CACNA1I

Chr 22AD

calcium voltage-gated channel subunit alpha1 I

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

NCBI Gene: 8911 ENSG00000100346 UniProt: Q9P0X4 OMIM: 608230

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the pore-forming alpha subunit of a voltage gated calcium channel. The encoded protein is a member of a subfamily of calcium channels referred to as is a low voltage-activated, T-type, calcium channel. The channel encoded by this protein is characterized by a slower activation and inactivation compared to other T-type calcium channels. This protein may be involved in calcium signaling in neurons. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2011]

OMIM ResearchGenerating clinical summary…

GOFmechanismAD1 OMIM phenotype

Clinical Summary— CACNA1I

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 482 VUS of 601 total submissions

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Some data sources returned errors (1)

gnomad: TimeoutError: The operation was aborted due to timeout

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

This gene — mechanism propensity

0.5869th %ile

GOF

0.79top 25%

LOF

0.52top 25%

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median · 1 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

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.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 33704440 ↗

ClinVar Variant Classifications

601 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS482

Likely Benign69

Benign26

Conflicting2

Pathogenic

Likely Pathogenic

482

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	3	0	0	4
Likely Pathogenic	0	2	0	0	2
VUS	14	461	6	1	482
Likely Benign	0	20	5	44	69
Benign	0	8	2	16	26
Conflicting	—				2
Total	15	494	13	61	585

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap CACNA1I — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →