Hereditary spherocytosis: genes and variants

Genes linked to Hereditary spherocytosis

• SLC4A1: Band 3 anion transport protein

  In red blood cells it exchanges chloride and bicarbonate to support carbon-dioxide transport, while in renal intercalated cells it is required for acid-base regulation. Pathogenic variants can cause hereditary spherocytosis or distal renal tubular acidosis depending on the affected function.

  13 disease-causing and 82 uncertain variants in SLC4A1 are linked to Hereditary spherocytosis.

• SPTB: Spectrin beta chain, erythrocytic

  It contributes beta-spectrin to the red-blood-cell membrane skeleton, linking the lipid bilayer to actin and ankyrin complexes. Pathogenic variants can cause hereditary spherocytosis, elliptocytosis, or related congenital hemolytic anemia.

  7 disease-causing and 38 uncertain variants in SPTB are linked to Hereditary spherocytosis.

• SPTA1: Spectrin alpha chain, erythrocytic 1

  It forms the alpha-spectrin lattice underlying the red-blood-cell membrane and provides elasticity needed to survive repeated passage through the circulation. Pathogenic variants cause hereditary elliptocytosis, hereditary spherocytosis, or severe hereditary pyropoikilocytosis.

  2 disease-causing and 122 uncertain variants in SPTA1 are linked to Hereditary spherocytosis.

Where Hereditary spherocytosis variants cluster

• SPTB Spectrin 17 (positions 2013–2075): 3 of 7 disease-causing changes, 14.5× more than its size predicts.
• SLC4A1 (Microbial infection) 5ABC region (positions 720–761): 4 of 13 disease-causing changes, 6.7× more than its size predicts.
• SLC4A1 Transmembrane (positions 486–506): 3 of 13 disease-causing changes, 10.0× more than its size predicts.
• SPTB Actin-binding (positions 2–275): 4 of 7 disease-causing changes, 4.5× more than its size predicts.
• SLC4A1 Involved in anion transport (positions 559–630): 3 of 13 disease-causing changes, 2.9× more than its size predicts.

Known disease-causing variants in Hereditary spherocytosis

Which prediction tools work for Hereditary spherocytosis

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: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 89 out of 100
• SIFT: 88 out of 100
• CADD: 88 out of 100

Same protein, different disease

• Autosomal dominant distal renal tubular acidosis is also caused by SLC4A1 variants; they fall mostly in different places as the Hereditary spherocytosis variants (11 disease-causing).
• Cryohydrocytosis is also caused by SLC4A1 variants; they fall mostly in different places as the Hereditary spherocytosis variants (9 disease-causing).
• Elliptocytosis 2 is also caused by SPTB variants; they fall mostly in different places as the Hereditary spherocytosis variants (3 disease-causing).
• Elliptocytosis 2 is also caused by SPTA1 variants; they fall mostly in different places as the Hereditary spherocytosis variants (3 disease-causing).

Diseases related to Hereditary spherocytosis

• Elliptocytosis 2, also linked to SPTA1 and SPTB
• Pyropoikilocytosis, hereditary, also linked to SPTA1 and SPTB
• Hemolytic anemia, also linked to SLC4A1 and SPTB
• Renal tubulopathies, also linked to SLC4A1
• Autosomal dominant distal renal tubular acidosis, also linked to SLC4A1
• Cryohydrocytosis, also linked to SLC4A1
• Southeast Asian ovalocytosis, also linked to SLC4A1
• BLOOD GROUP, WALDNER, also linked to SLC4A1
• BLOOD GROUP--SWANN SYSTEM, also linked to SLC4A1
• Renal tubular acidosis, distal, 4, with hemolytic anemia, also linked to SLC4A1

Frequently asked questions

Which genes are linked to Hereditary spherocytosis?

In CATVariant, Hereditary spherocytosis is linked to 3 analyzed proteins: SLC4A1 (Band 3 anion transport protein), SPTB (Spectrin beta chain, erythrocytic) and SPTA1 (Spectrin alpha chain, erythrocytic 1).

How many genetic variants are linked to Hereditary spherocytosis?

366 variants: 22 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 242 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hereditary spherocytosis 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 Hereditary spherocytosis?

Among tools not trained on clinical labels, phyloP separates this disease's known disease-causing variants from harmless ones best (AUROC 0.89, based on 12 disease-causing and 73 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.

Download every variant as CSV · Browse all diseases · Methods · About the Center