Menkes kinky-hair syndrome: genes and variants

Genes linked to Menkes kinky-hair syndrome

• ATP7A: Copper-transporting ATPase 1

  It delivers copper to secretory-pathway enzymes and exports excess copper from cells, making it essential for systemic copper distribution. Loss-of-function variants cause Menkes disease or occipital horn syndrome, while some hypomorphic alleles produce distal motor neuropathy.

  29 disease-causing and 564 uncertain variants in ATP7A are linked to Menkes kinky-hair syndrome.

Where Menkes kinky-hair syndrome variants cluster

• ATP7A Cytoplasmic (positions 1012–1356): 14 of 29 disease-causing changes, 2.1× more than its size predicts.
• ATP7A Transmembrane (positions 1386–1405): 3 of 29 disease-causing changes, 7.8× more than its size predicts.

Known disease-causing variants in Menkes kinky-hair syndrome

Which prediction tools work for Menkes kinky-hair syndrome

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

• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 94 out of 100
• AlphaMissense: 94 out of 100
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 84 out of 100

Same protein, different disease

• X-linked distal spinal muscular atrophy type 3 is also caused by ATP7A variants; they fall mostly in different places as the Menkes kinky-hair syndrome variants (6 disease-causing).

Diseases related to Menkes kinky-hair syndrome

• Ehlers-Danlos syndrome, also linked to ATP7A
• Cutis laxa, also linked to ATP7A
• X-linked distal spinal muscular atrophy type 3, also linked to ATP7A

Frequently asked questions

Which genes are linked to Menkes kinky-hair syndrome?

In CATVariant, Menkes kinky-hair syndrome is linked to 1 analyzed protein: ATP7A (Copper-transporting ATPase 1).

How many genetic variants are linked to Menkes kinky-hair syndrome?

779 variants: 29 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 564 are of uncertain significance or have conflicting reports.

Which uncertain variants in Menkes kinky-hair syndrome 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 Menkes kinky-hair syndrome?

Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 25 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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