Wilson disease: genes and variants

Genes linked to Wilson disease

• ATP7B: Copper-transporting ATPase 2

  A copper-transporting ATPase that moves excess copper out of cells and helps deliver it from liver cells into bile. Its trafficking between intracellular membranes is central to copper homeostasis, and ATP7B dysfunction causes Wilson disease.

  222 disease-causing and 992 uncertain variants in ATP7B are linked to Wilson disease.

Where Wilson disease variants cluster

• ATP7B Cytoplasmic (positions 995–1322): 107 of 222 disease-causing changes, 2.1× more than its size predicts.
• ATP7B Transmembrane (positions 765–785): 18 of 222 disease-causing changes, 5.7× more than its size predicts.
• ATP7B Transmembrane (positions 973–994): 10 of 222 disease-causing changes, 3.0× more than its size predicts.
• ATP7B Transmembrane (positions 698–717): 8 of 222 disease-causing changes, 2.6× more than its size predicts.
• ATP7B Transmembrane (positions 1352–1371): 6 of 222 disease-causing changes, 2.0× more than its size predicts.

Known disease-causing variants in Wilson disease

Showing 60 of 222.

Uncertain variants in Wilson disease that look disease-causing

Which prediction tools work for Wilson disease

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

• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 93 out of 100
• phyloP: 91 out of 100
• ESM1b (LLR): 91 out of 100
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 90 out of 100
• CATVariant: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 82 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 82 out of 100

Diseases related to Wilson disease

• Hearing loss, also linked to ATP7B
• Breast-ovarian cancer, familial, susceptibility to, 1, also linked to ATP7B

Frequently asked questions

Which genes are linked to Wilson disease?

In CATVariant, Wilson disease is linked to 1 analyzed protein: ATP7B (Copper-transporting ATPase 2).

How many genetic variants are linked to Wilson disease?

1,272 variants: 222 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 992 are of uncertain significance or have conflicting reports.

Which uncertain variants in Wilson disease look disease-causing?

40 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example ATP7B M1359I, ATP7B S744F, ATP7B P840T, ATP7B T894I and ATP7B A1074V. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Wilson disease?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 156 disease-causing and 17 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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