CACNG2

Chr 22AD

calcium voltage-gated channel auxiliary subunit gamma 2

Also known as: MRD10

NCBI Gene: 10369 ENSG00000166862 UniProt: Q9Y698 OMIM: 602911

CACNG2 encodes a transmembrane AMPA receptor regulatory protein (TARP) that controls trafficking and gating properties of AMPA-selective glutamate receptors, which mediate fast excitatory neurotransmission and are crucial for synaptic plasticity, learning and memory. Mutations cause autosomal dominant intellectual developmental disorder. This gene is highly constrained against loss-of-function variants (pLI 0.92, LOEUF 0.38), suggesting intolerance to protein disruption.

OMIM ResearchSummary from RefSeq, OMIM, 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. The AMPA subtype of ionotropic glutamate receptors are ligand gated ion channels that are typically activated by glutamate released from presynaptic neuron terminals and mediate fast neurotransmission in excitatory synapses. TARPs thus play an important role in synaptic plasticity, learning and memory. Mutations in this gene cause an autosomal dominant form of cognitive disability. [provided by RefSeq, Jul 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.381 OMIM phenotype

Clinical Summary— CACNG2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

54 VUS of 69 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.38LOEUF

pLI 0.923

Z-score 3.03

OE 0.08 (0.03–0.38)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.09Z-score

OE missense 0.59 (0.51–0.68)

119 obs / 202.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.38)

0≤0.351.4

Missense OE?0.59 (0.51–0.68)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 1 / 12.6Missense obs/exp: 119 / 202.9Syn Z: -0.07

This gene — mechanism propensity

0.5771th %ile

GOF

0.6345th %ile

LOF

0.65top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.38

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

69 submitted variants in ClinVar

ClinVar

Classification Summary

VUS54

Likely Benign11

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	3	49	1	1	54
Likely Benign	0	1	3	7	11
Benign	0	0	0	1	1
Total	3	50	4	9	66

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap CACNG2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →