CNR1

Chr 6

cannabinoid receptor 1

Also known as: CANN6, CB-R, CB1, CB1A, CB1K5, CB1R, CNR

NCBI Gene: 1268 ENSG00000118432 UniProt: P21554 OMIM: 114610

The protein is a G-protein coupled receptor for endogenous cannabinoids that regulates neurotransmission, energy metabolism, and inflammatory responses throughout the central nervous system and peripheral tissues. Mutations cause early-onset epileptic encephalopathy and neurodevelopmental disorders with seizures, developmental delay, and movement abnormalities. The gene shows autosomal recessive inheritance and demonstrates significant constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes one of two cannabinoid receptors. The cannabinoids, principally delta-9-tetrahydrocannabinol and synthetic analogs, are psychoactive ingredients of marijuana. The cannabinoid receptors are members of the guanine-nucleotide-binding protein (G-protein) coupled receptor family, which inhibit adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. The two receptors have been found to be involved in the cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana. Multiple transcript variants encoding two different protein isoforms have been described for this gene. [provided by RefSeq, May 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.60

Clinical Summary— CNR1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.51) — some intolerance to loss-of-function variants.

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.60LOEUF

pLI 0.507

Z-score 2.42

OE 0.19 (0.08–0.60)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

2.62Z-score

OE missense 0.57 (0.50–0.65)

165 obs / 290.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.08–0.60)

0≤0.351.4

Missense OE?0.57 (0.50–0.65)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 2 / 10.5Missense obs/exp: 165 / 290.7Syn Z: -0.43

This gene — mechanism propensity

0.6743th %ile

GOF

0.80top 10%

LOF

0.4234th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). 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

DNprediction 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.