67)
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.1.02
0≤1.21.6
LoF obs/exp: 17 / 119.1Missense obs/exp: 797 / 1253.5Syn Z: -0.28

ClinVar Variant Classifications

770 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2
Likely Pathogenic4
VUS452
Likely Benign305
Benign5
Conflicting2
2
Pathogenic
4
Likely Pathogenic
452
VUS
305
Likely Benign
5
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
2
0
2
Likely Pathogenic
1
3
0
0
4
VUS
16
393
33
10
452
Likely Benign
0
1
150
154
305
Benign
0
0
4
1
5
Conflicting
—2
Total17397189165770

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

View in ClinVar →

Protein Context — Lollipop Plot

CACNA1D · protein map & ClinVar variants

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

Gene2Phenotype Curations

CACNA1D-related sinoatrial node dysfunction and deafness

strong
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEar
G2P ↗

CACNA1D-related primary aldosteronism, seizures, and neurologic abnormalities

strong
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — CACNA1D
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
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
Autophagy in the physiological endometrium and cancer.
Devis-Jauregui L et al.·Autophagy
2021Review
Congenital hyperinsulinism: recent updates on molecular mechanisms, diagnosis and management.
Giri D et al.·J Pediatr Endocrinol Metab
2021Review
CACNA1D-Related Channelopathies: From Hypertension to Autism.
Ortner NJ·Handb Exp Pharmacol
2023Review
De novo CACNA1D Ca(2+) channelopathies: clinical phenotypes and molecular mechanism.
Ortner NJ et al.·Pflugers Arch
2020Review
The human channel gating-modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome-like phenotype in mice.
Ortner NJ et al.·JCI Insight
2023
Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer.
Liu ZX et al.·JAMA Netw Open
2022Cohort
Rare variants in neuronal excitability genes influence risk for bipolar disorder.
Ament SA et al.·Proc Natl Acad Sci U S A
2015
Genetics of primary hyperaldosteronism.
Dutta RK et al.·Endocr Relat Cancer
2016Review
Genomics of benign adrenocortical tumors.
Jouinot A et al.·J Steroid Biochem Mol Biol
2019Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Aberrant calcium signaling and neuronal activity in the L271H CACNA1D (Cav1.3) iPSC model of neurodevelopmental disease.
Tisch M et al.·Mol Psychiatry
2026Functional
The SWI/SNF chromatin-remodeling subunit DPF2 regulates macrophage inflammation in intestinal injury via the CACNA1D-mediated MAPK pathway.
Ji M et al.·Proc Natl Acad Sci U S A
2025Functional
Pharmacogenomic insights into amlodipine response: the role of CACNA1D, CACNA1C, and TRIB3 variants in hypertensive patients.
Babaresh WM et al.·PLoS One
2025🔓 Open AccessCohort
CACNA1D is a circadian gene and causes familial advanced sleep phase.
Webb JM et al.·Proc Natl Acad Sci U S A
2025🔓 Open Access
Polymorphisms in the calcium voltage-gated channel subunit Alpha1 D (CACNA1D) gene are associated with spontaneous preterm birth in Taiwanese women.
Chang TY et al.·J Formos Med Assoc
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Primary AldosteronismSecondary HypertensionAldosterone-Producing Adenoma

PETAL Trial: Impact of Gallium-68 Pentixafor PET-CT on Surgical Outcomes in Primary Aldosteronism

RECRUITING
NCT07027254Phase NASeoul National University HospitalStarted 2025-06-25
68Ga-pentixafor PET/CT
Primary Aldosteronism

Pathological Type，Gene Mutation and Clinical Characteristics of Unilateral Primary Aldosteronism

RECRUITING
NCT06597630Qifu LiStarted 2023-12-01
Tissue specimens were stained by histopathology of hematoxylin-eosin

External Resources

Links to major genomics databases and tools