Primary myelofibrosis: genes and variants

Genes linked to Primary myelofibrosis

• 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.

  5 disease-causing and 3 uncertain variants in MPL are linked to Primary myelofibrosis.

• 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.

  0 disease-causing and 3 uncertain variants in JAK2 are linked to Primary myelofibrosis.

• ACVR1: Activin receptor type-1

  It transduces BMP-family signals that regulate bone formation and developmental patterning. Recurrent activating variants cause fibrodysplasia ossificans progressiva by making connective-tissue cells abnormally responsive to osteogenic signaling, and somatic variants also occur in diffuse midline glioma.

  0 disease-causing and 0 uncertain variants in ACVR1 are linked to Primary myelofibrosis.

• 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 Primary myelofibrosis.

• FLT3: Receptor-type tyrosine-protein kinase FLT3

  Its signaling supports survival and expansion of early hematopoietic progenitors. Internal tandem duplications and kinase-domain mutations produce constitutive activity in acute myeloid leukemia and are important prognostic markers and therapeutic targets.

  0 disease-causing and 0 uncertain variants in FLT3 are linked to Primary myelofibrosis.

• JAK1: Tyrosine-protein kinase JAK1

  It couples many cytokine receptors to STAT transcription factors and is essential for interferon, interleukin, and growth-factor signaling. Loss-of-function can cause immunodeficiency, whereas activating alterations contribute to inflammatory disease and some malignancies.

  0 disease-causing and 0 uncertain variants in JAK1 are linked to Primary myelofibrosis.

• 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 6 uncertain variants in SH2B3 are linked to Primary myelofibrosis.

Known disease-causing variants in Primary myelofibrosis

Same protein, different disease

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

Diseases related to Primary myelofibrosis

• Thrombocythemia 2, also linked to CALR, JAK2, MPL and SH2B3
• Hypothyroidism, also linked to FLT3, JAK1 and SH2B3
• Acquired polycythemia vera, also linked to FLT3, JAK1 and JAK2
• Acute myeloid leukemia, also linked to FLT3 and JAK2
• Essential thrombocythemia, also linked to JAK2 and MPL
• Primary familial polycythemia due to EPO receptor mutation, also linked to JAK2 and SH2B3
• Gastrointestinal stromal tumor, also linked to FLT3
• Congenital amegakaryocytic thrombocytopenia, also linked to MPL
• Multiple myeloma, also linked to FLT3
• Progressive myositis ossificans, also linked to ACVR1
• Type 1 diabetes mellitus, also linked to SH2B3
• Inflammatory bowel disease, also linked to JAK2

Frequently asked questions

Which genes are linked to Primary myelofibrosis?

In CATVariant, Primary myelofibrosis is linked to 7 analyzed proteins: MPL (Thrombopoietin receptor), JAK2 (Tyrosine-protein kinase JAK2), ACVR1 (Activin receptor type-1), CALR (Calreticulin), FLT3 (Receptor-type tyrosine-protein kinase FLT3), JAK1 (Tyrosine-protein kinase JAK1) and 1 more.

How many genetic variants are linked to Primary myelofibrosis?

29 variants: 5 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 12 are of uncertain significance or have conflicting reports.

Which uncertain variants in Primary myelofibrosis look disease-causing?

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

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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