JAK2
Chr 9ADSomaticJanus kinase 2
Also known as: JTK10
This gene encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signalling. The primary isoform of this protein has an N-terminal FERM domain that is required for erythropoietin receptor association, an SH2 domain that binds STAT transcription factors, a pseudokinase domain and a C-terminal tyrosine kinase domain. Cytokine binding induces autophosphorylation and activation of this kinase. This kinase then recruits and phosphorylates signal transducer and activator of transcription (STAT) proteins. Growth factors like TGF-beta 1 also induce phosphorylation and activation of this kinase and translocation of downstream STAT proteins to the nucleus where they influence gene transcription. Mutations in this gene are associated with numerous inflammatory diseases and malignancies. This gene is a downstream target of the pleiotropic cytokine IL6 that is produced by B cells, T cells, dendritic cells and macrophages to produce an immune response or inflammation. Disregulation of the IL6/JAK2/STAT3 signalling pathways produces increased cellular proliferation and myeloproliferative neoplasms of hematopoietic stem cells. A nonsynonymous mutation in the pseudokinase domain of this gene disrupts the domains inhibitory effect and results in constitutive tyrosine phosphorylation activity and hypersensitivity to cytokine signalling. This gene and the IL6/JAK2/STAT3 signalling pathway is a therapeutic target for the treatment of excessive inflammatory responses to viral infections. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Mild missense constraint
This gene — mechanism propensity
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
References
ClinVar Variant Classifications
382 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 0 | 0 | 0 |
Likely Pathogenic | 0 | 2 | 0 | 0 | 2 |
VUS | 8 | 212 | 18 | 3 | 241 |
Likely Benign | 1 | 4 | 42 | 65 | 112 |
Benign | 0 | 0 | 7 | 2 | 9 |
Conflicting | — | 1 | |||
| Total | 9 | 218 | 67 | 70 | 365 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →16 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap JAK2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →
Protein Context — Lollipop Plot
JAK2 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Ruxolitinib Maintenance Post-Hematopoietic Stem Cell Transplant T-Cell Lymphoma
RECRUITINGPrevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History
NOT YET RECRUITINGClonal Hematopoiesis in Giant Cell Arteritis
NOT YET RECRUITINGTasquinimod in Patients with Myelofibrosis Refractory to or Intolerant for JAK2 Inhibition
RECRUITINGCART123 Cells With or Without Ruxolitinib in Relapsed/Refractory Acute Myeloid Leukemia
RECRUITINGElotuzumab for the Treatment of JAK2-Mutated Myelofibrosis
ACTIVE NOT RECRUITINGRelevance of Peripheral Cells in the Pathophysiology of Chronic Myelomonocytic Leukemia (CMML)
RECRUITINGStandard Immunosuppressive Therapy Combined With Romiplostim N01 as First-line Treatment for Severe Aplastic Anemia
RECRUITINGAnalysis of Drug Resistance in Immune Checkpoint Inhibitors of Non-small Cell Lung Cancer
RECRUITINGEffects of Ketone Bodies on Insulin Sensitivity
RECRUITINGA Clinical Trial of TQ05105 Tablets Combined With TQB3617 Capsules in the Treatment of Myelofibrosis (MF)
RECRUITINGUnveiling the Germline Predisposition to Myeloproliferative Neoplasms
RECRUITINGExternal Resources
Links to major genomics databases and tools