NPC2

Summary

NPC2 (NPC intracellular cholesterol transporter 2, HGNC:14537) is a protein-coding gene on chromosome 14q24.3, encoding NPC intracellular cholesterol transporter 2 (P61916). Intracellular cholesterol transporter which acts in concert with NPC1 and plays an important role in the egress of cholesterol from the lysosomal compartment.

This gene encodes a protein containing a lipid recognition domain. The encoded protein may function in regulating the transport of cholesterol through the late endosomal/lysosomal system. Mutations in this gene have been associated with Niemann-Pick disease, type C2 and frontal lobe atrophy.

Source: NCBI Gene 10577 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Niemann-Pick disease, type C2 (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 305 total — 29 pathogenic, 28 likely-pathogenic
• Phenotypes (HPO): 38
• MANE Select transcript: NM_006432

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14537
Approved symbol	NPC2
Name	NPC intracellular cholesterol transporter 2
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	HE1, NP-C2, EDDM1
Ensembl gene	ENSG00000119655
Ensembl biotype	protein_coding
OMIM	601015
Entrez	10577

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 nonsense_mediated_decay

ENST00000238633, ENST00000434013, ENST00000541064, ENST00000553490, ENST00000554482, ENST00000555592, ENST00000555619, ENST00000556009, ENST00000557510, ENST00000851979, ENST00000932865, ENST00000932868

RefSeq mRNA: 3 — MANE Select: NM_006432 NM_001363688, NM_001375440, NM_006432

CCDS: CCDS32121, CCDS86413, CCDS91904

Canonical transcript exons

ENST00000555619 — 5 exons

Exon	Start	End
ENSE00000808157	74484415	74484587
ENSE00002450393	74479940	74480288
ENSE00002478802	74493193	74493305
ENSE00003534117	74480702	74480779
ENSE00003588585	74486329	74486436

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 99.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 270.9652 / max 7926.8170, expressed in 1823 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144037	190.4742	1814
144038	55.3971	1812
144036	18.6157	1680
144039	5.0108	1587
144040	1.4675	885

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.99	gold quality
cauda epididymis	UBERON:0004360	99.85	gold quality
epididymis	UBERON:0001301	99.77	gold quality
lower lobe of lung	UBERON:0008949	99.59	gold quality
right lobe of thyroid gland	UBERON:0001119	99.56	gold quality
left lobe of thyroid gland	UBERON:0001120	99.56	gold quality
stromal cell of endometrium	CL:0002255	99.50	gold quality
thyroid gland	UBERON:0002046	99.50	gold quality
right lung	UBERON:0002167	99.49	gold quality
caput epididymis	UBERON:0004358	99.48	gold quality
upper lobe of lung	UBERON:0008948	99.47	gold quality
seminal vesicle	UBERON:0000998	99.46	gold quality
gall bladder	UBERON:0002110	99.46	gold quality
periodontal ligament	UBERON:0008266	99.46	gold quality
upper lobe of left lung	UBERON:0008952	99.46	gold quality
monocyte	CL:0000576	99.44	gold quality
mononuclear cell	CL:0000842	99.40	gold quality
leukocyte	CL:0000738	99.39	gold quality
lung	UBERON:0002048	99.34	gold quality
decidua	UBERON:0002450	99.34	gold quality
right adrenal gland cortex	UBERON:0035827	99.33	gold quality
adenohypophysis	UBERON:0002196	99.29	gold quality
synovial joint	UBERON:0002217	99.29	gold quality
endocervix	UBERON:0000458	99.28	gold quality
pigmented layer of retina	UBERON:0001782	99.28	gold quality
right ovary	UBERON:0002118	99.28	gold quality
olfactory bulb	UBERON:0002264	99.27	gold quality
retina	UBERON:0000966	99.26	gold quality
right adrenal gland	UBERON:0001233	99.26	gold quality
left ovary	UBERON:0002119	99.26	gold quality

Single-cell (SCXA)

Detected in 47 experiment(s), a significant marker in 39.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	5831.07
E-MTAB-6308	yes	5389.89
E-MTAB-8530	yes	4103.40
E-MTAB-8221	yes	3718.22
E-HCAD-11	yes	3241.99
E-MTAB-8495	yes	3157.23
E-MTAB-6701	yes	2721.22
E-MTAB-6653	yes	2621.72
E-MTAB-10662	yes	2203.27
E-MTAB-8207	yes	2131.68
E-MTAB-10553	yes	2033.13
E-CURD-112	yes	1714.31
E-GEOD-139324	yes	1540.92
E-MTAB-10042	yes	1539.04
E-CURD-95	yes	1283.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting NPC2, 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-1208	99.70	68.28	1533
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-6776-3P	98.38	66.34	655
HSA-MIR-653-3P	98.31	67.71	1542
HSA-MIR-4717-5P	98.19	67.97	894
HSA-MIR-4435	95.90	65.47	1201

Literature-anchored findings (GeneRIF, showing 40)

• mutational analysis and genotype/phenotype correlation in NPC2 group (PMID:11567215)
• 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)
• Adult-onset NPC2 with lysosomal storage virtually restricted to neurons represents a novel phenotypic and genotypic variant with diffuse cognitive impairment and focal frontal involvement described for the first time. (PMID:12447927)
• NPC2 protein has binding sites with a role in efficient secretion (PMID:12591949)
• NPC1 and NPC2 have a role in the regulation of sterol homeostasis through generation of LDL cholesterol-derived oxysterols (PMID:12719428)
• The HE1 transcript was affected by the obstruction of the epididymis with little or no mRNA detectable along the epididymis. (PMID:14662784)
• Functional characterization of the mutant proteins showed an excellent genotype-phenotype correlation in the three cases for whom a clinical history was available (PMID:15937921)
• NPC2 is secreted from the liver into bile and plasma, where it may have a functional role in cholesterol transport in normal and disease conditions. (PMID:16374838)
• NPC2 protein has a role in the egress of LDL derived cholesterol out of the endosomal/lysosomal compartment (PMID:16606609)
• Compared with normal men, seminal plasma of vasectomized men is characterized by a major decrease in immunodetectable HE1/NPC2 and surgical vasectomy reversal will normalize seminal plasma HE1/NPC2 amount to similar level of that of normal mem. (PMID:16772431)
• NPC2 has a direct and specialized function in lysosomal sterol transport (PMID:17018531)
• p.P120S mutation, the first naturally occurring missense mutation located in the cholesterol-binding Evolutionarily Constrained Regions D domain, results in reduced amounts of a protein capable to reach the lysosome, but unable to bind cholesterol. (PMID:17470133)
• role of the AP-3 pathway in targeting of NP-C proteins; study found although mouse NPC1 & hNPC2 co-localize with AP-3 to a similar extent in fibroblasts, hNPC2 preferentially co-localizes with AP-1; targeting of both NPC1 & NPC2 is dependent on AP-3 (PMID:17895371)
• NPC2 plays an important role in endo/lysosomal cholesterol trafficking by markedly accelerating the rates of cholesterol transport. Rates of sterol transfer from and between membranes were increased by as much as 2 orders of magnitude by NPC2. (PMID:18823126)
• 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)
• NPC2 binds C2 domain of human Nedd4L. (PMID:19664597)
• Niemann-Pick type C2 protein levels are increased in the presence of Nogo-B receptor, and Nogo-B receptor enhances Niemann-Pick type C2 protein protein stability. (PMID:19723497)
• physiological and coordinate downregulation of the NPC1 and NPC2 genes/proteins promotes the sequestration of LDL-derived cholesterol within endocytic compartments and serves a role in maintaining intracellular cholesterol homeostasis (PMID:19746448)
• The results suggest that NPC1 and NPC2 can function independently of one another in the egress of certain membrane-impermeable lysosomal cargo. (PMID:20007703)
• NPC2 as a novel intracrine/autocrine factor that controls adipocyte differentiation and function (PMID:20650896)
• NPC2 protein interacts N-ternimal domain of NPC1 protein, thereby opening an entry pore on NPC1 protein and allowing cholesterol to transfer without passing through the water phase. (PMID:20674861)
• a novel mechanism where NPC2 by negatively regulating ERK 1/2 MAPK phosphorylation may efficiently suppress development of maladaptive tissue remodeling and inflammation. (PMID:21084287)
• NPC2 protein of certain cells forms papillae coupled with apoptosis that creates open space (PMID:21253586)
• mechanism of sterol transport by cyclodextrins using in vitro model systems and fluorescence spectroscopy and NPC2-deficient fibroblasts (PMID:21740003)
• overexpression of ABCA1 alone is able to correct the mobilization of cholesterol from late endosomes/lysosomes and the formation of HDL particles in NPC1- but not NPC2-deficient human fibroblasts (PMID:22179027)
• This is the first report demonstrating that GNMT plays an important role in regulating cholesterol homeostasis via interaction with NPC2 (PMID:22183894)
• Loss of Niemann Pick type C proteins 1 and 2 greatly enhances HIV infectivity and is associated with accumulation of HIV Gag and cholesterol in late endosomes/lysosomes. (PMID:22273177)
• The NPC2 delivers cholesterol to the perimeter membrane of late endosomes, where it becomes available for transport to mitochondria without requiring NPC1. (PMID:22962690)
• Treatment of NPC1-null or NPC2-deficient cells with cyclodextrin was effective in reducing cholesterol storage as well as the endocytic accumulation of sialoglycoproteins, demonstrating a direct link between cholesterol storage and abnormal recycling. (PMID:23733943)
• The p.Pro120Ser causing mutation in NPC2 observed in the Iranian patients was earlier observed in the only other NPC2 patient reported from the Middle East. (PMID:23791309)
• NPC2-deficiency leads to a dramatic up-regulation of the arachidonic acid (AA) metabolic pathway in human fibroblasts. (PMID:23814065)
• an atomistic model is proposed of the transfer of cholesterol from NPC2 to NPC1(NTD) through the formation of an intermediate NPC1(NTD)-NPC2 complex (PMID:24001314)
• Recombinant NPC2 protein increases triglyceride levels in body fat. (PMID:24438076)
• these results suggest that the vitamin A-mediated antimicrobial mechanism against M. tuberculosis requires NPC2-dependent expression and function, indicating a key role for cellular cholesterol regulation in the innate immune response. (PMID:24501203)
• Suggest role for mouse epididymal NPC2 in regulating male fertility. (PMID:24709320)
• twelve individuals were subsequently confirmed to be NP-C by DNA analysis of NPC1 and NPC2 genes, with the early infantile form, the late infantile form, the juvenile form, and the adult form (PMID:24915861)
• heterozygous mutations in the NPC1/2 gene might be a risk factor for Alzheimer’s disease (PMID:25220527)
• Data suggest that in order for the ligand cholesterol to slide from one binding pocket to the other (from NPC2 to NPC1), cholesterol undergoes conformational change/isomerization to accommodate the bent transfer pathway between the 2 binding pockets. (PMID:25251378)
• NPC2 may play an important role in negatively regulate cell proliferation. (PMID:25754535)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	npc2.1	ENSDARG00000090912
danio_rerio	npc2.2	ENSDARG00000096979
mus_musculus	Npc2	ENSMUSG00000021242
rattus_norvegicus	Npc2	ENSRNOG00000012062
drosophila_melanogaster	Npc2a	FBGN0031381

Protein

Protein identifiers

NPC intracellular cholesterol transporter 2 — P61916 (reviewed: P61916)

Alternative names: Epididymal secretory protein E1, Human epididymis-specific protein 1, Niemann-Pick disease type C2 protein

All UniProt accessions (9): A0A024R6C0, E7EMS2, P61916, G3V2V8, G3V3D1, G3V3E8, H0YIZ1, H0YJE2, J3KMY5

UniProt curated annotations — full annotation on UniProt →

Function. Intracellular cholesterol transporter which acts in concert with NPC1 and plays an important role in the egress of cholesterol from the 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. May bind and mobilize cholesterol that is associated with membranes. NPC2 binds cholesterol with a 1:1 stoichiometry. Can bind a variety of sterols, including lathosterol, desmosterol and the plant sterols stigmasterol and beta-sitosterol. The secreted form of NCP2 regulates biliary cholesterol secretion via stimulation of ABCG5/ABCG8-mediated cholesterol transport.

Subunit / interactions. Interacts with NPC1 (via the second lumenal domain) in a cholestrol-dependent manner. Interacts with NUS1/NgBR, the interaction stabilizes NCP2 and regulates cholesterol trafficking. Interacts with DHDDS. Interacts with NEDD4L (via C2 domain). Interacts with NPC1L1.

Subcellular location. Secreted. Endoplasmic reticulum. Lysosome.

Tissue specificity. Detected in gallbladder bile. Detected in fibroblasts, kidney, liver, spleen, small intestine, placenta and testis (at protein level). Epididymis.

Disease relevance. Niemann-Pick disease C2 (NPC2) [MIM:607625] 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 C2 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. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Binds cholesterol in a hydrophobic pocket; there are no hydrogen bonds between the sterol and the protein.

Induction. Down-regulated in response to enterovirus 71 (EV71) infection.

Similarity. Belongs to the NPC2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P61916-1	1	yes
P61916-2	2

RefSeq proteins (3): NP_001350617, NP_001362369, NP_006423* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003172	ML_dom	Domain
IPR014756	Ig_E-set	Homologous_superfamily
IPR033916	ML_Npc2-like	Domain
IPR039670	NPC2-like	Family

Pfam: PF02221

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (28 total): strand 10, sequence variant 8, disulfide bond 3, glycosylation site 2, signal peptide 1, chain 1, modified residue 1, helix 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5KWY	X-RAY DIFFRACTION	2.4
6W5V	ELECTRON MICROSCOPY	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61916-F1	92.88	0.86

Functional residue map

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

Post-translational modifications (1): 116

Disulfide bonds (3): 27–140, 42–47, 93–99

Glycosylation sites (2): 58, 135

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-8964038	LDL clearance

MSigDB gene sets: 412 (showing top): DAVIES_MULTIPLE_MYELOMA_VS_MGUS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_STEROL_HOMEOSTASIS, GOCC_SECRETORY_GRANULE, LFA1_Q6, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, HSIAO_HOUSEKEEPING_GENES, KEGG_LYSOSOME, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_LIPID_HOMEOSTASIS, GOBP_CHOLESTEROL_EFFLUX

GO Biological Process (17): cholesterol metabolic process (GO:0008203), response to virus (GO:0009615), gene expression (GO:0010467), cholesterol storage (GO:0010878), phospholipid transport (GO:0015914), regulation of isoprenoid metabolic process (GO:0019747), cholesterol transport (GO:0030301), intracellular sterol transport (GO:0032366), intracellular cholesterol transport (GO:0032367), cholesterol efflux (GO:0033344), cholesterol homeostasis (GO:0042632), glycolipid transport (GO:0046836), lipid metabolic process (GO:0006629), lipid transport (GO:0006869), steroid metabolic process (GO:0008202), sterol transport (GO:0015918), sterol metabolic process (GO:0016125)

GO Molecular Function (5): cholesterol binding (GO:0015485), enzyme binding (GO:0019899), cholesterol transfer activity (GO:0120020), protein binding (GO:0005515), sterol binding (GO:0032934)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), lysosome (GO:0005764), late endosome (GO:0005770), endoplasmic reticulum (GO:0005783), azurophil granule lumen (GO:0035578), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Plasma lipoprotein clearance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid transport	3
sterol transport	2
intracellular anatomical structure	2
cholesterol transport	2
vacuolar lumen	2
sterol metabolic process	1
secondary alcohol metabolic process	1
response to other organism	1
macromolecule biosynthetic process	1
lipid storage	1
organophosphate ester transport	1
isoprenoid metabolic process	1
regulation of lipid metabolic process	1
intracellular lipid transport	1
intracellular sterol transport	1
sterol homeostasis	1
carbohydrate derivative transport	1
primary metabolic process	1
transport	1
lipid localization	1
lipid metabolic process	1
organic hydroxy compound transport	1
steroid metabolic process	1
sterol binding	1
alcohol binding	1
protein binding	1
cholesterol binding	1
sterol transfer activity	1
binding	1
steroid binding	1
cellular anatomical structure	1
lytic vacuole	1
endosome	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
secretory granule lumen	1
azurophil granule	1
lysosome	1
extracellular vesicle	1

Protein interactions and networks

STRING

1566 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPC2	NPC1	O15118	998
NPC2	STARD3	Q14849	926
NPC2	STARD3NL	O95772	860
NPC2	NPC1L1	Q9UHC9	824
NPC2	SCAP	Q12770	704
NPC2	STAR	P49675	672
NPC2	SMPD1	P17405	663
NPC2	CHIT1	Q13231	650
NPC2	LIPA	P38571	646
NPC2	NR1I2	O75469	588
NPC2	LAMP2	P13473	577
NPC2	OSBPL5	Q9H0X9	570
NPC2	GLB1	P16278	570
NPC2	ABCA1	O95477	560
NPC2	PIGR	P01833	556

IntAct

67 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
	NPC2	psi-mi:“MI:0407”(direct interaction)	0.780
	NPC2	psi-mi:“MI:0915”(physical association)	0.780
NPC1	NPC2	psi-mi:“MI:0915”(physical association)	0.670
NPC1	NPC2	psi-mi:“MI:0407”(direct interaction)	0.670
NEGR1	NPC2	psi-mi:“MI:0915”(physical association)	0.640
NPC2	NEGR1	psi-mi:“MI:0915”(physical association)	0.640
NEGR1	NPC2	psi-mi:“MI:0403”(colocalization)	0.640
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
LRP1	NME4	psi-mi:“MI:0914”(association)	0.530
RRAGA	NPC2	psi-mi:“MI:0914”(association)	0.530
	PLOD2	psi-mi:“MI:0914”(association)	0.530
PIEZO1	CLGN	psi-mi:“MI:0914”(association)	0.530
NPC2	NME2P1	psi-mi:“MI:0914”(association)	0.530
HLA-DRA	ENTPD6	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
SPCS3	ENTPD6	psi-mi:“MI:0914”(association)	0.530

BioGRID (73): NPC2 (Affinity Capture-MS), NPC2 (Affinity Capture-MS), NPC2 (Two-hybrid), NPC2 (Two-hybrid), HK3 (Affinity Capture-MS), NME2 (Affinity Capture-MS), CFB (Affinity Capture-MS), TTR (Affinity Capture-MS), NPC2 (Affinity Capture-MS), NPC2 (Affinity Capture-MS), IRGQ (Affinity Capture-MS), NME2P1 (Affinity Capture-MS), NPC2 (Affinity Capture-MS), NPC2 (Affinity Capture-MS), NPC2 (Affinity Capture-MS)

ESM2 similar proteins: A5A6I6, A6QP57, B0FHH8, O02380, O93429, O94183, O97763, P02787, P02789, P05090, P08071, P09571, P0CP28, P0CP29, P12346, P17900, P19134, P23593, P27425, P31729, P49278, P51910, P61916, P61917, P61918, P79345, P79815, P79819, P80384, P80426, P80429, Q08188, Q25481, Q28895, Q29290, Q29443, Q336T5, Q4X136, Q52FS9, Q60648

Diamond homologs: A1EA99, O97763, P61916, P61917, P61918, P79345, Q28895, Q965E2, Q9DGJ3, Q9VQ62, Q9Z0J0, Q25481, O02380, Q9NFQ4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NPC2	“down-regulates activity”	ERK1/2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 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.

GO biological processes:

GO term	Partners	Fold	FDR
integrin-mediated signaling pathway	6	15.3×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	28
Uncertain significance	67
Likely benign	144
Benign	6

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074431	NC_000014.8:g.(?74959886)(74959987_?)del	Pathogenic
1455561	NM_006432.5(NPC2):c.106G>T (p.Glu36Ter)	Pathogenic
1457423	NM_006432.5(NPC2):c.281dup (p.Ser95fs)	Pathogenic
1459810	NM_006432.5(NPC2):c.165C>G (p.Tyr55Ter)	Pathogenic
1921786	NM_006432.5(NPC2):c.3G>T (p.Met1Ile)	Pathogenic
2088012	NM_006432.5(NPC2):c.2T>G (p.Met1Arg)	Pathogenic
21456	NM_006432.5(NPC2):c.141C>A (p.Cys47Ter)	Pathogenic
21457	NM_006432.5(NPC2):c.27del (p.Leu10fs)	Pathogenic
21458	NM_006432.5(NPC2):c.295T>C (p.Cys99Arg)	Pathogenic
21459	NM_006432.5(NPC2):c.332del (p.Asn111fs)	Pathogenic
2425592	NC_000014.8:g.(?74951108)(74953149_?)del	Pathogenic
2425593	NC_000014.8:g.(?74946967)(74947492_?)del	Pathogenic
242903	NM_006432.5(NPC2):c.82+2T>C	Pathogenic
2708050	NM_006432.5(NPC2):c.129del (p.Thr44fs)	Pathogenic
2766060	NM_006432.5(NPC2):c.130_131del (p.Thr44fs)	Pathogenic
2846910	NM_006432.5(NPC2):c.2T>A (p.Met1Lys)	Pathogenic
2982084	NM_006432.5(NPC2):c.12_18del (p.Ala5fs)	Pathogenic
3242250	NM_006432.5(NPC2):c.17_18insCAGGAAACGC (p.Thr7fs)	Pathogenic
3383995	NM_006432.5(NPC2):c.289del (p.Ile97fs)	Pathogenic
4087706	NM_006432.5(NPC2):c.406C>T (p.Gln136Ter)	Pathogenic
553522	NM_006432.5(NPC2):c.422G>A (p.Trp141Ter)	Pathogenic
557572	NM_006432.5(NPC2):c.3G>A (p.Met1Ile)	Pathogenic
643285	NM_006432.5(NPC2):c.79dup (p.Cys27fs)	Pathogenic
831251	NC_000014.9:g.(?74480264)(74493284_?)del	Pathogenic
8477	NM_006432.5(NPC2):c.58G>T (p.Glu20Ter)	Pathogenic
8480	NM_006432.5(NPC2):c.352G>T (p.Glu118Ter)	Pathogenic
8482	NM_006432.5(NPC2):c.199T>C (p.Ser67Pro)	Pathogenic
8485	NM_006432.5(NPC2):c.436C>T (p.Gln146Ter)	Pathogenic
915429	NM_006432.5(NPC2):c.157C>T (p.Gln53Ter)	Pathogenic
1332736	NM_006432.5(NPC2):c.297C>G (p.Cys99Trp)	Likely pathogenic

SpliceAI

957 predictions. Top by Δscore:

Variant	Effect	Δscore
14:74480700:A:AC	donor_gain	1.0000
14:74480701:C:CC	donor_gain	1.0000
14:74480701:CGAT:C	donor_gain	1.0000
14:74480775:TTTAT:T	acceptor_gain	1.0000
14:74480776:TTAT:T	acceptor_gain	1.0000
14:74480777:TATCT:T	acceptor_loss	1.0000
14:74480779:TCTGG:T	acceptor_loss	1.0000
14:74480780:C:CC	acceptor_gain	1.0000
14:74480780:CTGG:C	acceptor_loss	1.0000
14:74480781:T:G	acceptor_loss	1.0000
14:74484411:TTA:T	donor_loss	1.0000
14:74484412:TACAG:T	donor_loss	1.0000
14:74484413:A:AC	donor_gain	1.0000
14:74484413:ACAGA:A	donor_loss	1.0000
14:74484414:C:CA	donor_loss	1.0000
14:74484414:C:CC	donor_gain	1.0000
14:74484414:CA:C	donor_gain	1.0000
14:74484414:CAG:C	donor_gain	1.0000
14:74484414:CAGA:C	donor_gain	1.0000
14:74484585:TAT:T	acceptor_gain	1.0000
14:74484587:TCTAA:T	acceptor_loss	1.0000
14:74484588:C:CC	acceptor_gain	1.0000
14:74484588:C:T	acceptor_loss	1.0000
14:74484589:T:C	acceptor_loss	1.0000
14:74486324:CGCA:C	donor_gain	1.0000
14:74486327:A:AC	donor_gain	1.0000
14:74486328:C:CT	donor_gain	1.0000
14:74486328:CTG:C	donor_gain	1.0000
14:74486363:T:TA	donor_gain	1.0000
14:74480700:ACGAT:A	donor_gain	0.9900

AlphaMissense

1000 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:74480761:A:G	W128R	0.997
14:74480761:A:T	W128R	0.997
14:74480754:A:G	L130P	0.995
14:74480759:C:A	W128C	0.995
14:74480759:C:G	W128C	0.995
14:74484482:C:G	C99S	0.995
14:74484483:A:G	C99R	0.995
14:74484483:A:T	C99S	0.995
14:74484500:C:G	C93S	0.995
14:74484501:A:T	C93S	0.995
14:74484524:A:C	F85C	0.995
14:74486330:G:C	S63R	0.995
14:74486330:G:T	S63R	0.995
14:74486332:T:G	S63R	0.995
14:74486336:G:C	F61L	0.995
14:74486336:G:T	F61L	0.995
14:74486337:A:G	F61S	0.995
14:74486338:A:G	F61L	0.995
14:74486349:A:T	V57D	0.995
14:74486379:C:G	C47S	0.995
14:74486380:A:T	C47S	0.995
14:74484422:T:C	Y119C	0.993
14:74484523:A:C	F85L	0.993
14:74484523:A:T	F85L	0.993
14:74484525:A:G	F85L	0.993
14:74486343:A:T	V59D	0.993
14:74486380:A:G	C47R	0.993
14:74486395:A:G	C42R	0.993
14:74480724:C:T	C140Y	0.992
14:74486337:A:C	F61C	0.992

dbSNP variants (sampled 300 via entrez): RS1000030169 (14:74494298 G>A), RS1000046958 (14:74492214 T>C,G), RS1000340124 (14:74484882 G>A), RS1001095669 (14:74480982 G>A,T), RS1001728150 (14:74494688 A>G), RS1001734476 (14:74480868 G>A), RS1001748858 (14:74480399 G>A,C,T), RS1002249807 (14:74481852 C>T), RS1002340489 (14:74493662 T>C), RS1002389680 (14:74493494 G>A,C,T), RS1002738914 (14:74482803 G>T), RS1002741007 (14:74486387 G>A,T), RS1002750257 (14:74482399 G>A), RS1002931704 (14:74484768 A>C), RS1002939874 (14:74490125 C>T)

Disease associations

OMIM: gene MIM:601015 | disease phenotypes: MIM:607625, MIM:257220

GenCC curated gene-disease

Disease	Classification	Inheritance
Niemann-Pick disease, type C2	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 C2	Definitive	AR

Mondo (10): Niemann-Pick disease, type C2 (MONDO:0011873), Niemann-Pick disease type C (MONDO:0018982), microcephaly (MONDO:0001149), Niemann-Pick disease, type C1 (MONDO:0009757), Niemann-Pick disease (MONDO:0001982), 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), Niemann-Pick disease type C, juvenile neurologic onset (MONDO:0016309), Niemann-Pick disease type C, adult neurologic onset (MONDO:0016310)

Orphanet (1): Niemann-Pick disease type C (Orphanet:646)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000511	Vertical supranuclear gaze palsy
HP:0000709	Psychosis
HP:0000726	Dementia
HP:0000733	Motor stereotypy
HP:0000952	Jaundice
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:0001332	Dystonia
HP:0001522	Death in infancy
HP:0001561	Polyhydramnios
HP:0001744	Splenomegaly
HP:0001791	Fetal ascites
HP:0001982	Sea-blue histiocytosis
HP:0002015	Dysphagia
HP:0002093	Respiratory insufficiency
HP:0002185	Neurofibrillary tangles
HP:0002206	Pulmonary fibrosis
HP:0002240	Hepatomegaly
HP:0002371	Loss of speech
HP:0002524	Cataplexy
HP:0002643	Neonatal respiratory distress
HP:0002878	Respiratory failure
HP:0003349	Low cholesterol esterification rate
HP:0003623	Neonatal onset

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003457_3	Soluble receptor for advanced glycation end-product levels	3.000000e-06
GCST009725_70	Intraocular pressure	3.000000e-08
GCST010002_156	Refractive error	7.000000e-25

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007819	advanced glycation end-product measurement
EFO:0004695	intraocular pressure measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
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
C536119	Niemann-Pick disease, type C2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs140130028	NPC2, SYNDIG1L		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression	4
bisphenol A	increases expression	3
Resveratrol	affects cotreatment, increases expression	3
Air Pollutants	increases oxidation, affects expression, decreases expression, affects cotreatment, increases abundance	3
sodium arsenite	affects expression, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Copper	affects cotreatment, increases expression, affects binding	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
arsenite	affects binding, increases reaction	1
sodium bichromate	decreases expression	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
tamibarotene	increases expression	1
yessotoxin	increases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
archazolid B	increases expression	1
bisphenol S	affects cotreatment, increases methylation	1
jinfukang	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
NSC 689534	affects binding, increases expression	1
bisphenol AF	increases expression	1

Cellosaurus cell lines

11 cell lines: 5 finite cell line, 3 cancer cell line, 1 transformed cell line, 1 embryonic stem cell, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B3CM	Abcam HEK293T NPC2 KO	Transformed cell line	Female
CVCL_D5F4	HeLa::TMEM192-3xHA NPC2 KO	Cancer cell line	Female
CVCL_DA48	GM17910	Finite cell line	Male
CVCL_DA76	GM18424	Finite cell line	Female
CVCL_DA77	GM18429	Finite cell line	Male
CVCL_DA79	GM18455	Finite cell line	Male
CVCL_E2EC	HAP1 NPC2 (-) 2	Cancer cell line	Male
CVCL_E3BQ	H9 AAVS1-TRE3G-NGN2 TMEM192-3xHA NPC2-/-	Embryonic stem cell	Female
CVCL_UL88	AKOSi001-A	Induced pluripotent stem cell	Male
CVCL_W153	GM18445	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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
NCT03158324	PHASE2	UNKNOWN	Phase IIa Dose-Expansion and Biomarker Study of OPB-111077
NCT03734809	PHASE2	ACTIVE_NOT_RECRUITING	NEO-SPACE Trial: Pembrolizumab and Chemoradiation in Nasopharyngeal Cancer
NCT07267338	PHASE2	NOT_YET_RECRUITING	Pembrolizumab + MRGOO3 as Neoadjuvant in NPC
NCT04945421	PHASE1	COMPLETED	IBI310 in Combination With Siltilimab in Subjects With Anti-PD-1/PD-L1 Resistance R/M NPC
NCT01747135	PHASE1	COMPLETED	Hydroxypropyl Beta Cyclodextrin for Niemann-Pick Type C1 Disease
NCT02939547	PHASE1	COMPLETED	Study of the Pharmacokinetics of Trappsol and Effects on Potential Biomarkers of Niemann-Pick C1 (NPC1)
NCT03893071	PHASE1	UNKNOWN	Open-Label Study of Long-Term Safety and Efficacy of Intravenous Trappsol Cyclo (HPβCD) in Niemann-Pick Disease Type C
NCT00316498	PHASE1	COMPLETED	Saccadic Eye Movements in Patients With Niemann-Pick Type C Disease
NCT00410566	PHASE1	TERMINATED	Safety Study of rhASM Enzyme Replacement Therapy in Adults With Acid Sphingomyelinase Deficiency (Niemann-Pick Disease)
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT06719479	PHASE2/PHASE3	NOT_YET_RECRUITING	A Clinical Trial to Evaluate Effect of IAE0972 Combined with Chemotherapy for R/M HNSCC or NPC(Note: It is Currently Phase II.).
NCT01744587	Not specified	COMPLETED	Epstein-Barr Virus Reactivation and the Effect of EGCG on Virus Reactivation in Remission Patients
NCT03352778	Not specified	COMPLETED	IMRT vs 2DRT for NPC Patients
NCT03973723	Not specified	COMPLETED	Plasma EBV DNA Monitoring in Post-treatment NPC Patients
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT02912793	PHASE1/PHASE2	COMPLETED	Safety and Efficacy of Intravenous Trappsol Cyclo (HPBCD) in Niemann-Pick Type C Patients
NCT03887533	PHASE1/PHASE2	TERMINATED	Combined Intrathecal and Intravenous VTS-270 Therapy for Liver and Neurological Disease Associated With Niemann-Pick Disease, Type C1
NCT03201627	EARLY_PHASE1	UNKNOWN	Study of Lithium Carbonate to Treat Niemann-Pick Type C1 Disease
NCT05642221	Not specified	COMPLETED	Functional Near-Infrared Spectroscopy (fNIRS) Combined With Diffuse Correlation Spectroscopy (DCS) in Neurocognitive Disease as Compared to Healthy Neurotypical Controls
NCT00176904	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism