GRK2

Chr 11

G protein-coupled receptor kinase 2

Also known as: ADRBK1, BARK1, BETA-ARK1

NCBI Gene: 156 ENSG00000173020 UniProt: P25098

This gene encodes G protein-coupled receptor kinase 2, which phosphorylates beta-adrenergic receptors and other G protein-coupled receptors to regulate their desensitization and is critical for normal heart function and embryonic development. The gene is highly constrained against loss-of-function variants (pLI=1.0, LOEUF=0.18), but no established Mendelian disease has been definitively associated with GRK2 mutations in humans. Elevated expression has been observed in patients with heart failure and Alzheimer's disease, though causality remains unclear.

ResearchSummary from RefSeq, UniProt

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]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

107

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

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Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.07 (0.03–0.18)

0≤0.351.4

Missense OE?0.57 (0.51–0.63)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 3 / 43.7Missense obs/exp: 254 / 445.0Syn Z: -1.03

Background carrier burden — how many people carry a rare variant somewhere in GRK2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

742 rare PASS variants

Rare truncating (LoF)

1 in 1,200

69 rare PASS variants

Rare synonymous (reference)

1 in 120

470 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GRK2. 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 170	1 in 950
South Asian	~43k	1 in 110	1 in 4,400
Remaining (unassigned)	~30k	1 in 120	1 in 1,100
European (Finnish)	~27k	1 in 290	1 in 1,800
Admixed American	~22k	1 in 140	1 in 1,400
African / African American	~21k	1 in 94	≈ 1 in 4,400
East Asian	~20k	1 in 97	1 in 1,600
Ashkenazi Jewish	~13k	1 in 730	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 120	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 20 of 21 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: 20 of 21 (exon 1 below).? see exons ↓