CACNA1C

Chr 12AD

calcium voltage-gated channel subunit alpha1 C

Also known as: CACH2, CACN2, CACNA1C-IT2, CACNL1A1, CCHL1A1, CaV1.2, LQT8, NEDHLSS

NCBI Gene: 775ENSG00000151067UniProt: Q13936

This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

Primary Disease Associations & Inheritance

Brugada syndrome 3MIM #611875
AD
Long QT syndrome 8MIM #618447
AD
Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizuresMIM #620029
AD
Timothy syndromeMIM #601005
AD
666
ClinVar variants
20
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— CACNA1C
🧬
Gene-Disease Validity (ClinGen)
short QT syndrome · ADDisputed

Disputed — evidence questions this relationship

4 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
20 Pathogenic / Likely Pathogenic· 321 VUS of 666 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

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.
0.10LOEUF
pLI 1.000
Z-score 8.94
OE 0.05 (0.02–0.10)
Highly constrained

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

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.
6.47Z-score
OE missense 0.50 (0.46–0.53)
643 obs / 1298.7 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.05 (0.02–0.10)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.50 (0.46–0.53)
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.0.99
0≤1.21.6
LoF obs/exp: 5 / 102.7Missense obs/exp: 643 / 1298.7Syn Z: 0.11

ClinVar Variant Classifications

666 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic13
VUS321
Likely Benign318
Benign4
Conflicting3
7
Pathogenic
13
Likely Pathogenic
321
VUS
318
Likely Benign
4
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
2
4
0
7
Likely Pathogenic
2
9
2
0
13
VUS
8
274
32
7
321
Likely Benign
0
8
163
147
318
Benign
0
1
2
1
4
Conflicting
—3
Total11294203155666

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

View in ClinVar →

Protein Context — Lollipop Plot

CACNA1C · protein map & ClinVar variants

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

Gene2Phenotype Curations

CACNA1C-related short QT syndrome

disputed
ADUndeterminedUncertain
Cardiac
G2P ↗

CACNA1C-related Brugada syndrome

disputed
ADUndeterminedUncertain
Cardiac
G2P ↗

CACNA1C-related Timothy syndrome

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. DisordersCardiac
G2P ↗
missense variant

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Brugada syndrome 3

MIM #611875

Molecular basis of disorder known

Autosomal dominant

Long QT syndrome 8

MIM #618447

Molecular basis of disorder known

Autosomal dominant

Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

MIM #620029

Molecular basis of disorder known

Autosomal dominant

Timothy syndrome

MIM #601005

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — CACNA1C
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetics of bipolar disorder.
Craddock N et al.·Lancet
2013Review
Calcium channelopathies and intellectual disability: a systematic review.
Kessi M et al.·Orphanet J Rare Dis
2021Review
Antisense oligonucleotide therapeutic approach for Timothy syndrome.
Chen X et al.·Nature
2024
Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.
Rodan LH et al.·Genet Med
2021
An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.
Adler A et al.·Circulation
2020
Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
Cross-Disorder Group of the Psychiatric Genomics Consortium·Lancet
2013
Qi-Po-Sheng-Mai granule ameliorates Ach-CaCl(2) -induced atrial fibrillation by regulating calcium homeostasis in cardiomyocytes.
Shi S et al.·Phytomedicine
2023
Genetic Basis of Severe Childhood-Onset Cardiomyopathies.
Vasilescu C et al.·J Am Coll Cardiol
2018
Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory.
Lieve KV et al.·Genet Test Mol Biomarkers
2013Cohort
Timothy syndrome iPSC modeling.
Bekdash R et al.·Mol Cell Neurosci
2020Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Frequent Loss of CACNA1C Is Associated With Poor Prognosis in Non-Small Cell Lung Cancer.
Dasgupta S et al.·FASEB J
2026
Ergothioneine attenuates whole-abdominal irradiation-induced multi-organ injury via the gut-heart-brain axis by modulating calcium voltage-gated channel subunit alpha1 C (Cacna1c) expression.
Ding X et al.·Mol Biomed
2026🔓 Open Access
Generation of a homozygous and heterozygous iPSC line carrying a variant of uncertain significance in CACNA1C, associated with Brugada syndrome.
Vandendriessche B et al.·Stem Cell Res
2025
Severe Neurodevelopmental Disorder due to Klinefelter Syndrome and CACNA1C Variant: A Case Report.
El Kamel El Lebbi I et al.·Case Rep Pediatr
2025🔓 Open AccessCase report
CACNA1C is associated with auditory related fear enhancement in single prolonged stress male rats.
Ding J et al.·J Affect Disord
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
High-riskBipolar DisorderAtypical Depression

A Cohort Study of Disease Prediction Model for High-risk Population With Bipolar Disorder

RECRUITING
NCT07031661Shanghai Mental Health CenterStarted 2024-10-15
This was an observational study with no intervention.
Mediation of 5G Effects on Sleep

A Causal Role for Voltage-gated Cav1.2 Calcium Channels in Mediating 5G FR1 Effects on Sleep-associated Brain Health in Humans

RECRUITING
NCT06998368Phase NAHans-Peter LandoltStarted 2024-10-22
Nimodipine Capsules5G RF-EMF
Male Infertility

Efficacy Study of a Food Supplement With Myo-inositol, N-Acetyl-Cystein, Zinc and Vitamins on Sperm DNA Fragmentation

RECRUITING
NCT04959864Phase NAGYNOVStarted 2021-07-07
Isitol®Placebo

External Resources

Links to major genomics databases and tools