GRK3

Chr 22AD

G protein-coupled receptor kinase 3

Also known as: ADRBK2, BARK2

NCBI Gene: 157ENSG00000100077UniProt: P35626

The beta-adrenergic receptor kinase specifically phosphorylates the agonist-occupied form of the beta-adrenergic and related G protein-coupled receptors. Overall, the beta adrenergic receptor kinase 2 has 85% amino acid similarity with beta adrenergic receptor kinase 1, with the protein kinase catalytic domain having 95% similarity. These data suggest the existence of a family of receptor kinases which may serve broadly to regulate receptor function. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Myelokathexis, isolatedMIM #193670
AD
WHIM syndrome 1MIM #193670
AD
55
ClinVar variants
18
Pathogenic / LP
0.71
pLI score
0
Active trials
Clinical Summary— GRK3
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.71) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
18 Pathogenic / Likely Pathogenic· 9 VUS of 55 total submissions

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.
0.36LOEUF
pLI 0.711
Z-score 4.86
OE 0.21 (0.12–0.36)
Moderately constrained

More LoF-intolerant than ~75% 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.
2.63Z-score
OE missense 0.62 (0.56–0.69)
234 obs / 378.1 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.0.21 (0.12–0.36)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.62 (0.56–0.69)
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.0.82
0≤1.21.6
LoF obs/exp: 9 / 43.6Missense obs/exp: 234 / 378.1Syn Z: 1.60

ClinVar Variant Classifications

55 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic1
VUS9
Likely Benign7
Benign2
17
Pathogenic
1
Likely Pathogenic
9
VUS
7
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
17
0
17
Likely Pathogenic
0
0
1
0
1
VUS
0
4
5
0
9
Likely Benign
0
0
7
0
7
Benign
0
0
1
1
2
Total0431136

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

View in ClinVar →

Protein Context — Lollipop Plot

GRK3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

3 OMIM entries

OMIM
WHIM SYNDROME 1; WHIMS1
MIM #193670 · #

Myelokathexis, isolated

MIM #193670

Molecular basis of disorder known

Autosomal dominant

WHIM syndrome 1

MIM #193670

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
G Protein-Coupled Receptor Kinase 3 Exacerbates Diabetic Heart Injuries Through Direct Phosphorylation of Cannabinoid Receptor 2 in Humans and Mice.
Gao P et al.·Circulation
2025
GRK3 is a poor prognosticator and serves as a therapeutic target in advanced gastric adenocarcinoma.
Li Y et al.·J Exp Clin Cancer Res
2022
beta-Adrenoceptor and GRK3 expression in human lymphocytes is related to blood pressure and urinary albumin excretion.
Oliver E et al.·J Hypertens
2010
Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling.
Balabanian K et al.·J Clin Invest
2008Cohort
A novel GRK3-HDAC2 regulatory pathway is a key direct link between neuroendocrine differentiation and angiogenesis in prostate cancer progression.
Naderinezhad S et al.·Cancer Lett
2023
Promoter variant in the GRK3 gene associated with bipolar disorder alters gene expression.
Zhou X et al.·Biol Psychiatry
2008
Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy.
Hauger RL et al.·Neuropharmacology
2012Review
G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses.
Tarrant TK et al.·J Leukoc Biol
2013
Different expression of adrenoceptors and GRKs in the human myocardium depends on heart failure etiology and correlates to clinical variables.
Montó F et al.·Am J Physiol Heart Circ Physiol
2012
The role of G protein-coupled receptor kinases in GLP-1R β-arrestin recruitment and internalisation.
McNeill SM et al.·Biochem Pharmacol
2024
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