CACNG8

Chr 19

calcium voltage-gated channel auxiliary subunit gamma 8

NCBI Gene: 59283 ENSG00000142408 UniProt: Q8WXS5

The encoded protein is a transmembrane AMPA receptor regulatory protein (TARP) that regulates trafficking and gating properties of AMPA-selective glutamate receptors and modulates L-type calcium channel activity. Mutations cause early-onset epileptic encephalopathy with severe developmental delays and intellectual disability, following an autosomal recessive inheritance pattern. This gene is highly constrained against loss-of-function variants, indicating critical importance for normal neurodevelopment.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a type I transmembrane AMPA receptor regulatory protein (TARP). TARPs regulate both trafficking and channel gating of the AMPA receptors. 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, a type II TARP and a calcium channel gamma subunit. The mRNA for this gene is believed to initiate translation from a non-AUG (CUG) start codon. [provided by RefSeq, Dec 2010]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.29

LOEUF· LoF intol.

LOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.964

Z-score 2.98

OE 0.00 (0.00–0.29)

Highly constrained

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

Missense Constraint?

2.34Z-score

OE missense 0.50 (0.42–0.60)

89 obs / 176.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.29)

0≤0.351.4

Missense OE?0.50 (0.42–0.60)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 0 / 10.3Missense obs/exp: 89 / 176.3Syn Z: -0.05

Background carrier burden — how many people carry a rare variant somewhere in CACNG8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

509 rare PASS variants

Rare truncating (LoF)

1 in 2,300

42 rare PASS variants

Rare synonymous (reference)

1 in 220

353 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CACNG8. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 210	1 in 2,200
South Asian	~43k	1 in 120	1 in 2,900
Remaining (unassigned)	~30k	1 in 210	1 in 1,800
European (Finnish)	~27k	1 in 590	1 in 2,400
Admixed American	~22k	1 in 430	≈ 1 in 6,300
African / African American	~21k	1 in 110	1 in 3,700
East Asian	~20k	1 in 160	≈ 1 in 12,000
Ashkenazi Jewish	~13k	1 in 310	≈ 1 in 2,900
Middle Eastern	~2,884	1 in 170	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 3 of 4 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 4.? see exons ↓