Niemann-Pick disease, type A: genes and variants

Genes linked to Niemann-Pick disease, type A

• SMPD1: Sphingomyelin phosphodiesterase

  It hydrolyzes sphingomyelin to ceramide in lysosomes and participates in membrane-lipid turnover and stress signaling. Biallelic loss-of-function variants cause acid sphingomyelinase deficiency, including Niemann-Pick disease types A and B.

  129 disease-causing and 157 uncertain variants in SMPD1 are linked to Niemann-Pick disease, type A.

• NPC1: NPC intracellular cholesterol transporter 1

  It moves cholesterol and other lipids out of late endosomes and lysosomes so they can be redistributed throughout the cell. Biallelic loss-of-function variants cause Niemann-Pick disease type C with progressive neurologic and visceral lipid-storage disease.

  1 disease-causing and 1 uncertain variants in NPC1 are linked to Niemann-Pick disease, type A.

Known disease-causing variants in Niemann-Pick disease, type A

Showing 60 of 130.

Uncertain variants in Niemann-Pick disease, type A that look disease-causing

Which prediction tools work for Niemann-Pick disease, type A

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)
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 94 out of 100
• SIFT: 91 out of 100
• phyloP: 86 out of 100

Same protein, different disease

• Niemann-Pick disease, type C1 is also caused by NPC1 variants; they fall mostly in different places as the Niemann-Pick disease, type A variants (175 disease-causing).
• Niemann-Pick disease, type C is also caused by NPC1 variants; they fall mostly in different places as the Niemann-Pick disease, type A variants (60 disease-causing).

Diseases related to Niemann-Pick disease, type A

• Sphingomyelin/cholesterol lipidosis, also linked to NPC1 and SMPD1
• Niemann-Pick disease, type C1, also linked to NPC1
• Alzheimer disease, also linked to SMPD1
• Niemann-Pick disease, type B, also linked to SMPD1
• Niemann-Pick disease, type C, also linked to NPC1
• Dystonic disorder, also linked to NPC1
• Parkinson disease, also linked to SMPD1

Frequently asked questions

Which genes are linked to Niemann-Pick disease, type A?

In CATVariant, Niemann-Pick disease, type A is linked to 2 analyzed proteins: SMPD1 (Sphingomyelin phosphodiesterase) and NPC1 (NPC intracellular cholesterol transporter 1).

How many genetic variants are linked to Niemann-Pick disease, type A?

321 variants: 130 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 158 are of uncertain significance or have conflicting reports.

Which uncertain variants in Niemann-Pick disease, type A look disease-causing?

13 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SMPD1 H427L, SMPD1 L204F, SMPD1 R378H, SMPD1 R378S and SMPD1 P477Q. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Niemann-Pick disease, type A?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 71 disease-causing and 30 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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