GAK

Chr 4

cyclin G associated kinase

Also known as: DNAJ26, DNAJC26

NCBI Gene: 2580 ENSG00000178950 UniProt: O14976 OMIM: 602052

GAK encodes a protein that associates with cyclin G and CDK5 and functions as an auxilin homolog involved in clathrin-coated vesicle uncoating and clathrin-mediated endocytosis. Mutations cause autosomal recessive early-onset parkinsonism with pyramidal signs and intellectual disability. The gene is highly constrained against loss-of-function variants (LOEUF 0.408), consistent with its role in fundamental cellular trafficking processes.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

In all eukaryotes, the cell cycle is governed by cyclin-dependent protein kinases (CDKs), whose activities are regulated by cyclins and CDK inhibitors in a diverse array of mechanisms that involve the control of phosphorylation and dephosphorylation of Ser, Thr or Tyr residues. Cyclins are molecules that possess a consensus domain called the 'cyclin box.' In mammalian cells, 9 cyclin species have been identified, and they are referred to as cyclins A through I. Cyclin G is a direct transcriptional target of the p53 tumor suppressor gene product and thus functions downstream of p53. GAK is an association partner of cyclin G and CDK5. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.41

Clinical Summary— GAK

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

230 VUS of 300 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GAK

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.005

Z-score 5.33

OE 0.27 (0.18–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.02Z-score

OE missense 1.00 (0.94–1.06)

816 obs / 817.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.27 (0.18–0.41)

0≤0.351.4

Missense OE?1.00 (0.94–1.06)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 17 / 62.5Missense obs/exp: 816 / 817.7Syn Z: -2.90

This gene — mechanism propensity

0.5770th %ile

GOF

0.6442th %ile

LOF

0.3551th %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

300 submitted variants in ClinVar

ClinVar

Classification Summary

VUS230

Likely Benign21

Benign9

230

VUS

Likely Benign

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	230	0	230
Likely Benign	12	9	21
Benign	5	4	9
Total	247	13	260

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

View in ClinVar →

148 pathogenic / likely-pathogenic (of 175) ClinVar copy-number / structural variants overlap GAK — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →