NPC1

Summary

NPC1 (NPC intracellular cholesterol transporter 1, HGNC:7897) is a protein-coding gene on chromosome 18q11.2, encoding NPC intracellular cholesterol transporter 1 (O15118). Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment.

This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.

Source: NCBI Gene 4864 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Niemann-Pick disease, type C1 (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 27
• Clinical variants (ClinVar): 2,826 total — 267 pathogenic, 269 likely-pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes — 90 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000271

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7897
Approved symbol	NPC1
Name	NPC intracellular cholesterol transporter 1
Location	18q11.2
Locus type	gene with protein product
Status	Approved
Aliases	SLC65A1
Ensembl gene	ENSG00000141458
Ensembl biotype	protein_coding
OMIM	607623
Entrez	4864

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 20 protein_coding, 6 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000269228, ENST00000540608, ENST00000586150, ENST00000586718, ENST00000587163, ENST00000587223, ENST00000588867, ENST00000590301, ENST00000590723, ENST00000591051, ENST00000591075, ENST00000591107, ENST00000591955, ENST00000593280, ENST00000897526, ENST00000897527, ENST00000897528, ENST00000897529, ENST00000897530, ENST00000926493, ENST00000926494, ENST00000949151, ENST00000949152, ENST00000949153, ENST00000949154, ENST00000949155, ENST00000949156, ENST00000949157

RefSeq mRNA: 1 — MANE Select: NM_000271 NM_000271

CCDS: CCDS11878

Canonical transcript exons

ENST00000269228 — 25 exons

Exon	Start	End
ENSE00000948758	23539811	23540001
ENSE00000948759	23539355	23539470
ENSE00000948761	23536673	23536876
ENSE00000948763	23534446	23534559
ENSE00001136952	23533355	23533517
ENSE00001793580	23572074	23572180
ENSE00001838887	23586287	23586506
ENSE00001939978	23531442	23532284
ENSE00003463749	23541068	23541208
ENSE00003467386	23557117	23557190
ENSE00003470040	23544960	23545149
ENSE00003493637	23556243	23556613
ENSE00003517757	23544344	23544526
ENSE00003559203	23554758	23554984
ENSE00003592379	23561360	23561527
ENSE00003601721	23538542	23538671
ENSE00003604131	23551627	23551727
ENSE00003606174	23560231	23560480
ENSE00003611981	23573452	23573574
ENSE00003613100	23540448	23540537
ENSE00003617020	23541306	23541433
ENSE00003620768	23548006	23548108
ENSE00003636419	23535469	23535700
ENSE00003637231	23568823	23568998
ENSE00003674838	23543455	23543569

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.5619 / max 391.0589, expressed in 1821 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171354	38.6321	1821
171353	0.9298	175

Top tissues by expression

297 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.69	gold quality
oocyte	CL:0000023	99.48	gold quality
adrenal tissue	UBERON:0018303	98.94	gold quality
middle frontal gyrus	UBERON:0002702	98.65	gold quality
corpus callosum	UBERON:0002336	98.35	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.33	gold quality
cartilage tissue	UBERON:0002418	97.27	gold quality
right adrenal gland cortex	UBERON:0035827	97.20	gold quality
right adrenal gland	UBERON:0001233	96.89	gold quality
spinal cord	UBERON:0002240	96.89	gold quality
adrenal cortex	UBERON:0001235	96.63	gold quality
adrenal gland	UBERON:0002369	96.58	gold quality
left adrenal gland cortex	UBERON:0035825	96.51	gold quality
left adrenal gland	UBERON:0001234	96.49	gold quality
inferior vagus X ganglion	UBERON:0005363	95.88	gold quality
parotid gland	UBERON:0001831	95.86	gold quality
medial globus pallidus	UBERON:0002477	95.65	gold quality
upper lobe of left lung	UBERON:0008952	95.42	gold quality
globus pallidus	UBERON:0001875	95.24	gold quality
upper lobe of lung	UBERON:0008948	95.23	gold quality
saliva-secreting gland	UBERON:0001044	94.95	gold quality
inferior olivary complex	UBERON:0002127	94.89	gold quality
minor salivary gland	UBERON:0001830	94.88	gold quality
right lung	UBERON:0002167	94.88	gold quality
skin of leg	UBERON:0001511	94.18	gold quality
amniotic fluid	UBERON:0000173	94.08	gold quality
medulla oblongata	UBERON:0001896	93.92	gold quality
lower esophagus mucosa	UBERON:0035834	93.79	gold quality
mouth mucosa	UBERON:0003729	93.67	gold quality
skin of abdomen	UBERON:0001416	93.64	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-8498	yes	13.37
E-MTAB-9067	yes	12.19
E-MTAB-9801	yes	6.89
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1, CREB1, CTCF, FOXO1, PPARA, SREBF1, SREBF2

miRNA regulators (miRDB)

58 targeting NPC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-378A-5P	99.65	66.33	1311

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Mutational analysis of the complete genomic sequence of NPC1 and characterization of haplotypes suggest that the expression of missense mutations is influenced by haplotypic background. (PMID:11754101)
• Niemann-Pick C1 protein regulates cholesterol transport to the trans-Golgi network and plasma membrane caveolae. (PMID:11907140)
• Review of NPC1 and HE1/NPC2 roles regulating cholesterol transport through endosomal/lysosomal system and in Niemann-Pick type C disease (PMID:12125814)
• NPC2, NPC1 and MLN64 may act in an ordered sequence to sense cholesterol, effect sterol movement, and consequently, influence the process of vesicular trafficking. (PMID:12398991)
• 15 mutations, eight of which were previously unreported, from Niemann-Pick type C disease patients (PMID:12401890)
• Our results will contribute to defining the association between the clinical phenotypes and the genetic abnormalities in Niemann-Pick C disease. (PMID:12408188)
• NPC1 and NPC2 have a role in the regulation of sterol homeostasis through generation of LDL cholesterol-derived oxysterols (PMID:12719428)
• findings suggest that sequestration of theta-toxin to raft-enriched cell surface vesicles may underlie reduced sensitivity of NPC1-deficient cells to theta-toxin. (PMID:15069562)
• Results demonstrate that there is direct binding between Niemann-Pick type C1 protein (NPC1) and azocholestanol, which does not require NPC2 but requires a functional sterol-sensing domain within NPC1. (PMID:15314240)
• Data show that multiple signals are responsible for the trafficking of NPC1 to the endosomal compartment, including the dileucine motif and a previously unidentified signal residing within the putative sterol-sensing domain transmembrane domain 3. (PMID:15347664)
• first example of a splicing defect due to a mutation in the lariat branch point sequence in an intron of NPC1, found in Niemann-Pick type C patients (PMID:15459971)
• fatty acid flux through NPC1-deficient lysosomes is normal (PMID:15632139)
• ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein and translocates copper from the cytosol to the late endosomal lumen, participating in biliary copper excretion via lysosomes (PMID:15681833)
• Six novel NPC1 mutations were identified of which three are missense mutations located in the cysteine-rich domain. These are the first NPC1 mutations reported from Chinese patients with NPC. (PMID:15774455)
• D787N and L657F are activating NPC1 mutations provide evidence for a conserved mechanism for the sterol-sensing domain among cholesterol homeostatic proteins. (PMID:15908696)
• proposes a new hypothesis for the potential action or function of the NPC1 protein in the endosome; in this context, the relationship of NPC2 and NPC1 is also discussed. (PMID:16054367)
• NPC1 has a role in a vesicle-mediated pathway responsible for the clearance of drugs from cells and provides an explanation for a drug sequestration phenotype exhibited by the MDR HL-60 cell line (PMID:16174794)
• cholesterol contributes directly to the sequestration of Rab9 on Niemann-Pick type C cell membranes, which in turn, disrupts mannose 6-phosphate receptor trafficking (PMID:16644737)
• Ubiquitylation of NPC1 and its association with the ESCRT complex are controlled by endosomal cholesterol levels utilizing a mechanism that involves NPC2. (PMID:16757520)
• We report a Japanese patient with NPC caused by a homozygous c.2974 G > T mutation of the NPC1 gene,presenting with cataplexy at the age of 9 years and moderately low CSF-hypocretin 1 level. (PMID:16778374)
• Modulation of human NPC1L1 expression and promoter activity by cholesterol in a =sterol regulatory element binding protein-2 dependent mechanism. (PMID:17008555)
• NPC1 protein function is non-essential for the trafficking and removal of cellular cholesterol by ApoAI if the down-stream defects in ABCA1 and ABCG1 regulation in NPC disease cells are corrected using an LXR agonist (PMID:17020879)
• mutations in the NPC1 gene impair verbal working memory more than visuospatial working memory (PMID:17160616)
• I1061T NPC1 NPC1 mutant cells displayed an inappropriate homeostatic response to accumulated intracellular cholesterol. In addition, a number of striking parallels were observed between NPC disease and Alzheimer’s disease. (PMID:17183645)
• human NPC1 can functionally substitute for the Caenorhabditis elegans genes ncr-1 and/or ncr-2. (PMID:17662536)
• Sterol binding site on luminal loop-1 is not essential for NPC1 function in fibroblasts, but may function in other cells where NPC1 deficiency produces more complicated lipid abnormalities. (PMID:17989072)
• novel approaches to treat NPC disease caused by the NPC1(I1061T) mutation (PMID:18216017)
• Transport of LDL-derived cholesterol from late endosomes/lysosomes to the sterol-regulatory pool is regulated by the NPC1 protein and promotes feedback inhibition of the SREBP pathway. (PMID:18272927)
• NPC-1 is sterol-regulated, achieved by SREBP protein acting via the sterol regulated element and the E-box sequences. (PMID:18272928)
• Niemann-Pick C1 functions in regulating lysosomal amine content (PMID:18591242)
• NPC1 deficiency causes an imbalance in the intracellular redox state, which could be restored by ALLO treatment in vitro (PMID:18774957)
• This study show an association of genetic variation in NPC1 with SLAD and/or aging. (PMID:18834923)
• ATP7B localizes in the late endosomes. Copper in the late endosomes is transported to the secretory compartment via NPC1-dependent pathway and incorporated into apo-ceruloplasmin to form holo-ceruloplasmin. (PMID:19007772)
• The use of fluorescent cholesterol analogs provides novel information on the molecular properties of the sterol-binding site in the full-length NPC1 protein. (PMID:19029290)
• Tau plays a critical role in the regulation of autophagy in NPC1-deficient cells. (PMID:19074461)
• In addition to FTO and MC4R, we detected significant association of obesity with three new risk loci in NPC1 (endosomal/lysosomal Niemann-Pick C1 gene), near MAF (encoding the transcription factor c-MAF) and near PTER (phosphotriesterase-related gene). (PMID:19151714)
• NPC1 gene mutation analysis identified all of the mutant alleles including three novel mutations. (PMID:19206179)
• Results characterize mutations in the NPC1 and 2 genes in 34 unrelated patients including 32 patients with mutations in NPC1 gene and two patients in NPC2 gene, with 33 distinct genotypes encountered. (PMID:19252935)
• Cholesterol trafficking mediated by NPC1 is needed for efficient HIV-1 production and Gag accumulation in endosomal/lysosomal compartments. (PMID:19474101)
• High-resolution structures of the N-terminal domain (NTD) of NPC1 and complexes with cholesterol & 25-hydroxycholesterol are described; NPC1(NTD) binds cholesterol in an orientation opposite to NPC2: 3beta-hydroxyl buried and isooctyl side chain exposed. (PMID:19563754)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	npc1	ENSDARG00000017180
mus_musculus	Npc1	ENSMUSG00000024413
rattus_norvegicus	Npc1	ENSRNOG00000012016
drosophila_melanogaster	Npc1a	FBGN0024320
caenorhabditis_elegans		WBGENE00003562

Paralogs (10): NPC1L1 (ENSG00000015520), SCAP (ENSG00000114650), PTCH2 (ENSG00000117425), DISP2 (ENSG00000140323), DISP1 (ENSG00000154309), PTCHD1 (ENSG00000165186), PTCHD3 (ENSG00000182077), PTCH1 (ENSG00000185920), DISP3 (ENSG00000204624), PTCHD4 (ENSG00000244694)

Protein

Protein identifiers

NPC intracellular cholesterol transporter 1 — O15118 (reviewed: O15118)

Alternative names: Niemann-Pick C1 protein

All UniProt accessions (6): O15118, K7EIH7, K7ENZ0, K7EQ23, K7ERM4, K7ERW2

UniProt curated annotations — full annotation on UniProt →

Function. Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment. Unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes is transferred by NPC2 to the cholesterol-binding pocket in the N-terminal domain of NPC1. Cholesterol binds to NPC1 with the hydroxyl group buried in the binding pocket. Binds oxysterol with higher affinity than cholesterol. May play a role in vesicular trafficking in glia, a process that may be crucial for maintaining the structural and functional integrity of nerve terminals. Inhibits cholesterol-mediated mTORC1 activation throught its interaction with SLC38A9. (Microbial infection) Acts as an endosomal entry receptor for ebolavirus.

Subunit / interactions. Interacts (via the second lumenal domain) with NPC2. Interacts with TMEM97; the interaction may decrease NPC1 availability to the cell. Interacts with TIM1. Interacts with SLC38A9; this interaction inhibits cholesterol-mediated mTORC1 activation via its sterol transport activity. (Microbial infection) Interacts with ebolavirus glycoprotein.

Subcellular location. Late endosome membrane. Lysosome membrane.

Post-translational modifications. N-glycosylated.

Disease relevance. Niemann-Pick disease C1 (NPC1) [MIM:257220] A lysosomal storage disorder that affects the viscera and the central nervous system. It is due to defective intracellular processing and transport of low-density lipoprotein derived cholesterol. It causes accumulation of cholesterol in lysosomes, with delayed induction of cholesterol homeostatic reactions. Niemann-Pick disease type C1 has a highly variable clinical phenotype. Clinical features include variable hepatosplenomegaly and severe progressive neurological dysfunction such as ataxia, dystonia and dementia. The age of onset can vary from infancy to late adulthood. An allelic variant of Niemann-Pick disease type C1 is found in people with Nova Scotia ancestry. Patients with the Nova Scotian clinical variant are less severely affected. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. A cysteine-rich N-terminal domain and a C-terminal domain containing a di-leucine motif necessary for lysosomal targeting are critical for mobilization of cholesterol from lysosomes.

Similarity. Belongs to the patched family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15118-1	1	yes
O15118-2	2

RefSeq proteins (1): NP_000262* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000731	SSD	Domain
IPR004765	NPC1-like	Family
IPR032190	NPC1_N	Domain
IPR053956	NPC1_MLD	Domain
IPR053958	HMGCR/SNAP/NPC1-like_SSD	Domain

Pfam: PF12349, PF16414, PF22314

Catalyzed reactions (Rhea), 1 shown:

• cholesterol(in) = cholesterol(out) (RHEA:39747)

UniProt features (382 total): sequence variant 167, helix 55, mutagenesis site 38, strand 35, glycosylation site 19, disulfide bond 15, topological domain 14, turn 14, transmembrane region 13, splice variant 3, region of interest 2, binding site 2, signal peptide 1, chain 1, domain 1, short sequence motif 1, site 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
3GKJ	X-RAY DIFFRACTION	1.6
3GKI	X-RAY DIFFRACTION	1.8
3GKH	X-RAY DIFFRACTION	1.81
5F18	X-RAY DIFFRACTION	2
5F1B	X-RAY DIFFRACTION	2.3
8EUS	X-RAY DIFFRACTION	2.3
5KWY	X-RAY DIFFRACTION	2.4
5HNS	X-RAY DIFFRACTION	2.45
6W5S	ELECTRON MICROSCOPY	3
9DZ2	ELECTRON MICROSCOPY	3.31
5U74	X-RAY DIFFRACTION	3.33
5U73	X-RAY DIFFRACTION	3.35
9NPR	ELECTRON MICROSCOPY	3.53
6W5R	ELECTRON MICROSCOPY	3.6
6W5T	ELECTRON MICROSCOPY	3.7
6W5U	ELECTRON MICROSCOPY	3.9
6W5V	ELECTRON MICROSCOPY	4
6UOX	ELECTRON MICROSCOPY	4.02
3JD8	ELECTRON MICROSCOPY	4.43
5JNX	ELECTRON MICROSCOPY	6.56

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15118-F1	85.35	0.46

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 108 (important for cholesterol binding)

Ligand- & substrate-binding residues (2): 41; 79

Disulfide bonds (15): 25–74, 31–42, 63–109, 75–113, 97–238, 100–160, 177–184, 227–243, 240–247, 468–479, 516–533, 909–914, 956–1011, 957–979, 967–976

Glycosylation sites (19): 70, 122, 135, 158, 185, 222, 452, 459, 478, 524, 557, 572, 598, 916, 931, 961, 968, 1064, 1072

Mutagenesis-validated functional residues (38):

Position	Phenotype
25–257	decreases affinity for npc2. abolishes cholesterol transfer from npc2 to npc1.
26–27	nearly abolishes 25-hydroxycholesterol binding. reduces cholesterol binding.
39–41	strongly reduces cholesterol and 25-hydroxycholesterol binding.
41	nearly abolishes cholesterol and 25-hydroxycholesterol binding.
63	loss of function.
70	reduces glycosylation; when associated with q-122 and q-185. no effect on cholesterol and 25-hydroxycholesterol binding.
74–75	loss of function.
82–83	strongly reduces cholesterol and 25-hydroxycholesterol binding.
88	decreased affinity for npc2 and decreased cholesterol transfer from npc2 to npc1; when associated with a-92 and a-96.
92	decreased affinity for npc2 and decreased cholesterol transfer from npc2 to npc1; when associated with a-88 and a-96.
96	decreased affinity for npc2 and decreased cholesterol transfer from npc2 to npc1; when associated with a-88 and a-92.
97	loss of function.
101–102	strongly reduces 25-hydroxycholesterol binding. no effect on cholesterol binding.
106–108	nearly abolishes cholesterol and 25-hydroxycholesterol binding.
110–112	no effect on cholesterol and 25-hydroxycholesterol binding and transfer.
122	reduces glycosylation; when associated with q-70 and q-185. no effect on cholesterol and 25-hydroxycholesterol binding.
144–145	strongly reduces 25-hydroxycholesterol binding. no effect on cholesterol binding.
146–147	strongly reduces 25-hydroxycholesterol binding. no effect on cholesterol binding.
175–176	no effect on cholesterol or 25-hydroxycholesterol binding. decreases affinity for npc2. strongly reduces cholesterol tra
180–182	strongly reduces cholesterol transfer to liposomes in a npc2-dependent manner.
185	reduces glycosylation; when associated with q-70 and q-122. no effect on cholesterol and 25-hydroxycholesterol binding.
187–188	strongly reduces 25-hydroxycholesterol binding and cholesterol transfer to liposomes in a npc2-dependent manner.
191–192	no effect on cholesterol or 25-hydroxycholesterol binding. nearly abolishes cholesterol transfer to liposomes in a npc2-
195–196	strongly reduces 25-hydroxycholesterol binding. no effect on cholesterol binding.
197–198	strongly reduces cholesterol and 25-hydroxycholesterol binding.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8964038	LDL clearance

MSigDB gene sets: 427 (showing top): GOBP_CELLULAR_RESPONSE_TO_LIPOPROTEIN_PARTICLE_STIMULUS, GOBP_DIGESTION, GOBP_OLIGOSACCHARIDE_METABOLIC_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, GOBP_LYSOSOMAL_TRANSPORT, GOBP_BEHAVIOR, GOBP_STEROL_HOMEOSTASIS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOCC_VACUOLAR_MEMBRANE, GOBP_ADULT_BEHAVIOR, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_VACUOLAR_TRANSPORT

GO Biological Process (37): liver development (GO:0001889), endocytosis (GO:0006897), autophagy (GO:0006914), lysosomal transport (GO:0007041), adult walking behavior (GO:0007628), cholesterol metabolic process (GO:0008203), bile acid metabolic process (GO:0008206), glycoprotein biosynthetic process (GO:0009101), response to xenobiotic stimulus (GO:0009410), gene expression (GO:0010467), cholesterol storage (GO:0010878), programmed cell death (GO:0012501), sterol transport (GO:0015918), macroautophagy (GO:0016236), negative regulation of macroautophagy (GO:0016242), neurogenesis (GO:0022008), intestinal cholesterol absorption (GO:0030299), cholesterol transport (GO:0030301), membrane raft organization (GO:0031579), intracellular lipid transport (GO:0032365), intracellular cholesterol transport (GO:0032367), cholesterol efflux (GO:0033344), cholesterol homeostasis (GO:0042632), response to cadmium ion (GO:0046686), symbiont entry into host cell (GO:0046718), cellular response to steroid hormone stimulus (GO:0071383), cellular response to low-density lipoprotein particle stimulus (GO:0071404), establishment of protein localization to membrane (GO:0090150), negative regulation of epithelial cell apoptotic process (GO:1904036), negative regulation of TORC1 signaling (GO:1904262), cyclodextrin metabolic process (GO:2000900), obsolete protein glycosylation (GO:0006486), lipid metabolic process (GO:0006629), lipid transport (GO:0006869), steroid metabolic process (GO:0008202), sterol metabolic process (GO:0016125), establishment of localization in cell (GO:0051649)

GO Molecular Function (7): virus receptor activity (GO:0001618), transmembrane signaling receptor activity (GO:0004888), cholesterol binding (GO:0015485), signaling receptor activity (GO:0038023), cholesterol transfer activity (GO:0120020), lipid carrier activity (GO:0005319), protein binding (GO:0005515)

GO Cellular Component (15): extracellular region (GO:0005576), nuclear envelope (GO:0005635), lysosome (GO:0005764), lysosomal membrane (GO:0005765), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020), late endosome membrane (GO:0031902), membrane raft (GO:0045121), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), endosome (GO:0005768), endomembrane system (GO:0012505), vesicle (GO:0031982)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Plasma lipoprotein clearance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
endomembrane system	4
cytoplasm	3
macromolecule biosynthetic process	2
lipid transport	2
intracellular membrane-bounded organelle	2
gland development	1
hepaticobiliary system development	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
vacuolar transport	1
adult locomotory behavior	1
walking behavior	1
sterol metabolic process	1
secondary alcohol metabolic process	1
steroid metabolic process	1
monocarboxylic acid metabolic process	1
glycoprotein metabolic process	1
carbohydrate derivative biosynthetic process	1
response to chemical	1
lipid storage	1
signal transduction	1
cell death	1
organic hydroxy compound transport	1
autophagosome assembly	1
autophagy	1
negative regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
nervous system development	1
cell differentiation	1
lipid digestion	1
intestinal lipid absorption	1
sterol transport	1
membrane organization	1

Protein interactions and networks

STRING

2134 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPC1	NPC2	P61916	998
NPC1	GTPBP1	O00178	994
NPC1	OSBPL5	Q9H0X9	990
NPC1	TMEM97	Q5BJF2	978
NPC1	SLC38A9	Q8NBW4	964
NPC1	GP2	P55259	948
NPC1	SREBF2	Q12772	878
NPC1	STARD3	Q14849	863
NPC1	GRAMD1B	Q3KR37	809
NPC1	ABCA1	O95477	807
NPC1	ETFA	P13804	785
NPC1	HMGCR	P04035	776
NPC1	ABCG1	P45844	775
NPC1	STARD3NL	O95772	755
NPC1	SREBF1	P36956	755

IntAct

86 interactions, top by confidence:

A	B	Type	Score
	NPC1	psi-mi:“MI:0915”(physical association)	0.800
	NPC1	psi-mi:“MI:0407”(direct interaction)	0.800
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
NPC1	NPC2	psi-mi:“MI:0915”(physical association)	0.670
NPC1	NPC2	psi-mi:“MI:0407”(direct interaction)	0.670
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
N	NPC1	psi-mi:“MI:0915”(physical association)	0.590
NPC1	GP	psi-mi:“MI:0407”(direct interaction)	0.560
GP	NPC1	psi-mi:“MI:0407”(direct interaction)	0.560
	NPC1	psi-mi:“MI:0407”(direct interaction)	0.560
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
NCEH1	CLGN	psi-mi:“MI:0914”(association)	0.530
PON2	NPC1	psi-mi:“MI:0914”(association)	0.530
SIGMAR1	NPC1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
SEC11A	NPC1	psi-mi:“MI:0914”(association)	0.530
SLC15A4	PGRMC1	psi-mi:“MI:0914”(association)	0.530

BioGRID (428): NPC1 (Affinity Capture-MS), NPC1 (Affinity Capture-MS), NPC1 (Affinity Capture-MS), NPC1 (Affinity Capture-MS), NPC1 (Affinity Capture-MS), NPC1 (Affinity Capture-RNA), NPC1 (Protein-RNA), NPC1 (Synthetic Lethality), NPC1 (Affinity Capture-MS), NPC1 (Affinity Capture-MS), NPC1 (Affinity Capture-MS), NPC1 (Proximity Label-MS), NPC1 (Proximity Label-MS), NPC1 (Proximity Label-MS), NPC1 (Proximity Label-MS)

ESM2 similar proteins: A0A0K3AWM6, A0A161IUT7, A8XKF2, A9UY97, F1Q8R9, F4JRE0, G5ECQ2, G5EDW2, I1MSF2, K7LC65, O15118, O35604, O42579, O60353, O77277, O77438, O88917, O97831, P18537, P34389, P52867, P52887, P54002, P56941, Q12200, Q17330, Q19127, Q20026, Q29IL2, Q2U0S9, Q4ILH3, Q5GKZ7, Q5RCN4, Q61086, Q61089, Q6C0Z3, Q757X5, Q758B8, Q7Q5R9, Q80TR1

Diamond homologs: A0A125YWU9, O15118, O35604, Q12200, Q9VRC9, Q9Y6C5, P56941, Q6T3U3, Q6T3U4, Q8I266, Q9UHC9, Q09614, Q3KNS1, A6NIU2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Class A/1 (Rhodopsin-like receptors)	7	8.5×	2e-03
Neutrophil degranulation	12	4.5×	1e-03
Innate Immune System	10	4.2×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	5	14.0×	7e-03
ERAD pathway	5	11.6×	7e-03
positive regulation of cytosolic calcium ion concentration	6	9.0×	7e-03
adenylate cyclase-activating G protein-coupled receptor signaling pathway	6	8.7×	7e-03
G protein-coupled receptor signaling pathway	10	4.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

2826 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	267
Likely pathogenic	269
Uncertain significance	671
Likely benign	1205
Benign	64

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030709	NM_000271.5(NPC1):c.2297T>A (p.Leu766Ter)	Pathogenic
1050802	NM_000271.5(NPC1):c.2374-1G>A	Pathogenic
1066745	NM_000271.5(NPC1):c.2291C>T (p.Ala764Val)	Pathogenic
1068529	NM_000271.5(NPC1):c.3152_3153del (p.Phe1051fs)	Pathogenic
1068796	NM_000271.5(NPC1):c.2857_2858del (p.Gln953fs)	Pathogenic
1070529	NM_000271.5(NPC1):c.1654+1G>A	Pathogenic
1070840	NM_000271.5(NPC1):c.85G>T (p.Gly29Ter)	Pathogenic
1071436	NM_000271.5(NPC1):c.349C>T (p.Gln117Ter)	Pathogenic
1071500	NM_000271.5(NPC1):c.3122dup (p.Tyr1041Ter)	Pathogenic
1071813	NM_000271.5(NPC1):c.248_249del (p.Leu83fs)	Pathogenic
1071835	NM_000271.5(NPC1):c.3294dup (p.Ile1099fs)	Pathogenic
1072937	NM_000271.5(NPC1):c.2683G>T (p.Glu895Ter)	Pathogenic
1073904	NM_000271.5(NPC1):c.644del (p.His215fs)	Pathogenic
1073931	NM_000271.5(NPC1):c.2928C>A (p.Cys976Ter)	Pathogenic
1074756	NM_000271.5(NPC1):c.2823del (p.Trp942fs)	Pathogenic
1074872	NM_000271.5(NPC1):c.1531_1532del (p.Thr511fs)	Pathogenic
1075415	NM_000271.5(NPC1):c.3083_3084del (p.Gly1028fs)	Pathogenic
1076100	NM_000271.5(NPC1):c.350dup (p.Ser118fs)	Pathogenic
1076409	NM_000271.5(NPC1):c.3299_3300dup (p.Asn1101fs)	Pathogenic
132888	NM_000271.5(NPC1):c.1030del (p.Ser344fs)	Pathogenic
132889	NM_000271.5(NPC1):c.1502A>T (p.Asp501Val)	Pathogenic
132890	NM_000271.5(NPC1):c.1553G>A (p.Arg518Gln)	Pathogenic
132891	NM_000271.5(NPC1):c.1800del (p.Ile601fs)	Pathogenic
132892	NM_000271.5(NPC1):c.1832A>G (p.Asp611Gly)	Pathogenic
132894	NM_000271.5(NPC1):c.2128C>T (p.Gln710Ter)	Pathogenic
132895	NM_000271.5(NPC1):c.2177G>C (p.Arg726Thr)	Pathogenic
132897	NM_000271.5(NPC1):c.2302dup (p.Val768fs)	Pathogenic
132899	NM_000271.5(NPC1):c.2795dup (p.Tyr932Ter)	Pathogenic
132901	NM_000271.5(NPC1):c.416dup (p.Asn140fs)	Pathogenic
1331427	NM_000271.5(NPC1):c.3349dup (p.Leu1117fs)	Pathogenic

SpliceAI

7161 predictions. Top by Δscore:

Variant	Effect	Δscore
18:23506966:A:AG	acceptor_gain	1.0000
18:23506967:A:G	acceptor_gain	1.0000
18:23506968:A:G	acceptor_gain	1.0000
18:23506968:AGAAT:A	acceptor_gain	1.0000
18:23506969:G:GT	acceptor_gain	1.0000
18:23506969:GA:G	acceptor_gain	1.0000
18:23506969:GAAT:G	acceptor_gain	1.0000
18:23506969:GAATG:G	acceptor_gain	1.0000
18:23507051:TGTGG:T	donor_loss	1.0000
18:23507052:GTG:G	donor_gain	1.0000
18:23507053:TGGTA:T	donor_loss	1.0000
18:23507055:G:GG	donor_gain	1.0000
18:23507056:T:TC	donor_loss	1.0000
18:23509191:A:AG	acceptor_gain	1.0000
18:23509192:G:GG	acceptor_gain	1.0000
18:23515851:TTCA:T	acceptor_loss	1.0000
18:23515852:TCA:T	acceptor_loss	1.0000
18:23515853:CAG:C	acceptor_loss	1.0000
18:23515855:GGT:G	acceptor_gain	1.0000
18:23515992:TTAGG:T	donor_gain	1.0000
18:23515993:TAGG:T	donor_gain	1.0000
18:23515994:AGGGT:A	donor_loss	1.0000
18:23515995:GG:G	donor_gain	1.0000
18:23515996:GG:G	donor_gain	1.0000
18:23515996:GGTAA:G	donor_loss	1.0000
18:23515997:G:GG	donor_gain	1.0000
18:23516004:G:GT	donor_gain	1.0000
18:23519064:TACA:T	acceptor_loss	1.0000
18:23519065:ACAG:A	acceptor_loss	1.0000
18:23519066:C:G	acceptor_gain	1.0000

AlphaMissense

8433 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:23539419:C:A	W949C	0.999
18:23539419:C:G	W949C	0.999
18:23539440:C:A	W942C	0.999
18:23539440:C:G	W942C	0.999
18:23539442:A:G	W942R	0.999
18:23539442:A:T	W942R	0.999
18:23545026:G:C	S627R	0.999
18:23545026:G:T	S627R	0.999
18:23545028:T:G	S627R	0.999
18:23534536:G:C	F1167L	0.998
18:23534536:G:T	F1167L	0.998
18:23534538:A:G	F1167L	0.998
18:23538551:C:G	C1011S	0.998
18:23538552:A:T	C1011S	0.998
18:23539396:C:G	C957S	0.998
18:23539397:A:T	C957S	0.998
18:23551682:A:C	C533W	0.998
18:23551683:C:T	C533Y	0.998
18:23551684:A:G	C533R	0.998
18:23554763:G:C	C516W	0.998
18:23554764:C:T	C516Y	0.998
18:23554765:A:G	C516R	0.998
18:23554862:A:C	S483R	0.998
18:23554862:A:T	S483R	0.998
18:23554864:T:G	S483R	0.998
18:23561440:C:G	C184S	0.998
18:23561441:A:T	C184S	0.998
18:23561461:C:G	C177S	0.998
18:23561462:A:T	C177S	0.998
18:23561512:C:T	C160Y	0.998

dbSNP variants (sampled 300 via entrez): RS1000058998 (18:23534462 G>A,T), RS1000073339 (18:23549742 CTTTTTTT>C,CT,CTT,CTTT,CTTTT,CTTTTT,CTTTTTT,CTTTTTTTT,CTTTTTTTTT,CTTTTTTTTTT,CTTTTTTTTTTTT,CTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTAATTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT), RS1000090042 (18:23562132 A>T), RS1000096150 (18:23512137 C>T), RS1000189135 (18:23522885 C>A,T), RS1000197680 (18:23519473 G>A), RS1000226677 (18:23568808 T>G), RS1000230978 (18:23528626 C>T), RS1000237677 (18:23562901 C>T), RS1000287853 (18:23579266 C>T), RS1000298366 (18:23516886 C>T), RS1000352004 (18:23563194 T>C), RS1000465605 (18:23557502 A>T), RS1000475914 (18:23523997 C>T), RS1000511339 (18:23570376 A>C)

Disease associations

OMIM: gene MIM:607623 | disease phenotypes: MIM:257220, MIM:180860, MIM:607625, MIM:257200

GenCC curated gene-disease

Disease	Classification	Inheritance
Niemann-Pick disease, type C1	Definitive	Autosomal recessive
Niemann-Pick disease type C, severe perinatal form	Supportive	Autosomal recessive
Niemann-Pick disease type C, severe early infantile neurologic onset	Supportive	Autosomal recessive
Niemann-Pick disease type C, late infantile neurologic onset	Supportive	Autosomal recessive
Niemann-Pick disease type C, juvenile neurologic onset	Supportive	Autosomal recessive
Niemann-Pick disease type C, adult neurologic onset	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Niemann-Pick disease, type C1	Definitive	AR

Mondo (17): Niemann-Pick disease, type C1 (MONDO:0009757), Niemann-Pick disease type C (MONDO:0018982), Silver-Russell syndrome (MONDO:0008394), intellectual disability (MONDO:0001071), Niemann-Pick disease, type C2 (MONDO:0011873), nasopharyngeal carcinoma (MONDO:0015459), Niemann-Pick disease (MONDO:0001982), cerebellar ataxia (MONDO:0000437), lysosomal storage disease (MONDO:0002561), dystonic disorder (MONDO:0003441), Niemann-Pick disease type A (MONDO:0009756), capillary hemangioma (MONDO:0002407), Niemann-Pick disease type C, severe perinatal form (MONDO:0016306), Niemann-Pick disease type C, severe early infantile neurologic onset (MONDO:0016307), Niemann-Pick disease type C, late infantile neurologic onset (MONDO:0016308)

Orphanet (7): Niemann-Pick disease type C (Orphanet:646), Silver-Russell syndrome (Orphanet:813), Nasopharyngeal carcinoma (Orphanet:150), Rare ataxia (Orphanet:102002), Lysosomal disease (Orphanet:68366), Infantile neurovisceral acid sphingomyelinase deficiency (Orphanet:77292), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000511	Vertical supranuclear gaze palsy
HP:0000709	Psychosis
HP:0000726	Dementia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001744	Splenomegaly
HP:0001791	Fetal ascites
HP:0001982	Sea-blue histiocytosis
HP:0002015	Dysphagia
HP:0002066	Gait ataxia
HP:0002185	Neurofibrillary tangles
HP:0002240	Hepatomegaly
HP:0002371	Loss of speech
HP:0002524	Cataplexy
HP:0002529	Neuronal loss in central nervous system
HP:0003349	Low cholesterol esterification rate
HP:0003621	Juvenile onset
HP:0003640	CNS foam cells
HP:0003651	Foam cells
HP:0004333	Bone-marrow foam cells
HP:0006579	Prolonged neonatal jaundice
HP:0006583	Fatal liver failure in infancy

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST000317_11	Obesity	3.000000e-07
GCST000317_12	Obesity	8.000000e-08
GCST004610_85	White blood cell count	4.000000e-11
GCST004613_71	Sum neutrophil eosinophil counts	2.000000e-11
GCST004614_67	Granulocyte count	3.000000e-11
GCST004620_35	Sum basophil neutrophil counts	4.000000e-11
GCST004626_150	Myeloid white cell count	7.000000e-11
GCST004629_36	Neutrophil count	2.000000e-11
GCST005194_235	Coronary artery disease	6.000000e-07
GCST006611_22	HDL cholesterol	8.000000e-14
GCST006613_8	Triglycerides	1.000000e-08
GCST007576_85	Chronotype	4.000000e-10
GCST008129_90	Body mass index	1.000000e-17
GCST008549_16	Mental health study participation (provided email address)	7.000000e-09
GCST008549_9	Mental health study participation (provided email address)	1.000000e-10
GCST008595_216	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	1.000000e-10
GCST009524_48	Household income (MTAG)	1.000000e-09
GCST009602_12	Metabolic syndrome	4.000000e-11
GCST010139_1	Poultry consumption	1.000000e-09
GCST010173_120	Triglyceride levels	7.000000e-11
GCST010241_435	Apolipoprotein A1 levels	8.000000e-12
GCST010242_12	HDL cholesterol levels	3.000000e-17
GCST010244_316	Triglyceride levels	4.000000e-15
GCST010988_72	Adult body size	2.000000e-20
GCST010989_279	Body size at age 10	7.000000e-11
GCST011122_9	Walking pace	3.000000e-11
GCST90002394_420	Monocyte percentage of white cells	1.000000e-11

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0008328	chronotype measurement
EFO:0004340	body mass index
EFO:0010130	health study participation
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0009695	household income
EFO:0000195	metabolic syndrome
EFO:0008111	diet measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D020821	Dystonic Disorders	C10.228.662.300
D018324	Hemangioma, Capillary	C04.557.645.375.380
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D016464	Lysosomal Storage Diseases	C16.320.565.595; C18.452.648.595
D000077274	Nasopharyngeal Carcinoma	C04.557.470.200.623; C04.588.443.665.710.650.500; C07.550.350.650.500; C07.550.745.650.500; C09.647.710.650.500; C09.775.350.650.500; C09.775.549.650.500
D052536	Niemann-Pick Disease, Type A	C10.228.140.163.100.435.825.700.500; C15.604.250.410.625.500; C16.320.565.189.435.825.700.500; C16.320.565.398.641.803.730.500; C16.320.565.595.554.825.700.500; C18.452.132.100.435.825.700.500; C18.452.584.563.641.803.730.500; C18.452.648.189.435.825.700.500; C18.452.648.398.641.803.730.500; C18.452.648.595.554.825.700.500
D052556	Niemann-Pick Disease, Type C	C10.228.140.163.100.435.825.700.875; C15.604.250.410.625.875; C16.320.565.189.435.825.700.875; C16.320.565.398.641.803.730.875; C16.320.565.595.554.825.700.875; C18.452.132.100.435.825.700.875; C18.452.584.563.641.803.730.875; C18.452.648.189.435.825.700.875; C18.452.648.398.641.803.730.875; C18.452.648.595.554.825.700.875
D009542	Niemann-Pick Diseases	C10.228.140.163.100.435.825.700; C15.604.250.410.625; C16.320.565.189.435.825.700; C16.320.565.398.641.803.730; C16.320.565.595.554.825.700; C18.452.132.100.435.825.700; C18.452.584.563.641.803.730; C18.452.648.189.435.825.700; C18.452.648.398.641.803.730; C18.452.648.595.554.825.700
D056730	Silver-Russell Syndrome	C05.660.207.925; C16.131.077.855; C16.131.260.870; C16.320.180.870; C16.320.240.937; C16.320.447.750
C536119	Niemann-Pick disease, type C2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1293277 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

90 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 689,019 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1070	NABUMETONE	4	55,063
CHEMBL1089	PHENELZINE	4	18,793
CHEMBL1096	AMLEXANOX	4	4,195
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL1200930	RABEPRAZOLE SODIUM	4	3,361
CHEMBL1401	NITAZOXANIDE	4	9,504
CHEMBL1448	NICLOSAMIDE	4	14,322
CHEMBL1454910	NITROXOLINE	4	1,860
CHEMBL1484	NICARDIPINE	4	30,866
CHEMBL1563	DAUNORUBICIN HYDROCHLORIDE	4	28,670
CHEMBL15870	INDOPROFEN	4	22,854
CHEMBL160	CYCLOSPORINE	4	168,247
CHEMBL17157	TERFENADINE	4	25,393
CHEMBL1751	DIGOXIN	4	67,342
CHEMBL2	PRAZOSIN	4	31,107
CHEMBL21731	MAPROTILINE	4	19,686
CHEMBL254219	DIGITOXIN	4	16,757
CHEMBL276832	HYDRALAZINE	4	23,794
CHEMBL305660	EBASTINE	4	10,024
CHEMBL333826	DEQUALINIUM	4	1,116
CHEMBL359744	DOXORUBICIN HYDROCHLORIDE	4
CHEMBL378544	VINBLASTINE SULFATE	4
CHEMBL41	FLUOXETINE	4
CHEMBL421701	DITHIAZANINE IODIDE	4
CHEMBL422	TRIFLUOPERAZINE	4
CHEMBL428647	PACLITAXEL	4
CHEMBL445	NORTRIPTYLINE	4
CHEMBL45816	MIBEFRADIL	4
CHEMBL46516	FLUSPIRILENE	4
CHEMBL469	KETOROLAC	4

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC65 NPC-type cholesterol transporters

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	Potency	1	nM	CHEMBL1527169
8.70	Potency	2	nM	CHEMBL1328504
8.66	Potency	2.2	nM	CHEMBL1972959
8.15	Potency	7.1	nM	CHEMBL1393129
8.00	Potency	10	nM	CHEMBL3194013
7.90	Potency	12.6	nM	CHEMBL1573563
7.80	Potency	15.8	nM	CHEMBL1492399
7.65	Potency	22.4	nM	CHEMBL1394527
7.60	Potency	25.1	nM	CHEMBL3194739
7.60	Potency	25.1	nM	CHEMBL1314931
7.60	Potency	25.1	nM	CHEMBL1384292
7.60	Potency	25.1	nM	CHEMBL1594991
7.60	Potency	25.1	nM	CHEMBL1300237
7.55	Potency	28.2	nM	CHEMBL1473701
7.50	Potency	31.6	nM	CHEMBL1601652
7.50	Potency	31.6	nM	CHEMBL1564713
7.50	Potency	31.6	nM	CHEMBL1481543
7.40	Potency	39.8	nM	NICLOSAMIDE
7.30	Potency	50.1	nM	CHEMBL1382105
7.20	Potency	63.1	nM	CHEMBL1332512
7.19	Potency	65.1	nM	NICLOSAMIDE
7.15	Potency	70.8	nM	CHEMBL1557409
7.10	Potency	79.4	nM	CHEMBL1551716
7.10	Potency	79.4	nM	CHEMBL595840
7.10	Potency	79.4	nM	CHEMBL1584650
7.10	Potency	79.4	nM	CHEMBL3193405
7.10	Potency	79.4	nM	CHEMBL2003564
7.10	Potency	79.4	nM	CHEMBL1519965
7.10	Potency	79.4	nM	CHEMBL3191640
7.05	Potency	89.1	nM	CHEMBL3199855
7.05	Potency	89.1	nM	CHEMBL1537509
7.05	Potency	89.1	nM	CHEMBL1540112
7.05	Potency	89.1	nM	CHEMBL1503659
7.05	Potency	89.1	nM	CHEMBL1394246
7.05	Potency	89.1	nM	CHEMBL1470568
7.05	Potency	89.1	nM	CHEMBL1528067
7.05	Potency	89.1	nM	CHEMBL1357246
7.05	Potency	89.1	nM	CHEMBL3199409
7.05	Potency	89.1	nM	CHEMBL1308740
7.05	Potency	89.1	nM	CHEMBL1417932
7.05	Potency	89.1	nM	CHEMBL1340855
7.05	Potency	89.1	nM	CHEMBL1484158
7.05	Potency	89.1	nM	CHEMBL1574374
7.05	Potency	89.1	nM	CHEMBL1496375
7.05	Potency	89.1	nM	CHEMBL3210983
7.05	Potency	89.1	nM	CHEMBL3192138
7.05	Potency	89.1	nM	CHEMBL3195189
7.05	Potency	89.1	nM	CHEMBL1399952
7.05	Potency	89.1	nM	INDOPROFEN
7.05	Potency	89.1	nM	CHEMBL1489567

PubChem BioAssay actives

4 with measured affinity, of 89 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[[(3S,5R,6R,8S,9S,10R,13R,14S,17R)-5,6-dihydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl]oxy]-1-morpholin-4-ylethanone	1466792: Chaperone activity at FLAG/GFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as increase in localization of protein mutant in late endosomes after 24 hrs by Hoechst 33342 staining based fluorescence microscopic analysis	ec50	0.1500	uM
[(3S,8S,9S,10R,13R,14S,17R)-17-[(2R)-5-(dimethylamino)-5-oxopentan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] N,N-bis(2-hydroxyethyl)carbamate	768321: Binding affinity to NPC1 (unknown origin)	ec50	1.6000	uM
5-(cyclohexylmethyl)-6-oxophenanthridine-2-carboxamide	1466792: Chaperone activity at FLAG/GFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as increase in localization of protein mutant in late endosomes after 24 hrs by Hoechst 33342 staining based fluorescence microscopic analysis	ec50	3.6000	uM
6-oxo-5-pentylphenanthridine-2-carboxamide	1466792: Chaperone activity at FLAG/GFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as increase in localization of protein mutant in late endosomes after 24 hrs by Hoechst 33342 staining based fluorescence microscopic analysis	ec50	4.2000	uM

CTD chemical–gene interactions

89 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	4
Cyclosporine	increases expression	4
Cadmium Chloride	increases expression, decreases reaction, increases abundance, increases palmitoylation	3
bisphenol F	affects cotreatment, decreases expression, increases expression	2
sodium arsenite	increases expression	2
cobaltous chloride	increases expression	2
Acetaminophen	increases expression	2
Benzo(a)pyrene	decreases expression, affects methylation	2
Capsaicin	increases expression	2
Tetrachlorodibenzodioxin	affects reaction, decreases expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
Asbestos, Crocidolite	affects expression, increases expression	2
Particulate Matter	increases expression, increases abundance	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
trichostatin A	affects expression	1
o,p’-DDT	increases expression	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	increases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
manganese chloride	decreases expression, increases abundance	1
indirubin	increases expression	1
aflatoxin B2	decreases methylation	1
ciglitazone	affects binding, increases expression	1
beta-methylcholine	affects expression	1

ChEMBL screening assays

18 unique, capped per target: 13 binding, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614342	Functional	PUBCHEM_BIOASSAY: qHTS Assay for NPC1 Promoter Activators. (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL2328534	Binding	Binding affinity to human NPC1 expressed in LE/LY membrane of CHO cells at 25 uM by immunoblotting	Inhibition of Ebola Virus Infection: Identification of Niemann-Pick C1 as the Target by Optimization of a Chemical Probe. — ACS Med Chem Lett

Cellosaurus cell lines

86 cell lines: 40 finite cell line, 26 induced pluripotent stem cell, 11 transformed cell line, 8 cancer cell line, 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_7374	GM03123	Finite cell line	Female
CVCL_7375	GM03124	Transformed cell line	Female
CVCL_A4DG	AKOSi006-A	Induced pluripotent stem cell	Male
CVCL_A4DI	AKOSi004-A	Induced pluripotent stem cell	Female
CVCL_B5V1	TRNDi027-A	Induced pluripotent stem cell	Female
CVCL_B5V2	TRNDi027-B	Induced pluripotent stem cell	Female
CVCL_CX72	GM22566	Transformed cell line	Female
CVCL_CX73	GM22567	Transformed cell line	Male
CVCL_CX74	GM22568	Transformed cell line	Female
CVCL_CX75	GM23151	Finite cell line	Female

Clinical trials (associated diseases)

270 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01344356	PHASE4	COMPLETED	Stereotactic Body Radiotherapy for Head and Neck Tumors
NCT02293356	PHASE4	UNKNOWN	Phase IV Clinical Trial of Nimotuzumab in the Treatment of Nasopharyngeal Carcinoma
NCT02948699	PHASE4	UNKNOWN	A Research About Nutrition Impact for Local Advanced Nasopharyngeal Carcinoma Patients
NCT04292990	PHASE4	UNKNOWN	Comparison of Transdermal Fentanyl and Morphine for Oral Mucositis Pain in Nasopharyngeal Cancer Patients
NCT06457503	PHASE4	RECRUITING	A Study of Toripalimab in Combination With Cisplatin and Gemcitabine in Participants With Recurrent Metastatic Nasopharyngeal Cancer
NCT04860960	PHASE3	ACTIVE_NOT_RECRUITING	Phase 3 Study to Evaluate Intravenous Trappsol(R) Cyclo(TM) in Pediatric and Adult Patients With Niemann-Pick Disease Type C1
NCT01760564	PHASE3	COMPLETED	Application of Miglustat in Patients With Niemann-Pick Type C
NCT03919552	PHASE3	RECRUITING	Cisplatin-based and Carboplatin-based Chemoradiation in Locoregionally Advanced Nasopharyngeal Carcinoma
NCT06457906	PHASE3	RECRUITING	SRS/SRT/Hypo-RT Versus HA-WBRT for No More Than 10 Brain Metastases in SCLC
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00201344	PHASE3	TERMINATED	A Phase III Study of Radiotherapy With or Without Adjuvant C/T in Advanced Stage Nasopharyngeal Carcinoma Patients
NCT00201396	PHASE3	COMPLETED	A Multicenter Trial Comparing Induction C/T Followed by CCRT v.s. CCRT Alone in Stage IV Nasopharyngeal Carcinoma
NCT00370890	PHASE3	COMPLETED	A Trial of Adjuvant Chemotherapy in Nasopharyngeal Carcinoma Patients With Residual Epstein-Barr Virus (EBV) DNA Following Radiotherapy
NCT00379262	PHASE3	COMPLETED	Therapeutic Gain by Induction-concurrent Chemoradiotherapy and/or Accelerated Fractionation for Nasopharyngeal Carcinoma
NCT00535795	PHASE3	COMPLETED	Phase III: Assess Conventional RT w/ Conventional Plus Accelerated Boost RT in the Treatment of Nasopharyngeal CA
NCT00677118	PHASE3	UNKNOWN	Adjuvant Chemotherapy in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma
NCT00705627	PHASE3	UNKNOWN	A Multicenter Trial Comparing Multi-course Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma
NCT00828386	PHASE3	TERMINATED	Induction Chemotherapy and Chemoradiotherapy in Nasopharyngeal Cancers
NCT01074021	PHASE3	UNKNOWN	Nimotuzumab in Combination With Chemoradiation for Nasopharyngeal Cancer
NCT01245959	PHASE3	UNKNOWN	Induction Chemotherapy in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma
NCT01479504	PHASE3	UNKNOWN	A Multicenter Trial Evaluating the Efficacy of Nedaplatin in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma
NCT01536223	PHASE3	UNKNOWN	Efficacy Study of Neoadjuvant Chemotherapy With Chemoradiation Therapy for Nasopharyngeal Carcinoma
NCT01540136	PHASE3	COMPLETED	Concurrent Chemoradiotherapy With Nedaplatin Versus Cisplatin in Nasopharyngeal Carcinoma
NCT01817023	PHASE3	UNKNOWN	The Role of Concurrent Chemotherapy for Lower Risk Locally Advanced Nasopharyngeal Carcinoma(NPC) in the Era of IMRT
NCT01872962	PHASE3	UNKNOWN	Induction Gemcitabine and Cisplatin in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma
NCT01915134	PHASE3	UNKNOWN	Endostatin in Combination With Chemotherapy for Metastatic Nasopharyngeal Carcinoma
NCT02012062	PHASE3	COMPLETED	Concurrent Nimotuzumab Versus Cisplatin With Radiotherapy for Locoregionally Advanced NPC
NCT02111460	PHASE3	UNKNOWN	Chemotherapy Combined With Radiotherapy vs Chemotherapy Alone for Distant Metastatic Nasopharyngeal Carcinoma
NCT02137096	PHASE3	TERMINATED	Autologous Stem Cell Transplantation for Patients With Recurrent Nasopharyngeal Carcinoma
NCT02301208	PHASE3	UNKNOWN	Weekly Cisplatin or Nedaplatin Concurrent With Intensity-modulated Radiation Therapy in Nasopharyngeal Carcinoma
NCT02363400	PHASE3	TERMINATED	A Phase III Trial in NPC With Post-radiation Detectable Plasma EBV DNA
NCT02434614	PHASE3	UNKNOWN	Induction Chemotherapy Followed by IMRT With or Without Concurrent Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma
NCT02460419	PHASE3	COMPLETED	Maintenance Capecitabine Plus Best Supportive Care Versus Best Supportive Care for Metastatic Nasopharyngeal Carcinoma
NCT02460887	PHASE3	ACTIVE_NOT_RECRUITING	The Role of Induction Gemcitabine and Cisplatin in Locoregionally Advanced Nasopharyngeal Carcinoma in the Era of IMRT
NCT02500940	PHASE3	UNKNOWN	Comparison the Effects of Different Neoadjuvant Chemotherapy Regimen on Acute Toxicity, Tumor Response, and Survival in Patients With Advanced Nasopharyngeal Carcinoma
NCT02512315	PHASE3	UNKNOWN	A Trial On 4 Cycles Of Neoadjuvant Chemotherapy Plus Concurrent Chemoradiation In N2-3 Nasopharyngeal Carcinoma