GRK4

protein-coding

G protein-coupled receptor kinase 4, the group of AGC family kinases

Gene summary

This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates the activated forms of G protein-coupled receptors thus initiating its deactivation. This gene has been linked to both genetic and acquired hypertension. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

Previous symbols:

GPRK2L

MANE transcript

NM_182982.3

Inheritance

—

ClinVar variants

U:98B:7

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr4:2,963,571-3,040,760

External References & Databases

Ensembl (ENSG00000125388)

Transcript & Mutation Effects

hg38 • Region Span ~77.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRK4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 93

not providedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182982.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	2 clinvar	1 clinvar	4
missense			96 clinvar	3 clinvar		99
nonsense					1 clinvar	1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	98	5	2	105

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_182982.3	RefSeq	NP_892027.2	16	MANE Select
ENST00000398052.9	Ensembl	ENSP00000381129.4	16	MANE Select
NM_001004056.2	RefSeq	NP_001004056.1	15	Standard
NM_001004057.2	RefSeq	NP_001004057.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
Chemokine signaling pathway - Homo sapiens (human)
Morphine addiction - Homo sapiens (human)
Myometrial Relaxation and Contraction Pathways
Chemokine signaling pathway

Biological Process

G protein-coupled receptor internalization
protein phosphorylation
signal transduction
regulation of G protein-coupled receptor signaling pathway
regulation of rhodopsin mediated signaling pathway

Molecular Function

G protein-coupled receptor kinase activity
ATP binding
rhodopsin kinase activity

Cellular Component

cytosol
cell cortex
dendrite
neuronal cell body
photoreceptor disc membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000398052
Coding exons: 16
Length: 77140
Individuals with no LoFs: 125573
Homozygous LoFs: 2
Heterozygous LoFs: 173
Defined: 125748
p: 0.000696

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.580	344	315	1.09	0.0000160	3796
Missense (PolyPhen)		132	125.05	1.0556		1518
Synonymous	-0.861	132	120	1.10	0.00000674	1016
Loss of Function	1.15	27	34.3	0.788	0.00000160	439

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00077	0.00075	rare
Ashkenazi Jewish	0.0045	0.0044	notable
East Asian	0.00038	0.00038	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00038	0.00038	rare
South Asian	0.0015	0.0014	notable
Other	0.0013	0.0013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Specifically phosphorylates the activated forms of G protein-coupled receptors. GRK4-alpha can phosphorylate rhodopsin and its activity is inhibited by calmodulin; the other three isoforms do not phosphorylate rhodopsin and do not interact with calmodulin. GRK4-alpha and GRK4-gamma phosphorylate DRD3. Phosphorylates ADRB2. {ECO:0000269|PubMed:19520868, ECO:0000269|PubMed:8626439}.;

Intolerance Scores

LoFtool: 0.965
RVIS EVS: 0.6
RVIS percentile EVS: 82.87

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.970

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High