Niemann-Pick disease, type C2
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Also known as Niemann-Pick disease type C2NPC2type C2 Niemann-Pick disease
Summary
Niemann-Pick disease, type C2 (MONDO:0011873) is a disease caused by NPC2 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.
At a glance
- Causal gene: NPC2 (GenCC Definitive)
- Cohort genes: 3
- ClinVar variants: 265
- Clinical trials: 1
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | Niemann-Pick disease, type C2 |
| Mondo ID | MONDO:0011873 |
| MeSH | C536119 |
| OMIM | 607625 |
| DOID | DOID:0070114 |
| NCIT | C126865 |
| UMLS | C1843366 |
| MedGen | 335942 |
| GARD | 0003992 |
| Is cancer (heuristic) | no |
Also known as: Niemann-Pick disease type C2 · Niemann-Pick disease, type C2 · NPC2 · type C2 Niemann-Pick disease
Data availability: 265 ClinVar variants · 6 GenCC gene-disease records · 6 cell lines.
Disease family
Classification path: disease › human disease › disease by body system or component › immune system disorder › lymphoid system disorder › lymphatic system disorder › histiocytosis › non-Langerhans cell histiocytosis › Niemann-Pick disease › Niemann-Pick disease type C › Niemann-Pick disease, type C2
Related subtypes (6): Niemann-Pick disease, type C1, Niemann-Pick disease type C, severe perinatal form, Niemann-Pick disease type C, severe early infantile neurologic onset, Niemann-Pick disease type C, late infantile neurologic onset, Niemann-Pick disease type C, juvenile neurologic onset, Niemann-Pick disease type C, adult neurologic onset
Genetics & variants
GWAS landscape
No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.
Variant details and genetic-evidence tiers
ClinVar germline variants
265 retrieved; paginated sample, class counts are floors:
131 likely benign, 54 uncertain significance, 29 pathogenic, 28 likely pathogenic, 13 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 3 benign/likely benign, 1 benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1710501 | NM_000271.5(NPC1):c.2291C>A (p.Ala764Glu) | NPC1 | Pathogenic | criteria provided, single submitter |
| 1074431 | NC_000014.8:g.(?74959886)(74959987_?)del | NPC2 | Pathogenic | criteria provided, single submitter |
| 1075176 | NM_006432.5(NPC2):c.279dup (p.Lys94Ter) | NPC2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 132902 | NM_006432.5(NPC2):c.3G>C (p.Met1Ile) | NPC2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1455561 | NM_006432.5(NPC2):c.106G>T (p.Glu36Ter) | NPC2 | Pathogenic | criteria provided, single submitter |
| 1457423 | NM_006432.5(NPC2):c.281dup (p.Ser95fs) | NPC2 | Pathogenic | criteria provided, single submitter |
| 1459810 | NM_006432.5(NPC2):c.165C>G (p.Tyr55Ter) | NPC2 | Pathogenic | criteria provided, single submitter |
| 1921786 | NM_006432.5(NPC2):c.3G>T (p.Met1Ile) | NPC2 | Pathogenic | criteria provided, single submitter |
| 2088012 | NM_006432.5(NPC2):c.2T>G (p.Met1Arg) | NPC2 | Pathogenic | criteria provided, single submitter |
| 21455 | NM_006432.5(NPC2):c.133C>T (p.Gln45Ter) | NPC2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 21456 | NM_006432.5(NPC2):c.141C>A (p.Cys47Ter) | NPC2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 21457 | NM_006432.5(NPC2):c.27del (p.Leu10fs) | NPC2 | Pathogenic | no assertion criteria provided |
| 21458 | NM_006432.5(NPC2):c.295T>C (p.Cys99Arg) | NPC2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 21459 | NM_006432.5(NPC2):c.332del (p.Asn111fs) | NPC2 | Pathogenic | criteria provided, single submitter |
| 2425592 | NC_000014.8:g.(?74951108)(74953149_?)del | NPC2 | Pathogenic | criteria provided, single submitter |
| 2425593 | NC_000014.8:g.(?74946967)(74947492_?)del | NPC2 | Pathogenic | criteria provided, single submitter |
| 242903 | NM_006432.5(NPC2):c.82+2T>C | NPC2 | Pathogenic | no assertion criteria provided |
| 2708050 | NM_006432.5(NPC2):c.129del (p.Thr44fs) | NPC2 | Pathogenic | criteria provided, single submitter |
| 2766060 | NM_006432.5(NPC2):c.130_131del (p.Thr44fs) | NPC2 | Pathogenic | criteria provided, single submitter |
| 2846910 | NM_006432.5(NPC2):c.2T>A (p.Met1Lys) | NPC2 | Pathogenic | criteria provided, single submitter |
| 2982084 | NM_006432.5(NPC2):c.12_18del (p.Ala5fs) | NPC2 | Pathogenic | criteria provided, single submitter |
| 3242250 | NM_006432.5(NPC2):c.17_18insCAGGAAACGC (p.Thr7fs) | NPC2 | Pathogenic | no assertion criteria provided |
| 4087706 | NM_006432.5(NPC2):c.406C>T (p.Gln136Ter) | NPC2 | Pathogenic | criteria provided, single submitter |
| 553522 | NM_006432.5(NPC2):c.422G>A (p.Trp141Ter) | NPC2 | Pathogenic | criteria provided, single submitter |
| 557572 | NM_006432.5(NPC2):c.3G>A (p.Met1Ile) | NPC2 | Pathogenic | criteria provided, single submitter |
| 643285 | NM_006432.5(NPC2):c.79dup (p.Cys27fs) | NPC2 | Pathogenic | criteria provided, single submitter |
| 831251 | NC_000014.9:g.(?74480264)(74493284_?)del | NPC2 | Pathogenic | criteria provided, single submitter |
| 8477 | NM_006432.5(NPC2):c.58G>T (p.Glu20Ter) | NPC2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 8479 | NM_006432.5(NPC2):c.190+5G>A | NPC2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 8480 | NM_006432.5(NPC2):c.352G>T (p.Glu118Ter) | NPC2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 11 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
GenCC gene–disease validity (cohort genes)
the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.
| Gene | Classification | Inheritance | Disease | Records |
|---|---|---|---|---|
| NPC2 | Definitive | Autosomal recessive | Niemann-Pick disease, type C2 | 11 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| NPC2 | Orphanet:216972 | Niemann-Pick disease type C, severe perinatal form |
| NPC2 | Orphanet:216975 | Niemann-Pick disease type C, severe early infantile neurologic onset |
| NPC2 | Orphanet:216978 | Niemann-Pick disease type C, late infantile neurologic onset |
| NPC2 | Orphanet:216981 | Niemann-Pick disease type C, juvenile neurologic onset |
| NPC2 | Orphanet:216986 | Niemann-Pick disease type C, adult neurologic onset |
| NPC1 | Orphanet:216972 | Niemann-Pick disease type C, severe perinatal form |
| NPC1 | Orphanet:216975 | Niemann-Pick disease type C, severe early infantile neurologic onset |
| NPC1 | Orphanet:216978 | Niemann-Pick disease type C, late infantile neurologic onset |
| NPC1 | Orphanet:216981 | Niemann-Pick disease type C, juvenile neurologic onset |
| NPC1 | Orphanet:216986 | Niemann-Pick disease type C, adult neurologic onset |
Cohort genes → proteins
3 cohort genes, 3 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 3 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| NPC2 | HGNC:14537 | ENSG00000119655 | P61916 | NPC intracellular cholesterol transporter 2 | gencc,clinvar |
| ACYP1 | HGNC:179 | ENSG00000119640 | P07311 | Acylphosphatase-1 | clinvar |
| NPC1 | HGNC:7897 | ENSG00000141458 | O15118 | NPC intracellular cholesterol transporter 1 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| NPC2 | NPC intracellular cholesterol transporter 2 | Intracellular cholesterol transporter which acts in concert with NPC1 and plays an important role in the egress of cholesterol from the lysosomal compartment. |
| NPC1 | NPC intracellular cholesterol transporter 1 | Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment. |
Protein-family classification
Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33
Family distribution
Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.
| Family | Genes | Fold | FDR |
|---|---|---|---|
| Phosphatase | 1 | 28.0× | 0.071 |
| Other/Unknown | 2 | 1.2× | 0.587 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| NPC2 | Other/Unknown | no | ML_dom, Ig_E-set, ML_Npc2-like | |
| ACYP1 | Phosphatase | yes | Acylphosphatase-like_dom, Acylphosphatase_CS, Acylphosphatase | |
| NPC1 | Other/Unknown | no | SSD, NPC1-like, NPC1_N |
Expression context
Cohort genes with no expression data: 0.
3 cohort genes are a single-cell marker in ≥1 SCXA experiment.
Breadth distribution (Bgee present_calls)
| Bucket | Genes |
|---|---|
| narrow (1-5 tissues) | 0 |
| moderate (6-20) | 0 |
| broad (>20) | 3 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| cauda epididymis | 1 |
| corpus epididymis | 1 |
| epididymis | 1 |
| right lung | 1 |
| right uterine tube | 1 |
| ventricular zone | 1 |
| adrenal tissue | 1 |
| oocyte | 1 |
| secondary oocyte | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| NPC2 | 296 | ubiquitous | marker | corpus epididymis, cauda epididymis, epididymis |
| ACYP1 | 276 | ubiquitous | marker | right uterine tube, right lung, ventricular zone |
| NPC1 | 292 | ubiquitous | marker | secondary oocyte, oocyte, adrenal tissue |
Protein interactions among cohort
Intra-cohort edges: 1.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| NPC1 | 2,648 |
| NPC2 | 1,706 |
| ACYP1 | 627 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| NPC1 | NPC2 | intact, string_interaction |
Structural data
PDB: 3 · AlphaFold-only: 0 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| NPC1 | O15118 | 20 |
| ACYP1 | P07311 | 7 |
| NPC2 | P61916 | 2 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).
Pathways by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| LDL clearance | 2 | 543.8× | 6e-06 | NPC2, NPC1 |
| Neutrophil degranulation | 1 | 11.5× | 0.085 | NPC2 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| cholesterol storage | 2 | 1605.0× | 2e-05 | NPC2, NPC1 |
| intracellular cholesterol transport | 2 | 864.2× | 3e-05 | NPC2, NPC1 |
| cholesterol transport | 2 | 488.5× | 7e-05 | NPC2, NPC1 |
| cholesterol efflux | 2 | 351.1× | 1e-04 | NPC2, NPC1 |
| cholesterol metabolic process | 2 | 130.6× | 6e-04 | NPC2, NPC1 |
| cholesterol homeostasis | 2 | 104.0× | 7e-04 | NPC2, NPC1 |
| regulation of isoprenoid metabolic process | 1 | 5617.3× | 8e-04 | NPC2 |
| cyclodextrin metabolic process | 1 | 5617.3× | 8e-04 | NPC1 |
| intracellular lipid transport | 1 | 1872.4× | 0.002 | NPC1 |
| glycolipid transport | 1 | 1872.4× | 0.002 | NPC2 |
| gene expression | 2 | 53.2× | 0.002 | NPC2, NPC1 |
| membrane raft organization | 1 | 1123.5× | 0.003 | NPC1 |
| intracellular sterol transport | 1 | 1123.5× | 0.003 | NPC2 |
| sterol transport | 1 | 936.2× | 0.003 | NPC1 |
| establishment of protein localization to membrane | 1 | 624.1× | 0.004 | NPC1 |
| intestinal cholesterol absorption | 1 | 468.1× | 0.005 | NPC1 |
| programmed cell death | 1 | 432.1× | 0.005 | NPC1 |
| negative regulation of epithelial cell apoptotic process | 1 | 401.2× | 0.005 | NPC1 |
| negative regulation of macroautophagy | 1 | 374.5× | 0.005 | NPC1 |
| cellular response to steroid hormone stimulus | 1 | 351.1× | 0.005 | NPC1 |
| phosphate-containing compound metabolic process | 1 | 330.4× | 0.005 | ACYP1 |
| bile acid metabolic process | 1 | 330.4× | 0.005 | NPC1 |
| cellular response to low-density lipoprotein particle stimulus | 1 | 295.6× | 0.005 | NPC1 |
| response to cadmium ion | 1 | 244.2× | 0.006 | NPC1 |
| lysosomal transport | 1 | 234.1× | 0.006 | NPC1 |
| phospholipid transport | 1 | 234.1× | 0.006 | NPC2 |
| adult walking behavior | 1 | 165.2× | 0.008 | NPC1 |
| symbiont entry into host cell | 1 | 133.8× | 0.010 | NPC1 |
| glycoprotein biosynthetic process | 1 | 112.3× | 0.011 | NPC1 |
| negative regulation of TORC1 signaling | 1 | 108.0× | 0.011 | NPC1 |
Therapeutics
Drug target analysis
Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2
Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Genes with an approved drug
The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.
| Symbol | Example approved molecule |
|---|---|
| NPC1 | NABUMETONE |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| NPC1 | 90 | 4 |
| NPC2 | 0 | 0 |
| ACYP1 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| NABUMETONE | 4 | NPC1 |
| PHENELZINE | 4 | NPC1 |
| AMLEXANOX | 4 | NPC1 |
| IDARUBICIN | 4 | NPC1 |
| RABEPRAZOLE SODIUM | 4 | NPC1 |
| NITAZOXANIDE | 4 | NPC1 |
| NICLOSAMIDE | 4 | NPC1 |
| NITROXOLINE | 4 | NPC1 |
| NICARDIPINE | 4 | NPC1 |
| DAUNORUBICIN HYDROCHLORIDE | 4 | NPC1 |
| INDOPROFEN | 4 | NPC1 |
| CYCLOSPORINE | 4 | NPC1 |
| TERFENADINE | 4 | NPC1 |
| DIGOXIN | 4 | NPC1 |
| PRAZOSIN | 4 | NPC1 |
| MAPROTILINE | 4 | NPC1 |
| DIGITOXIN | 4 | NPC1 |
| HYDRALAZINE | 4 | NPC1 |
| EBASTINE | 4 | NPC1 |
| DEQUALINIUM | 4 | NPC1 |
| DOXORUBICIN HYDROCHLORIDE | 4 | NPC1 |
| VINBLASTINE SULFATE | 4 | NPC1 |
| FLUOXETINE | 4 | NPC1 |
| DITHIAZANINE IODIDE | 4 | NPC1 |
| TRIFLUOPERAZINE | 4 | NPC1 |
| PACLITAXEL | 4 | NPC1 |
| NORTRIPTYLINE | 4 | NPC1 |
| MIBEFRADIL | 4 | NPC1 |
| FLUSPIRILENE | 4 | NPC1 |
| KETOROLAC | 4 | NPC1 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 0.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| NPC1 | 18 | Binding:13, Functional:5 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.
| Compound | Max phase | Cohort target (bioactivity) |
|---|---|---|
| NABUMETONE | 4 | NPC1 |
| PHENELZINE | 4 | NPC1 |
| AMLEXANOX | 4 | NPC1 |
| IDARUBICIN | 4 | NPC1 |
| RABEPRAZOLE SODIUM | 4 | NPC1 |
| NITAZOXANIDE | 4 | NPC1 |
| NICLOSAMIDE | 4 | NPC1 |
| NITROXOLINE | 4 | NPC1 |
| NICARDIPINE | 4 | NPC1 |
| DAUNORUBICIN HYDROCHLORIDE | 4 | NPC1 |
| INDOPROFEN | 4 | NPC1 |
| CYCLOSPORINE | 4 | NPC1 |
| TERFENADINE | 4 | NPC1 |
| DIGOXIN | 4 | NPC1 |
| PRAZOSIN | 4 | NPC1 |
| MAPROTILINE | 4 | NPC1 |
| DIGITOXIN | 4 | NPC1 |
| HYDRALAZINE | 4 | NPC1 |
| EBASTINE | 4 | NPC1 |
| DEQUALINIUM | 4 | NPC1 |
| DOXORUBICIN HYDROCHLORIDE | 4 | NPC1 |
| VINBLASTINE SULFATE | 4 | NPC1 |
| FLUOXETINE | 4 | NPC1 |
| DITHIAZANINE IODIDE | 4 | NPC1 |
| TRIFLUOPERAZINE | 4 | NPC1 |
| PACLITAXEL | 4 | NPC1 |
| NORTRIPTYLINE | 4 | NPC1 |
| MIBEFRADIL | 4 | NPC1 |
| FLUSPIRILENE | 4 | NPC1 |
| KETOROLAC | 4 | NPC1 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 1 | NPC1 |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 1 | ACYP1 |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 1 | NPC2 |
Undrugged target profiles
2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| NPC2 | 0 | NPC1 |
| ACYP1 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 1.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT03655223 | Not specified | ENROLLING_BY_INVITATION | Early Check: Expanded Screening in Newborns |