GRK4

Chr 4

G protein-coupled receptor kinase 4

Also known as: GPRK2L, GPRK4, GRK4a, IT11

NCBI Gene: 2868 ENSG00000125388 UniProt: 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.

ResearchSummary from RefSeq, UniProt

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]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.09

LOEUF

GOF

Mechanism· predicted

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?

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 OE?0.79 (0.58–1.09)

0≤0.351.4

Missense OE?1.09 (1.00–1.19)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 27 / 34.3Missense obs/exp: 344 / 315.0Syn Z: -0.86

Background carrier burden — how many people carry a rare variant somewhere in GRK4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 51

871 rare PASS variants

Rare truncating (LoF)

1 in 400

171 rare PASS variants

Rare synonymous (reference)

1 in 130

304 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GRK4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 82	1 in 510
South Asian	~43k	1 in 49	1 in 220
Remaining (unassigned)	~30k	1 in 47	1 in 290
European (Finnish)	~27k	1 in 300	1 in 2,400
Admixed American	~22k	1 in 57	1 in 240
African / African American	~21k	1 in 45	1 in 410
East Asian	~20k	1 in 57	1 in 550
Ashkenazi Jewish	~13k	1 in 190	1 in 1,200
Middle Eastern	~2,884	1 in 64	1 in 360

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 16 coding exons well covered in gnomAD exomes; exons 3, 4 marginal. Genomes: all 16.? see exons ↓