HCRTR2

Chr 6

hypocretin receptor 2

Also known as: ORXR2, OX2R, OXR2

NCBI Gene: 3062ENSG00000137252UniProt: O43614

The protein encoded by this gene is a G-protein coupled receptor involved in the regulation of feeding behavior. The encoded protein binds the hypothalamic neuropeptides orexin A and orexin B. A related gene (HCRTR1) encodes a G-protein coupled receptor that selectively binds orexin A. [provided by RefSeq, Jan 2009]

68
ClinVar variants
9
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— HCRTR2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
9 Pathogenic / Likely Pathogenic· 48 VUS of 68 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.64LOEUF
pLI 0.005
Z-score 2.86
OE 0.35 (0.21–0.64)
Tolerant

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.
0.98Z-score
OE missense 0.83 (0.74–0.93)
210 obs / 254.1 exp
Tolerant

Mild missense constraint

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.0.35 (0.21–0.64)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.74–0.93)
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.1.23
0≤1.21.6
LoF obs/exp: 8 / 22.7Missense obs/exp: 210 / 254.1Syn Z: -1.74

ClinVar Variant Classifications

68 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic2
VUS48
Likely Benign6
Benign4
Conflicting1
7
Pathogenic
2
Likely Pathogenic
48
VUS
6
Likely Benign
4
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
7
0
7
Likely Pathogenic
0
0
2
0
2
VUS
0
44
4
0
48
Likely Benign
0
3
1
2
6
Benign
0
1
0
3
4
Conflicting
—1
Total04814568

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

View in ClinVar →

Protein Context — Lollipop Plot

HCRTR2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Combined genotype of HCRTR2 and CLOCK variants in a large family of cluster headache with familial periodicity phenotype.
Popescu C·J Neurol
2023
Is HCRTR2 a genetic risk factor for Alzheimer's disease?
Gallone S et al.·Dement Geriatr Cogn Disord
2014
Absence of mutations in HCRT, HCRTR1 and HCRTR2 in patients with ROHHAD.
Barclay SF et al.·Respir Physiol Neurobiol
2016Case report
International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology.
Gotter AL et al.·Pharmacol Rev
2012Review
Combined effects of HCRTR1/2 gene variants and non-genetic factors on sleep-wake transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia.
Zheng Z et al.·Pharmacol Rep
2025
How hypocretin agonists may improve the quality of wake in narcolepsy.
Justinussen JL et al.·Trends Mol Med
2023Review
Evaluation of clinical and genetic factors in obstructive sleep apnoea.
de Lourdes Rabelo Guimarães M et al.·Acta Otorhinolaryngol Ital
2023
Narcolepsy-cataplexy and schizophrenia in adolescents.
Huang YS et al.·Sleep Med
2014
Bioinformatic analysis of neuropeptide related genes in patients diagnosed with invasive breast carcinoma.
Yay F et al.·Comput Biol Med
2024Cohort
The 1246G-->A polymorphism of the HCRTR2 gene is not associated with migraine.
Pinessi L et al.·Cephalalgia
2007
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools