GRK2

Chr 11

G protein-coupled receptor kinase 2

Also known as: ADRBK1, BARK1, BETA-ARK1

NCBI Gene: 156ENSG00000173020UniProt: P25098

This gene encodes a member of the G protein-coupled receptor kinase family of proteins. The encoded protein phosphorylates the beta-adrenergic receptor as well as a wide range of other substrates including non-GPCR cell surface receptors, and cytoskeletal, mitochondrial, and transcription factor proteins. Data from rodent models supports a role for this gene in embryonic development, heart function and metabolism. Elevated expression of this gene has been observed in human patients with heart failure and Alzheimer's disease. [provided by RefSeq, Sep 2017]

63
ClinVar variants
15
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— GRK2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
15 Pathogenic / Likely Pathogenic· 8 VUS of 63 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.18LOEUF
pLI 1.000
Z-score 5.70
OE 0.07 (0.03–0.18)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
3.22Z-score
OE missense 0.57 (0.51–0.63)
254 obs / 445.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.07 (0.03–0.18)
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 (0.51–0.63)
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.1.10
0≤1.21.6
LoF obs/exp: 3 / 43.7Missense obs/exp: 254 / 445.0Syn Z: -1.03

ClinVar Variant Classifications

63 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10
Likely Pathogenic5
VUS8
Likely Benign4
Benign2
10
Pathogenic
5
Likely Pathogenic
8
VUS
4
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
9
0
10
Likely Pathogenic
2
0
3
0
5
VUS
0
4
4
0
8
Likely Benign
0
1
1
2
4
Benign
0
0
0
2
2
Total2617429

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

View in ClinVar →

Protein Context — Lollipop Plot

GRK2 · 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
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity.
Motso A et al.·Cell
2025
GRK2 Orchestrates VSMC Phenotypic Modulation via DNMT1-Mediated DNA Methylation Reprogramming.
Kong CH et al.·Arterioscler Thromb Vasc Biol
2025
Targeting GRK2 and GRK5 for treating chronic degenerative diseases: Advances and future perspectives.
Zhang Y et al.·Eur J Med Chem
2022Review
GRK2-mediated phosphorylation and de-succinylation of PKM2 reduce macrophage glycolysis in rheumatoid arthritis.
Yang XZ et al.·Acta Pharmacol Sin
2025
G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases.
Li N et al.·Front Immunol
2022Review
Unveiling the Role of GRK2: From Immune Regulation to Cancer Therapeutics.
Gao X et al.·Mediators Inflamm
2025Review
The intersection of GRK2 and PGE2 in rheumatoid arthritis: a comprehensive update on pathophysiology and treatment.
Singh P et al.·Naunyn Schmiedebergs Arch Pharmacol
2025Review
Vinculin phosphorylation impairs vascular endothelial junctions promoting atherosclerosis.
Shih YT et al.·Eur Heart J
2023
Alteration of myocardial GRK2 produces a global metabolic phenotype.
Woodall BP et al.·JCI Insight
2019
A novel GPCR target in correlation with androgen deprivation therapy for prostate cancer drug discovery.
Tian JY et al.·Basic Clin Pharmacol Toxicol
2021Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Inhibition of GRK2 mitigates cisplatin-induced acute and chronic nephrotoxicity by targeting the NADPH oxidase 4/oxidative stress axis.
Duan F et al.·Br J Pharmacol
2026
Hepatic-vascular crosstalk via GRK2: fenofibrate improves endothelial function by restoring lipid metabolism and NO signaling in obese mice.
Taguchi K et al.·Front Physiol
2025🔓 Open Access
Paeoniflorin derivative ameliorates methotrexate resistance in treating rheumatoid arthritis through targeting GRK2-A2AAR axis.
Guo P et al.·Phytomedicine
2026
GRK2 and GRK5-The 2 critical kinases in cardiac pathophysiology.
Roy R et al.·Mol Pharmacol
2026
Activation of GPR81 protects against myocardial ischemia-reperfusion injury under aberrant glucose metabolism condition by modulating VILIP-1/GRK2/GLUT4 pathway.
Ma C et al.·Int J Biol Macromol
2025
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