CACNG1

Chr 17

calcium voltage-gated channel auxiliary subunit gamma 1

Also known as: CACNLG

NCBI Gene: 786 ENSG00000108878 UniProt: Q06432 OMIM: 114209

The gamma-1 subunit regulates voltage-gated calcium channels that produce L-type calcium currents in skeletal muscle and controls channel inactivation kinetics during excitation-contraction coupling. Mutations cause congenital myasthenic syndrome with autosomal recessive inheritance. This gene is extremely tolerant to loss-of-function variants, indicating that pathogenic mutations likely affect protein function through other mechanisms.

OMIM ResearchSummary from RefSeq, UniProt

Voltage-dependent calcium channels are composed of five subunits. The protein encoded by this gene represents one of these subunits, gamma, and is one of two known gamma subunit proteins. This particular gamma subunit is part of skeletal muscle 1,4-dihydropyridine-sensitive calcium channels and is an integral membrane protein that plays a role in excitation-contraction coupling. This gene is part of a functionally diverse eight-member protein subfamily of the PMP-22/EMP/MP20 family and is located in a cluster with two family members that function as transmembrane AMPA receptor regulatory proteins (TARPs). [provided by RefSeq, Dec 2010]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.82

Clinical Summary— CACNG1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

40 VUS of 46 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.82LOEUF

pLI 0.000

Z-score -0.54

OE 1.19 (0.74–1.82)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.32Z-score

OE missense 0.93 (0.81–1.07)

141 obs / 152.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.19 (0.74–1.82)

0≤0.351.4

Missense OE?0.93 (0.81–1.07)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 11 / 9.2Missense obs/exp: 141 / 152.2Syn Z: -0.22

This gene — mechanism propensity

0.5674th %ile

GOF

0.6932th %ile

LOF

0.3454th %ile

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

GOFprediction above median

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.

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

ClinVar Variant Classifications

46 submitted variants in ClinVar

ClinVar

Classification Summary

VUS40

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	40	40
Likely Benign	2	2
Benign	0	0
Total	42	42

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap CACNG1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →