Niemann-Pick disease: genes and variants
Explore variant evidence for Niemann-Pick disease across 2 analyzed proteins (NPC1, SMPD1). Linked ClinVar records include 315 pathogenic or likely pathogenic variants, 512 variants of uncertain significance and 128 with conflicting classifications.
Coverage includes proteins already analyzed in CATVariant, not every gene involved in this condition. Database links are associations, not an assessment of clinical gene–disease validity. Computable evidence prioritizes variants for expert review and does not reclassify them. Source labels are pooled across this disease family.
Data updated 2026-10-10. Automated aggregation, not a clinical review date.
Download variant evidence (CSV)
Genes linked to Niemann-Pick disease
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.
182 ClinVar pathogenic / likely pathogenic and 470 uncertain variants in NPC1 have source records linked to Niemann-Pick disease. Association strength is not clinical gene validity.
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.
133 ClinVar pathogenic / likely pathogenic and 170 uncertain variants in SMPD1 have source records linked to Niemann-Pick disease. Association strength is not clinical gene validity.
Where Niemann-Pick disease variants cluster
- NPC1 Lumenal (positions 854–1097): 57 of 182 ClinVar pathogenic / likely pathogenic variants, 1.6× more than its size predicts.
- NPC1 Transmembrane (positions 1151–1171): 10 of 182 ClinVar pathogenic / likely pathogenic variants, 3.3× more than its size predicts.
- NPC1 Transmembrane (positions 1195–1215): 8 of 182 ClinVar pathogenic / likely pathogenic variants, 2.7× more than its size predicts.
- NPC1 Transmembrane (positions 1125–1145): 6 of 182 ClinVar pathogenic / likely pathogenic variants, 2.0× more than its size predicts.
- NPC1 Cytoplasmic (positions 1172–1194): 6 of 182 ClinVar pathogenic / likely pathogenic variants, 1.8× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to Niemann-Pick disease
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| NPC1 C63R | 63 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 R404W | 404 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 P691L | 691 | SSD | Pathogenic / likely pathogenic (★★) |
| NPC1 P691Q | 691 | SSD | Pathogenic / likely pathogenic (★★) |
| NPC1 P691A | 691 | SSD | Pathogenic / likely pathogenic (★★) |
| NPC1 A764V | 764 | SSD | Pathogenic / likely pathogenic (★★) |
| NPC1 R789C | 789 | Cytoplasmic | Pathogenic / likely pathogenic (★★) |
| NPC1 F842L | 842 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| NPC1 S865L | 865 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 A926T | 926 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 A927V | 927 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 V950G | 950 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 R978C | 978 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 E1089K | 1089 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 M1142T | 1142 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| NPC1 N1156I | 1156 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| NPC1 C1168Y | 1168 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| NPC1 T1205R | 1205 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| NPC1 V1212L | 1212 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| NPC1 L1213V | 1213 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| SMPD1 L227P | 227 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 C228R | 228 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 R230C | 230 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 D280A | 280 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 G319R | 319 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 N385I | 385 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 N385S | 385 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 H423R | 423 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 H423Y | 423 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 F465S | 465 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 A484E | 484 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 S486R | 486 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 R498H | 498 | Pathogenic / likely pathogenic (★★) | |
| NPC1 C177Y | 177 | Important for cholesterol binding and cholestero | Pathogenic / likely pathogenic (★★) |
| NPC1 R404Q | 404 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 P474L | 474 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 P543L | 543 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 R615C | 615 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 R615H | 615 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 Y634C | 634 | SSD | Pathogenic / likely pathogenic (★★) |
| NPC1 Y634F | 634 | SSD | Pathogenic / likely pathogenic (★★) |
| NPC1 V664M | 664 | SSD | Pathogenic / likely pathogenic (★★) |
| NPC1 S734I | 734 | SSD | Pathogenic / likely pathogenic (★★) |
| NPC1 R789G | 789 | Cytoplasmic | Pathogenic / likely pathogenic (★★) |
| NPC1 A926V | 926 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 S940L | 940 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 D948N | 948 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 G992W | 992 | Lumenal | Pathogenic / likely pathogenic (★★) |
| NPC1 W1145R | 1145 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| NPC1 A1151T | 1151 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| NPC1 N1156S | 1156 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| NPC1 R1186H | 1186 | Cytoplasmic | Pathogenic / likely pathogenic (★★) |
| NPC1 T1205K | 1205 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| NPC1 V1212M | 1212 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| NPC1 L1213F | 1213 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| SMPD1 C159R | 159 | Saposin B-type | Pathogenic / likely pathogenic (★★) |
| SMPD1 G244R | 244 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 G247S | 247 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 D253H | 253 | Pathogenic / likely pathogenic (★★) | |
| SMPD1 H427R | 427 | Pathogenic / likely pathogenic (★★) |
Showing 60 of 315.
Uncertain variants prioritized for review in Niemann-Pick disease
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| NPC1 C479Y | 479 | Lumenal | Conflicting reports (★) | +7: 2 other pathogenic changes within 3 positions; C479S at the same position is pathogenic; seen in 6.6e-06 of gnomAD DNA copies; REVEL 0.941 |
| NPC1 R389C | 389 | Lumenal | Conflicting reports (★) | +7: 2 other pathogenic changes within 3 positions; R389L at the same position is pathogenic; seen in 6.8e-06 of gnomAD DNA copies; REVEL 0.928 |
| SMPD1 H427L | 427 | Conflicting reports (★) | +7: 8 other pathogenic changes within 3 positions; H427N at the same position is pathogenic; seen in 6.8e-07 of gnomAD DNA copies; REVEL 0.971 | |
| NPC1 N1156T | 1156 | Transmembrane | Conflicting reports (★) | +7: 2 other pathogenic changes within 3 positions; N1156I at the same position is pathogenic; seen in 6.9e-07 of gnomAD DNA copies; REVEL 0.854 |
| NPC1 H512R | 512 | Lumenal | Conflicting reports (★) | +7: 2 other pathogenic changes within 3 positions; H512Y at the same position is pathogenic; seen in 6.6e-06 of gnomAD DNA copies; REVEL 0.838 |
| NPC1 G1012C | 1012 | Lumenal | Uncertain | +7: 2 other pathogenic changes within 3 positions; G1012D at the same position is pathogenic; seen in 6.8e-07 of gnomAD DNA copies; REVEL 0.890 |
| NPC1 P401S | 401 | Lumenal | Uncertain | +7: 3 other pathogenic changes within 3 positions; P401T at the same position is pathogenic; seen in 8.9e-06 of gnomAD DNA copies; REVEL 0.776 |
| SMPD1 L204F | 204 | Uncertain (★★) | +7: 3 other pathogenic changes within 3 positions; L204I at the same position is pathogenic; seen in 0 of gnomAD DNA copies; REVEL 0.786 | |
| NPC1 R789H | 789 | Cytoplasmic | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; R789C at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.87 |
| SMPD1 R378H | 378 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; R378C at the same position is pathogenic; REVEL 0.943 | |
| SMPD1 R378S | 378 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; R378C at the same position is pathogenic; REVEL 0.914 | |
| SMPD1 P477Q | 477 | Conflicting reports (★) | +6: 4 other pathogenic changes within 3 positions; P477L at the same position is pathogenic; REVEL 0.903 | |
| SMPD1 Y369C | 369 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; Y369H at the same position is pathogenic; REVEL 0.981 | |
| NPC1 T1036M | 1036 | Lumenal | Conflicting reports (★) | +6: 5 other pathogenic changes within 3 positions; T1036A at the same position is pathogenic; REVEL 0.874 |
| SMPD1 R476Q | 476 | Conflicting reports (★) | +6: 4 other pathogenic changes within 3 positions; R476W at the same position is pathogenic; REVEL 0.801 | |
| SMPD1 R230H | 230 | Conflicting reports (★) | +6: 6 other pathogenic changes within 3 positions; R230C at the same position is pathogenic; REVEL 0.892 | |
| SMPD1 P331L | 331 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; P331S at the same position is pathogenic; seen in 6.6e-06 of gnomAD DNA copies; REVEL 0.726 | |
| NPC1 S734T | 734 | SSD | Conflicting reports (★) | +6: 3 other pathogenic changes within 3 positions; S734I at the same position is pathogenic; seen in 2.7e-06 of gnomAD DNA copies; REVEL 0.652 |
| SMPD1 A454V | 454 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; A454D at the same position is pathogenic; seen in 1.4e-06 of gnomAD DNA copies; REVEL 0.706 | |
| NPC1 S652L | 652 | SSD | Uncertain (★) | +6: S652W at the same position is pathogenic; REVEL 0.937 |
| NPC1 P471S | 471 | Lumenal | Uncertain (★) | +6: 4 other pathogenic changes within 3 positions; P471L at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.72 |
| SMPD1 P331T | 331 | Uncertain | +6: 2 other pathogenic changes within 3 positions; P331S at the same position is pathogenic; seen in 6.6e-06 of gnomAD DNA copies; REVEL 0.769 | |
| NPC1 S1169I | 1169 | Transmembrane | Uncertain (★) | +6: 4 other pathogenic changes within 3 positions; S1169R at the same position is pathogenic; REVEL 0.815 |
| SMPD1 A454T | 454 | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; A454D at the same position is pathogenic; seen in 1.4e-06 of gnomAD DNA copies; REVEL 0.709 | |
| NPC1 M866I | 866 | Lumenal | Uncertain (★★) | +6: 4 other pathogenic changes within 3 positions; M866T at the same position is pathogenic; seen in 0 of gnomAD DNA copies; REVEL 0.688 |
| SMPD1 A453T | 453 | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; A453D at the same position is pathogenic; seen in 2e-06 of gnomAD DNA copies; REVEL 0.657 |
Which prediction tools work for Niemann-Pick disease
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- REVEL: 97 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: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 95 out of 100
- SIFT: 92 out of 100
- phyloP: 84 out of 100
Diseases related to Niemann-Pick disease
- Alzheimer disease, also linked to SMPD1
- Parkinson disease, also linked to SMPD1
Frequently asked questions
Which genes have records linked to Niemann-Pick disease?
This view contains 2 analyzed proteins: NPC1, SMPD1. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.
What do the clinical classifications mean?
Linked records include 315 pathogenic or likely pathogenic variants, 512 variants of uncertain significance and 128 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.
Does the evidence score change a VUS classification?
No. 26 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.
Can I download the variant evidence?
Download the CSV for all 1,053 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses 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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