Pick disease: genes and variants

Genes linked to Pick disease

• PSEN1: Presenilin-1

  Its catalytic activity within gamma-secretase cleaves APP and many other membrane proteins, including Notch receptors. Pathogenic variants alter amyloid-beta production and are the most common known cause of autosomal dominant early-onset Alzheimer disease.

  26 disease-causing and 59 uncertain variants in PSEN1 are linked to Pick disease.

• MAPT: Microtubule-associated protein tau

  Its tau isoforms stabilize and organize neuronal microtubules, especially in axons, while also participating in transport and signaling. Pathogenic variants cause inherited frontotemporal dementia, and abnormal tau aggregation defines multiple neurodegenerative tauopathies.

  5 disease-causing and 6 uncertain variants in MAPT are linked to Pick disease.

Where Pick disease variants cluster

• PSEN1 Transmembrane (positions 249–272): 7 of 26 disease-causing changes, 5.2× more than its size predicts.
• PSEN1 Transmembrane (positions 83–103): 4 of 26 disease-causing changes, 3.4× more than its size predicts.
• MAPT Microtubule-binding domain (positions 561–685): 3 of 5 disease-causing changes, 3.6× more than its size predicts.
• PSEN1 Transmembrane (positions 133–153): 3 of 26 disease-causing changes, 2.6× more than its size predicts.

Known disease-causing variants in Pick disease

Which prediction tools work for Pick disease

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

• AlphaMissense: 97 out of 100
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 89 out of 100
• PolyPhen-2: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 72 out of 100

Same protein, different disease

• Alzheimer disease is also caused by PSEN1 variants; they fall partly in the same places as the Pick disease variants (88 disease-causing).
• Frontotemporal dementia is also caused by PSEN1 variants; they fall partly in the same places as the Pick disease variants (63 disease-causing).
• Acne inversa, familial, 3 is also caused by PSEN1 variants; they fall partly in the same places as the Pick disease variants (57 disease-causing).
• Frontotemporal dementia is also caused by MAPT variants; they fall mostly in different places as the Pick disease variants (17 disease-causing).
• Supranuclear palsy, progressive, 1 is also caused by MAPT variants; they fall partly in the same places as the Pick disease variants (6 disease-causing).

Diseases related to Pick disease

• Alzheimer disease, also linked to MAPT and PSEN1
• Frontotemporal dementia, also linked to MAPT and PSEN1
• Telangiectasia, hereditary hemorrhagic, type 2, also linked to PSEN1
• Dilated cardiomyopathy, also linked to PSEN1
• Acne inversa, familial, 3, also linked to PSEN1
• Parkinson disease, late-onset, also linked to MAPT
• Supranuclear palsy, progressive, 1, also linked to MAPT
• Familial isolated dilated cardiomyopathy, also linked to PSEN1
• Dementia, also linked to PSEN1
• Early-onset autosomal dominant Alzheimer disease, also linked to PSEN1
• Parkinson disease, also linked to MAPT

Frequently asked questions

Which genes are linked to Pick disease?

In CATVariant, Pick disease is linked to 2 analyzed proteins: PSEN1 (Presenilin-1) and MAPT (Microtubule-associated protein tau).

How many genetic variants are linked to Pick disease?

121 variants: 31 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 65 are of uncertain significance or have conflicting reports.

Which uncertain variants in Pick disease 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 Pick disease?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 25 disease-causing and 29 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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