Erythrocytosis, familial, 6: genes and variants

Genes linked to Erythrocytosis, familial, 6

• HBB: Hemoglobin subunit beta

  Beta-globin, one of the two major protein chains in adult hemoglobin. Hemoglobin uses these chains to transport oxygen from the lungs to tissues, and HBB variants are associated with sickle-cell disease and beta-thalassemia.

  31 disease-causing and 16 uncertain variants in HBB are linked to Erythrocytosis, familial, 6.

• HBA1: Hemoglobin subunit alpha

  It contributes alpha-globin chains that pair with beta-like globins to carry oxygen in red blood cells. Deletion or inactivation reduces alpha-globin production and causes alpha-thalassemia, with severity determined by the number and function of affected alpha-globin genes.

  16 disease-causing and 1 uncertain variants in HBA1 are linked to Erythrocytosis, familial, 6.

• EPAS1: Endothelial PAS domain-containing protein 1

  When stabilized by hypoxia, it activates hypoxia-responsive genes controlling erythropoiesis, angiogenesis, iron metabolism, and cellular adaptation to low oxygen. Activating variants can cause familial erythrocytosis, while somatic dysregulation is central to clear-cell renal carcinoma and some paragangliomas.

  5 disease-causing and 29 uncertain variants in EPAS1 are linked to Erythrocytosis, familial, 6.

Where Erythrocytosis, familial, 6 variants cluster

• EPAS1 NTAD (positions 496–542): 5 of 5 disease-causing changes, 18.5× more than its size predicts.

Known disease-causing variants in Erythrocytosis, familial, 6

Uncertain variants in Erythrocytosis, familial, 6 that look disease-causing

Which prediction tools work for Erythrocytosis, familial, 6

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

• REVEL: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 91 out of 100
• CATVariant: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100
• MetaLR: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 81 out of 100
• ESM1b (LLR): 68 out of 100
• phyloP: 62 out of 100

Same protein, different disease

• Beta thalassemia is also caused by HBB variants; they fall partly in the same places as the Erythrocytosis, familial, 6 variants (21 disease-causing).
• Beta-thalassemia HBB/LCRB is also caused by HBB variants; they fall in the same places as the Erythrocytosis, familial, 6 variants (18 disease-causing).
• Heinz body anemia is also caused by HBB variants; they fall in the same places as the Erythrocytosis, familial, 6 variants (12 disease-causing).
• Hemoglobinopathy is also caused by HBB variants; they fall partly in the same places as the Erythrocytosis, familial, 6 variants (12 disease-causing).
• Dominant beta-thalassemia is also caused by HBB variants; they fall partly in the same places as the Erythrocytosis, familial, 6 variants (11 disease-causing).
• Alpha Thalassemia is also caused by HBA1 variants; they fall in the same places as the Erythrocytosis, familial, 6 variants (10 disease-causing).

Diseases related to Erythrocytosis, familial, 6

• Heinz body anemia, also linked to HBA1 and HBB
• Alpha Thalassemia, also linked to HBA1 and HBB
• Malaria, also linked to HBB
• Beta thalassemia, also linked to HBB
• Atypical hemolytic-uremic syndrome, also linked to HBB
• Beta-thalassemia HBB/LCRB, also linked to HBB
• Hemoglobinopathy, also linked to HBB
• Dominant beta-thalassemia, also linked to HBB
• METHEMOGLOBINEMIA, BETA TYPE, also linked to HBB
• Hemoglobin H disease, also linked to HBA1
• Renal cell carcinoma, also linked to EPAS1
• Primary familial polycythemia due to EPO receptor mutation, also linked to HBA1

Frequently asked questions

Which genes are linked to Erythrocytosis, familial, 6?

In CATVariant, Erythrocytosis, familial, 6 is linked to 3 analyzed proteins: HBB (Hemoglobin subunit beta), HBA1 (Hemoglobin subunit alpha) and EPAS1 (Endothelial PAS domain-containing protein 1).

How many genetic variants are linked to Erythrocytosis, familial, 6?

120 variants: 52 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 46 are of uncertain significance or have conflicting reports.

Which uncertain variants in Erythrocytosis, familial, 6 look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example HBB D100E. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Erythrocytosis, familial, 6?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.91, based on 43 disease-causing and 28 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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