GRK6

Chr 5

G protein-coupled receptor kinase 6

Also known as: GPRK6

NCBI Gene: 2870 ENSG00000198055 UniProt: P43250 OMIM: 600869

The protein phosphorylates activated G protein-coupled receptors to initiate their desensitization and internalization, with particular involvement in dopamine receptor regulation in the striatum and chemokine receptor signaling. Mutations cause autosomal recessive dystonia-26 with early childhood onset, characterized by progressive movement disorders affecting the limbs and sometimes involving additional neurological features. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is poorly tolerated.

OMIM 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 their deactivation. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.57

Clinical Summary— GRK6

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

56 VUS of 76 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.57LOEUF

pLI 0.000

Z-score 3.50

OE 0.35 (0.23–0.57)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.81Z-score

OE missense 0.60 (0.54–0.67)

234 obs / 390.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.35 (0.23–0.57)

0≤0.351.4

Missense OE?0.60 (0.54–0.67)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 12 / 34.1Missense obs/exp: 234 / 390.2Syn Z: 0.17

This gene — mechanism propensity

0.5772th %ile

GOF

0.6736th %ile

LOF

0.3843th %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

76 submitted variants in ClinVar

ClinVar

Classification Summary

VUS56

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	56	0	56
Likely Benign	3	1	4
Benign	0	0	0
Total	59	1	60

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

View in ClinVar →

57 pathogenic / likely-pathogenic (of 69) ClinVar copy-number / structural variants overlap GRK6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →