OPRL1

Chr 20

opioid related nociceptin receptor 1

Also known as: KOR-3, KOR3, NOCIR, NOP, NOPr, OOR, OPRL, ORL1

NCBI Gene: 4987 ENSG00000125510 UniProt: P41146 OMIM: 602548

The protein is a G-protein coupled receptor that binds the neuropeptide nociceptin and modulates pain perception, locomotor activity, stress responses, and learning and memory through inhibition of adenylate cyclase and calcium channel activity. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.617), but no established human disease associations with OPRL1 mutations are currently documented in the provided data. This receptor system represents a potential therapeutic target for pain and neuropsychiatric conditions, though its role in pediatric neurogenetic disorders remains to be established.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the 7 transmembrane-spanning G protein-coupled receptor family, and functions as a receptor for the endogenous, opioid-related neuropeptide, nociceptin/orphanin FQ. This receptor-ligand system modulates a variety of biological functions and neurobehavior, including stress responses and anxiety behavior, learning and memory, locomotor activity, and inflammatory and immune responses. A promoter region between this gene and the 5'-adjacent RGS19 (regulator of G-protein signaling 19) gene on the opposite strand functions bi-directionally as a core-promoter for both genes, suggesting co-operative transcriptional regulation of these two functionally related genes. Alternatively spliced transcript variants have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Dec 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.62

Clinical Summary— OPRL1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.20) despite low pLI — interpret in context.

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ClinVar Variants

97 VUS of 107 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.62LOEUF

pLI 0.482

Z-score 2.38

OE 0.20 (0.08–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.41Z-score

OE missense 0.75 (0.66–0.84)

187 obs / 249.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.20 (0.08–0.62)

0≤0.351.4

Missense OE?0.75 (0.66–0.84)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 2 / 10.2Missense obs/exp: 187 / 249.9Syn Z: 0.01

This gene — mechanism propensity

0.7325th %ile

GOF

0.84top 5%

LOF

0.2969th %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.

ClinVar Variant Classifications

107 submitted variants in ClinVar

ClinVar

Classification Summary

VUS97

Likely Benign3

Benign3

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	97	0	97
Likely Benign	3	0	3
Benign	0	3	3
Total	100	3	103

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap OPRL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →