CNR1

Chr 6

cannabinoid receptor 1

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

NCBI Gene: 1268 ENSG00000118432 UniProt: P21554

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]

Primary Disease Associations & Inheritance

UniProtObesity

ClinVar variants

Pathogenic / LP

0.51

pLI score

Active trials

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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ClinVar Variants

14 Pathogenic / Likely Pathogenic· 40 VUS of 64 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

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.

0.60LOEUF

pLI 0.507

Z-score 2.42

OE 0.19 (0.08–0.60)

Moderately constrained

Typical tolerance to LoF variation

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.

2.62Z-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?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.0.19 (0.08–0.60)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.50–0.65)

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.1.05

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	14	0	14
Likely Pathogenic	0	0	0	0
VUS	36	4	0	40
Likely Benign	0	0	9	9
Benign	0	0	1	1
Total	36	18	10	64

CNR1

Primary Disease Associations & Inheritance

Population Genetics & Constraint

ClinVar Variant Classifications

Classification Summary

Curated Variants Distribution

Protein Context — Lollipop Plot

OMIM — Genotype-Phenotype Relationships

Gene Overview

ClinGen Curation

Disease Associations

External Resources

Variant Interpretation

Population Databases

Gene Resources