Thrombocythemia 2: genes and variants

Genes linked to Thrombocythemia 2

• MPL: Thrombopoietin receptor

  Thrombopoietin signaling through this pathway drives megakaryocyte maturation, platelet production, and hematopoietic stem-cell maintenance. Activating variants can cause myeloproliferative neoplasms or hereditary thrombocytosis, whereas loss-of-function variants cause congenital amegakaryocytic thrombocytopenia.

  7 disease-causing and 4 uncertain variants in MPL are linked to Thrombocythemia 2.

• JAK2: Tyrosine-protein kinase JAK2

  It transmits signals from erythropoietin, thrombopoietin, growth hormone, and other cytokine receptors into STAT-dependent transcription. The V617F gain-of-function variant is a major driver of polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

  2 disease-causing and 13 uncertain variants in JAK2 are linked to Thrombocythemia 2.

• SH2B3: SH2B adapter protein 3

  It restrains cytokine and growth-factor signaling in hematopoietic cells, including JAK-STAT pathways controlling blood-cell production. Loss-of-function variants can increase blood-cell proliferation and predispose to myeloproliferative neoplasms, while common variants influence autoimmune and hematologic traits.

  0 disease-causing and 4 uncertain variants in SH2B3 are linked to Thrombocythemia 2.

• CALR: Calreticulin

  It assists glycoprotein folding and buffers calcium within the endoplasmic reticulum. Somatic frameshift variants create abnormal C termini that activate thrombopoietin-receptor signaling and are major drivers of essential thrombocythemia and primary myelofibrosis.

  0 disease-causing and 0 uncertain variants in CALR are linked to Thrombocythemia 2.

Known disease-causing variants in Thrombocythemia 2

Which prediction tools work for Thrombocythemia 2

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 89 out of 100
• phyloP: 84 out of 100
• CADD: 79 out of 100

Same protein, different disease

• Congenital amegakaryocytic thrombocytopenia is also caused by MPL variants; they fall mostly in different places as the Thrombocythemia 2 variants (19 disease-causing).
• Essential thrombocythemia is also caused by MPL variants; they fall partly in the same places as the Thrombocythemia 2 variants (8 disease-causing).

Diseases related to Thrombocythemia 2

• Primary myelofibrosis, also linked to CALR, JAK2, MPL and SH2B3
• Essential thrombocythemia, also linked to JAK2 and MPL
• Primary familial polycythemia due to EPO receptor mutation, also linked to JAK2 and SH2B3
• Acute myeloid leukemia, also linked to JAK2
• Congenital amegakaryocytic thrombocytopenia, also linked to MPL
• Type 1 diabetes mellitus, also linked to SH2B3
• Hypothyroidism, also linked to SH2B3
• Inflammatory bowel disease, also linked to JAK2
• Myocardial infarction, also linked to SH2B3
• Ischemic stroke, also linked to SH2B3
• Acquired polycythemia vera, also linked to JAK2

Frequently asked questions

Which genes are linked to Thrombocythemia 2?

In CATVariant, Thrombocythemia 2 is linked to 4 analyzed proteins: MPL (Thrombopoietin receptor), JAK2 (Tyrosine-protein kinase JAK2), SH2B3 (SH2B adapter protein 3) and CALR (Calreticulin).

How many genetic variants are linked to Thrombocythemia 2?

39 variants: 9 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 21 are of uncertain significance or have conflicting reports.

Which uncertain variants in Thrombocythemia 2 look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Thrombocythemia 2?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.89, based on 9 disease-causing and 45 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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