Essential thrombocythemia: genes and variants

Genes linked to Essential thrombocythemia

• 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.

  8 disease-causing and 151 uncertain variants in MPL are linked to Essential thrombocythemia.

• IFNAR1: Interferon alpha/beta receptor 1

  Together with IFNAR2, it detects type I interferons and activates JAK-STAT antiviral and immunoregulatory programs. Loss-of-function can impair antiviral defense, while excessive pathway activation contributes to interferon-driven inflammatory disease.

  0 disease-causing and 0 uncertain variants in IFNAR1 are linked to Essential thrombocythemia.

• IFNAR2: Interferon alpha/beta receptor 2

  It provides the high-affinity ligand-binding component of the type I interferon receptor complex and triggers antiviral JAK-STAT signaling with IFNAR1. Biallelic loss-of-function variants can predispose to severe viral infections, including critical COVID-19 in some individuals.

  0 disease-causing and 0 uncertain variants in IFNAR2 are linked to Essential thrombocythemia.

• 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 0 uncertain variants in JAK2 are linked to Essential thrombocythemia.

• JAK3: Tyrosine-protein kinase JAK3

  It carries signals from cytokine receptors using the common gamma chain and is essential for T-cell and NK-cell development. Biallelic loss-of-function variants cause severe combined immunodeficiency, while activating somatic variants occur in selected leukemias and lymphomas.

  0 disease-causing and 0 uncertain variants in JAK3 are linked to Essential thrombocythemia.

Known disease-causing variants in Essential thrombocythemia

Which prediction tools work for Essential thrombocythemia

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

• MetaLR: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 90 out of 100
• PolyPhen-2: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Congenital amegakaryocytic thrombocytopenia is also caused by MPL variants; they fall partly in the same places as the Essential thrombocythemia variants (19 disease-causing).
• Thrombocythemia 2 is also caused by MPL variants; they fall in the same places as the Essential thrombocythemia variants (7 disease-causing).
• Primary myelofibrosis is also caused by MPL variants; they fall in the same places as the Essential thrombocythemia variants (5 disease-causing).

Diseases related to Essential thrombocythemia

• Acquired polycythemia vera, also linked to IFNAR1, IFNAR2, JAK2 and JAK3
• Thrombocythemia 2, also linked to JAK2 and MPL
• Primary myelofibrosis, also linked to JAK2 and MPL
• Melanoma, also linked to IFNAR1 and IFNAR2
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, also linked to JAK3
• Severe combined immunodeficiency disease, also linked to JAK3
• Acute myeloid leukemia, also linked to JAK2
• T-B+ severe combined immunodeficiency due to JAK3 deficiency, also linked to JAK3
• Congenital amegakaryocytic thrombocytopenia, also linked to MPL
• Inflammatory bowel disease, also linked to JAK2
• Systemic lupus erythematosus, also linked to IFNAR1
• Primary familial polycythemia due to EPO receptor mutation, also linked to JAK2

Frequently asked questions

Which genes are linked to Essential thrombocythemia?

In CATVariant, Essential thrombocythemia is linked to 5 analyzed proteins: MPL (Thrombopoietin receptor), IFNAR1 (Interferon alpha/beta receptor 1), IFNAR2 (Interferon alpha/beta receptor 2), JAK2 (Tyrosine-protein kinase JAK2) and JAK3 (Tyrosine-protein kinase JAK3).

How many genetic variants are linked to Essential thrombocythemia?

219 variants: 8 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 151 are of uncertain significance or have conflicting reports.

Which uncertain variants in Essential thrombocythemia 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 Essential thrombocythemia?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.90, based on 8 disease-causing and 62 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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