CACNA1G

Chr 17AD

calcium voltage-gated channel subunit alpha1 G

Also known as: Ca(V)T.1, Cav3.1, NBR13, SCA42, SCA42ND

NCBI Gene: 8913 ENSG00000006283 UniProt: O43497 OMIM: 604065

This gene encodes the alpha-1G subunit of T-type voltage-gated calcium channels, which generate low-threshold calcium currents essential for neuronal pacemaking, oscillations, and burst firing patterns. Mutations cause spinocerebellar ataxia 42 through an autosomal dominant inheritance pattern, with early-onset variants associated with severe neurodevelopmental deficits. The gene is highly constrained against loss-of-function variants, and mutations can cause disease predominantly through gain-of-function mechanisms that likely disrupt normal neuronal calcium signaling.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Voltage-sensitive 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, gene expression, cell motility, cell division, and cell death. This gene encodes a T-type, low-voltage activated calcium channel. The T-type channels generate currents that are both transient, owing to fast inactivation, and tiny, owing to small conductance. T-type channels are thought to be involved in pacemaker activity, low-threshold calcium spikes, neuronal oscillations and resonance, and rebound burst firing. Many alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Sep 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.212 OMIM phenotypes

Clinical Summary— CACNA1G

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Gene-Disease Validity (ClinGen)

spinocerebellar ataxia type 42 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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ClinVar Variants

31 unique Pathogenic / Likely Pathogenic· 801 VUS of 1504 total submissions

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GeneReview available — CACNA1G

Authoritative clinical overview · Recommended first read

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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 7.95

OE 0.13 (0.09–0.21)

Highly constrained

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

Missense Constraint?

4.64Z-score

OE missense 0.66 (0.62–0.69)

963 obs / 1462.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.13 (0.09–0.21)

0≤0.351.4

Missense OE?0.66 (0.62–0.69)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 13 / 97.9Missense obs/exp: 963 / 1462.1Syn Z: 0.98

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCACNA1G-related developmental disorder with hypotonia, epilepsy, and cerebral/cerebellar atrophyLOFAD

limitedCACNA1G-related intellectual developmental disorderLOFAR

Mechanism Note (expert annotation)

GOF

Cav3.1 (T-type) alpha subunit. Monoallelic pathogenic variants cause GOF with shifted voltage dependence and increased window current. G2P classifies as LOF, but electrophysiology data demonstrate gain-of-function at the channel level.1

This gene — mechanism propensity

0.5575th %ile

GOF

0.76top 25%

LOF

0.55top 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 · 90% of P/LP are missense

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

GOFEarly-onset severe spinocerebellar ataxia 42 with neurodevelopmental deficits (SCA42ND, MIM#604065) is an ultrarare autosomal dominant syndrome related to de novo CACNA1G gain-of-function pathogenic variants.2

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

References

ClinVar Variant Classifications

1504 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic28

VUS801

Likely Benign457

Benign108

Conflicting90

Pathogenic

Likely Pathogenic

801

VUS

457

Likely Benign

108

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	3	25	0	0	28
VUS	47	702	35	17	801
Likely Benign	2	93	138	224	457
Benign	0	9	63	36	108
Conflicting	—				90
Total	52	832	236	277	1,487

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap CACNA1G — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →