CACNA1I

Chr 22

calcium voltage-gated channel subunit alpha1 I

Also known as: Cav3.3, NEDSIS, ca(v)3.3

NCBI Gene: 8911ENSG00000100346UniProt: Q9P0X4

The protein forms the pore-forming alpha subunit of a low voltage-activated, T-type calcium channel that mediates calcium entry into excitable cells and supports pacemaking functions in neurons and calcium signaling in secretory cells. Mutations cause autosomal dominant neurodevelopmental disorder with speech impairment and with or without seizures. The gene is highly constrained against loss-of-function variants (pLI >0.99), indicating that heterozygous protein-disrupting variants are likely pathogenic.

ResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismLOEUF 0.20
Clinical Summary— CACNA1I
⚡
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
5 unique Pathogenic / Likely Pathogenic· 408 VUS of 500 total submissions
Explore recent and relevant literature in Research Assistant →
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
0.20LOEUF
pLI 1.000
Z-score 7.47
OE 0.12 (0.07–0.20)
Highly constrained

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

Missense Constraint
5.05Z-score
OE missense 0.59 (0.55–0.63)
712 obs / 1205.5 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios
LoF OE0.12 (0.07–0.20)
0≤0.351.4
Missense OE0.59 (0.55–0.63)
0≤0.61.4
Synonymous OE1.08
0≤1.21.6
LoF obs/exp: 10 / 83.8Missense obs/exp: 712 / 1205.5Syn Z: -1.48
DN
0.5869th %ile
GOF
0.79top 25%
LOF
0.52top 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
LOF20% of P/LP variants are LoF · LOEUF 0.20

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

GOFThus, our study implicates CACNA1I gain-of-function mutations in neurodevelopmental disorders, with a phenotypic spectrum ranging from borderline intellectual functioning to a severe neurodevelopmental disorder with epilepsy.PMID:33704440

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

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3
Likely Pathogenic2
VUS408
Likely Benign57
Benign14
Conflicting1
3
Pathogenic
2
Likely Pathogenic
408
VUS
57
Likely Benign
14
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
2
0
3
Likely Pathogenic
0
2
0
0
2
VUS
12
390
6
0
408
Likely Benign
0
16
5
36
57
Benign
0
7
1
6
14
Conflicting
—1
Total134151442485

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

View in ClinVar →

Protein Context — Lollipop Plot

CACNA1I · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 3 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients