CACNG2

Chr 22AD

calcium voltage-gated channel auxiliary subunit gamma 2

Also known as: MRD10

NCBI Gene: 10369ENSG00000166862UniProt: Q9Y698

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]

Primary Disease Associations & Inheritance

?Intellectual developmental disorder, autosomal dominant 10MIM #614256
AD
96
ClinVar variants
17
Pathogenic / LP
0.92
pLI score· haploinsufficient
1
Active trials
Clinical Summary— CACNG2
⚡
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.
📋
ClinVar Variants
17 Pathogenic / Likely Pathogenic· 64 VUS of 96 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.08 (0.03–0.38)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.51–0.68)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 1 / 12.6Missense obs/exp: 119 / 202.9Syn Z: -0.07

ClinVar Variant Classifications

96 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic1
VUS64
Likely Benign9
Benign1
16
Pathogenic
1
Likely Pathogenic
64
VUS
9
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
16
0
16
Likely Pathogenic
0
0
1
0
1
VUS
3
49
11
1
64
Likely Benign
0
0
2
7
9
Benign
0
0
0
1
1
Total34930991

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

View in ClinVar →

Protein Context — Lollipop Plot

CACNG2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Intellectual developmental disorder, autosomal dominant 10

MIM #614256

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
Docherty AR et al.·Am J Psychiatry
2023Meta-analysis
Rare variants in neuronal excitability genes influence risk for bipolar disorder.
Ament SA et al.·Proc Natl Acad Sci U S A
2015
From mouse to humans: discovery of the CACNG2 pain susceptibility gene.
Nissenbaum J·Clin Genet
2012Review
Exosomal circ-CACNG2 promotes cardiomyocyte apoptosis in multiple myeloma via modulating miR-197-3p/caspase3 axis.
Yu M et al.·Exp Cell Res
2022
CACNG2 polymorphisms associate with chronic pain after mastectomy.
Bortsov AV et al.·Pain
2019
Single gene defects in mice: the role of voltage-dependent calcium channels in absence models.
Burgess DL et al.·Epilepsy Res
1999Review
Genetic polymorphisms and prediction of chronic post-surgical pain after hysterectomy-a subgroup analysis of a multicenter cohort study.
Hoofwijk DMN et al.·Acta Anaesthesiol Scand
2019Cohort
A protein interaction based model for schizophrenia study.
Hsu PC et al.·BMC Bioinformatics
2008Functional
A bioinformatic analysis study of m(7)G regulator-mediated methylation modification patterns and tumor microenvironment infiltration in glioblastoma.
Wu X et al.·BMC Cancer
2022
Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.
Hamdan FF et al.·Am J Hum Genet
2011
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Breast CancerChronic PainAcute Pain

Evaluation And Risk Assessment For Persistent Postsurgical Pain After Breast Surgery

ACTIVE NOT RECRUITING
NCT03408717KK Women's and Children's HospitalStarted 2018-01-03
QuestionnairesMechanical Temporal Summation assessmentPain threshold assessment

External Resources

Links to major genomics databases and tools