GRK4

Chr 4

G protein-coupled receptor kinase 4

Also known as: GPRK2L, GPRK4, GRK4a, IT11

NCBI Gene: 2868ENSG00000125388UniProt: P32298

This protein phosphorylates activated G protein-coupled receptors to initiate their deactivation, with different isoforms showing specificity for various receptors including rhodopsin, dopamine D3 receptors, and beta-2 adrenergic receptors. The gene is extremely intolerant to loss-of-function variants, but no Mendelian pediatric neurological disorders have been established from GRK4 mutations. Variants in this gene have been associated with hypertension in population studies.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
12
Pubs (1 yr)
127
P/LP submissions
0%
P/LP missense
1.09
LOEUF
GOF
Mechanism· predicted
Clinical Summary— GRK4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
127 unique Pathogenic / Likely Pathogenic· 105 VUS of 263 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.09LOEUF
pLI 0.000
Z-score 1.15
OE 0.79 (0.58–1.09)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.58Z-score
OE missense 1.09 (1.00–1.19)
344 obs / 315.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.79 (0.58–1.09)
0≤0.351.4
Missense OE1.09 (1.00–1.19)
0≤0.61.4
Synonymous OE1.10
0≤1.21.6
LoF obs/exp: 27 / 34.3Missense obs/exp: 344 / 315.0Syn Z: -0.86
DN
0.5968th %ile
GOF
0.6832th %ile
LOF
0.4038th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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

263 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic122
Likely Pathogenic5
VUS105
Likely Benign5
Benign2
122
Pathogenic
5
Likely Pathogenic
105
VUS
5
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
122
0
122
Likely Pathogenic
0
0
5
0
5
VUS
0
89
16
0
105
Likely Benign
0
3
0
2
5
Benign
0
0
1
1
2
Total0921443239

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

View in ClinVar →

Protein Context — Lollipop Plot

GRK4 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta-Blocker Therapy.
Duarte JD et al.·Clin Pharmacol Ther
2024Guideline
The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction.
Li L et al.·Eur Heart J
2021
A cross-tissue transcriptome-wide association study reveals GRK4 as a novel susceptibility gene for COPD.
Chen G et al.·Sci Rep
2024
Inhibition of GRK4 reduces arrhythmia susceptibility and alleviates connexin43 dysregulation after myocardial infarction.
Yu J et al.·Biochem Pharmacol
2025
The importance of G protein-coupled receptor kinase 4 (GRK4) in pathogenesis of salt sensitivity, salt sensitive hypertension and response to antihypertensive treatment.
Rayner B et al.·Int J Mol Sci
2015Review
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients