Niemann-Pick disease, type C1

Summary

Niemann-Pick disease, type C1 (MONDO:0009757) is a disease caused by NPC1 (GenCC Definitive), with 7 cohort genes and 9 clinical trials. Top therapeutic interventions include lithium carbonate, 2-hydroxypropyl-beta-cyclodextrin, and adrabetadex.

At a glance

• Causal gene: NPC1 (GenCC Definitive)
• Cohort genes: 7
• ClinVar variants: 2,558
• Clinical trials: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Niemann-Pick disease, type C1
Mondo ID	MONDO:0009757
OMIM	257220
DOID	DOID:0070113
NCIT	C126864
SNOMED CT	18927009, 67855008
UMLS	C3179455
MedGen	465922
GARD	0024693
Is cancer (heuristic)	no

Also known as: Niemann-Pick disease type C1 · Niemann-Pick disease, type C1 · NPC1 · type C1 Niemann-Pick disease

Data availability: 2,558 ClinVar variants · 5 GenCC gene-disease records · 66 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › lymphoid system disorder › lymphatic system disorder › histiocytosis › non-Langerhans cell histiocytosis › Niemann-Pick disease › Niemann-Pick disease type C › Niemann-Pick disease, type C1

Related subtypes (6): Niemann-Pick disease, type C2, Niemann-Pick disease type C, severe perinatal form, Niemann-Pick disease type C, severe early infantile neurologic onset, Niemann-Pick disease type C, late infantile neurologic onset, Niemann-Pick disease type C, juvenile neurologic onset, Niemann-Pick disease type C, adult neurologic onset

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

345 likely benign, 146 uncertain significance, 50 pathogenic, 25 likely pathogenic, 16 pathogenic/likely pathogenic, 14 conflicting classifications of pathogenicity, 3 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1019102	NM_000271.5(NPC1):c.1901A>T (p.Tyr634Phe)	NPC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1026548	NM_000271.5(NPC1):c.3001A>G (p.Met1001Val)	NPC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030709	NM_000271.5(NPC1):c.2297T>A (p.Leu766Ter)	NPC1	Pathogenic	criteria provided, single submitter
1050802	NM_000271.5(NPC1):c.2374-1G>A	NPC1	Pathogenic	criteria provided, single submitter
1066745	NM_000271.5(NPC1):c.2291C>T (p.Ala764Val)	NPC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1066746	NM_000271.5(NPC1):c.1114C>T (p.Arg372Trp)	NPC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068516	NM_000271.5(NPC1):c.1123A>G (p.Thr375Ala)	NPC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068529	NM_000271.5(NPC1):c.3152_3153del (p.Phe1051fs)	NPC1	Pathogenic	criteria provided, single submitter
1068796	NM_000271.5(NPC1):c.2857_2858del (p.Gln953fs)	NPC1	Pathogenic	criteria provided, single submitter
1070529	NM_000271.5(NPC1):c.1654+1G>A	NPC1	Pathogenic	criteria provided, single submitter
1070840	NM_000271.5(NPC1):c.85G>T (p.Gly29Ter)	NPC1	Pathogenic	criteria provided, single submitter
1071316	NM_000271.5(NPC1):c.3044G>T (p.Gly1015Val)	NPC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071436	NM_000271.5(NPC1):c.349C>T (p.Gln117Ter)	NPC1	Pathogenic	criteria provided, single submitter
1071500	NM_000271.5(NPC1):c.3122dup (p.Tyr1041Ter)	NPC1	Pathogenic	criteria provided, single submitter
1071813	NM_000271.5(NPC1):c.248_249del (p.Leu83fs)	NPC1	Pathogenic	criteria provided, single submitter
1071835	NM_000271.5(NPC1):c.3294dup (p.Ile1099fs)	NPC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1072937	NM_000271.5(NPC1):c.2683G>T (p.Glu895Ter)	NPC1	Pathogenic	criteria provided, single submitter
1073904	NM_000271.5(NPC1):c.644del (p.His215fs)	NPC1	Pathogenic	criteria provided, single submitter
1073931	NM_000271.5(NPC1):c.2928C>A (p.Cys976Ter)	NPC1	Pathogenic	criteria provided, single submitter
1074756	NM_000271.5(NPC1):c.2823del (p.Trp942fs)	NPC1	Pathogenic	criteria provided, single submitter
1074872	NM_000271.5(NPC1):c.1531_1532del (p.Thr511fs)	NPC1	Pathogenic	criteria provided, single submitter
1075415	NM_000271.5(NPC1):c.3083_3084del (p.Gly1028fs)	NPC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076100	NM_000271.5(NPC1):c.350dup (p.Ser118fs)	NPC1	Pathogenic	criteria provided, single submitter
1076409	NM_000271.5(NPC1):c.3299_3300dup (p.Asn1101fs)	NPC1	Pathogenic	criteria provided, single submitter
132888	NM_000271.5(NPC1):c.1030del (p.Ser344fs)	NPC1	Pathogenic	no assertion criteria provided
132889	NM_000271.5(NPC1):c.1502A>T (p.Asp501Val)	NPC1	Pathogenic	no assertion criteria provided
132890	NM_000271.5(NPC1):c.1553G>A (p.Arg518Gln)	NPC1	Pathogenic	criteria provided, multiple submitters, no conflicts
132891	NM_000271.5(NPC1):c.1800del (p.Ile601fs)	NPC1	Pathogenic	criteria provided, single submitter
132892	NM_000271.5(NPC1):c.1832A>G (p.Asp611Gly)	NPC1	Pathogenic	no assertion criteria provided
132894	NM_000271.5(NPC1):c.2128C>T (p.Gln710Ter)	NPC1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NPC1	Definitive	Autosomal recessive	Niemann-Pick disease, type C1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPC1	Orphanet:216972	Niemann-Pick disease type C, severe perinatal form
NPC1	Orphanet:216975	Niemann-Pick disease type C, severe early infantile neurologic onset
NPC1	Orphanet:216978	Niemann-Pick disease type C, late infantile neurologic onset
NPC1	Orphanet:216981	Niemann-Pick disease type C, juvenile neurologic onset
NPC1	Orphanet:216986	Niemann-Pick disease type C, adult neurologic onset
SMPD1	Orphanet:77292	Infantile neurovisceral acid sphingomyelinase deficiency
SMPD1	Orphanet:77293	Chronic visceral acid sphingomyelinase deficiency
NPC2	Orphanet:216972	Niemann-Pick disease type C, severe perinatal form
NPC2	Orphanet:216975	Niemann-Pick disease type C, severe early infantile neurologic onset
NPC2	Orphanet:216978	Niemann-Pick disease type C, late infantile neurologic onset
NPC2	Orphanet:216981	Niemann-Pick disease type C, juvenile neurologic onset
NPC2	Orphanet:216986	Niemann-Pick disease type C, adult neurologic onset

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NPC1	HGNC:7897	ENSG00000141458	O15118	NPC intracellular cholesterol transporter 1	gencc,clinvar
SMPD1	HGNC:11120	ENSG00000166311	P17405	Sphingomyelin phosphodiesterase	clinvar
NPC2	HGNC:14537	ENSG00000119655	P61916	NPC intracellular cholesterol transporter 2	clinvar
ACYP1	HGNC:179	ENSG00000119640	P07311	Acylphosphatase-1	clinvar
ANKRD29	HGNC:27110	ENSG00000154065	Q8N6D5	Ankyrin repeat domain-containing protein 29	clinvar
SYNDIG1L	HGNC:32388	ENSG00000183379	A6NDD5	Synapse differentiation-inducing gene protein 1-like	clinvar
MIR4709	HGNC:41690	ENSG00000283944		microRNA 4709	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NPC1	NPC intracellular cholesterol transporter 1	Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment.
SMPD1	Sphingomyelin phosphodiesterase	Converts sphingomyelin to ceramide.
NPC2	NPC intracellular cholesterol transporter 2	Intracellular cholesterol transporter which acts in concert with NPC1 and plays an important role in the egress of cholesterol from the lysosomal compartment.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.29

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Phosphatase	1	12.0×	0.322
Scaffold/PPI	1	2.5×	0.609
Enzyme (other)	1	1.7×	0.609
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPC1	Other/Unknown	no		SSD, NPC1-like, NPC1_N
SMPD1	Enzyme (other)	yes	3.1.4.12	Calcineurin-like_PHP, SaposinB_dom, Saposin-like
NPC2	Other/Unknown	no		ML_dom, Ig_E-set, ML_Npc2-like
ACYP1	Phosphatase	yes		Acylphosphatase-like_dom, Acylphosphatase_CS, Acylphosphatase
ANKRD29	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Dendritic_Spine_Reg/Scaffold
SYNDIG1L	Other/Unknown	no		CD225/Dispanin_fam
MIR4709	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	6
unknown	1

Top tissues across cohort

Tissue	Cohort genes
right lung	2
adrenal tissue	1
oocyte	1
secondary oocyte	1
islet of Langerhans	1
stromal cell of endometrium	1
type B pancreatic cell	1
cauda epididymis	1
corpus epididymis	1
epididymis	1
right uterine tube	1
ventricular zone	1
parietal pleura	1
upper lobe of left lung	1
caudate nucleus	1
nucleus accumbens	1
putamen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NPC1	292	ubiquitous	marker	secondary oocyte, oocyte, adrenal tissue
SMPD1	262	ubiquitous	marker	type B pancreatic cell, stromal cell of endometrium, islet of Langerhans
NPC2	296	ubiquitous	marker	corpus epididymis, cauda epididymis, epididymis
ACYP1	276	ubiquitous	marker	right uterine tube, right lung, ventricular zone
ANKRD29	229	broad	marker	right lung, parietal pleura, upper lobe of left lung
SYNDIG1L	147	tissue_specific	yes	putamen, caudate nucleus, nucleus accumbens
MIR4709		tissue_specific	yes

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPC1	2,648
SMPD1	1,729
NPC2	1,706
ANKRD29	1,280
SYNDIG1L	674
ACYP1	627
MIR4709	0

Intra-cohort edges

A	B	Sources
NPC1	NPC2	intact, string_interaction
NPC2	SMPD1	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPC1	O15118	20
ACYP1	P07311	7
SMPD1	P17405	4
NPC2	P61916	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKRD29	Q8N6D5	91.86
SYNDIG1L	A6NDD5	55.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 7 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
LDL clearance	2	362.5×	8e-05	NPC1, NPC2
Glycosphingolipid metabolism	1	100.2×	0.026	SMPD1
Glycosphingolipid catabolism	1	97.6×	0.026	SMPD1
Regulation of clotting cascade	1	77.7×	0.026	SMPD1
Sphingolipid metabolism	1	56.0×	0.028	SMPD1
Metabolism of lipids	1	10.5×	0.123	SMPD1
Neutrophil degranulation	1	7.7×	0.142	NPC2
Metabolism	1	3.9×	0.237	SMPD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cholesterol storage	2	1203.7×	3e-05	NPC1, NPC2
cholesterol metabolic process	3	147.0×	3e-05	NPC1, SMPD1, NPC2
intracellular cholesterol transport	2	648.1×	6e-05	NPC1, NPC2
cholesterol transport	2	366.4×	2e-04	NPC1, NPC2
cholesterol efflux	2	263.3×	2e-04	NPC1, NPC2
symbiont entry into host cell	2	200.6×	3e-04	NPC1, SMPD1
regulation of isoprenoid metabolic process	1	4213.0×	0.002	NPC2
cyclodextrin metabolic process	1	4213.0×	0.002	NPC1
cholesterol homeostasis	2	78.0×	0.002	NPC1, NPC2
response to virus	2	72.0×	0.002	SMPD1, NPC2
termination of signal transduction	1	1404.3×	0.003	SMPD1
intracellular lipid transport	1	1404.3×	0.003	NPC1
glycolipid transport	1	1404.3×	0.003	NPC2
sphingomyelin metabolic process	1	842.6×	0.004	SMPD1
sphingomyelin catabolic process	1	842.6×	0.004	SMPD1
membrane raft organization	1	842.6×	0.004	NPC1
intracellular sterol transport	1	842.6×	0.004	NPC2
gene expression	2	39.9×	0.004	NPC1, NPC2
response to xenobiotic stimulus	2	34.5×	0.004	NPC1, SMPD1
sterol transport	1	702.2×	0.004	NPC1
response to type I interferon	1	468.1×	0.006	SMPD1
establishment of protein localization to membrane	1	468.1×	0.006	NPC1
glycosphingolipid catabolic process	1	383.0×	0.006	SMPD1
intestinal cholesterol absorption	1	351.1×	0.007	NPC1
programmed cell death	1	324.1×	0.007	NPC1
positive regulation of viral entry into host cell	1	300.9×	0.007	SMPD1
negative regulation of epithelial cell apoptotic process	1	300.9×	0.007	NPC1
negative regulation of macroautophagy	1	280.9×	0.007	NPC1
cellular response to steroid hormone stimulus	1	263.3×	0.007	NPC1
phosphate-containing compound metabolic process	1	247.8×	0.007	ACYP1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 2 of 7 evidence-associated genes (29%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NPC1	NABUMETONE
SMPD1	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NPC1	90	4
SMPD1	3	4
NPC2	0	0
ACYP1	0	0
ANKRD29	0	0
SYNDIG1L	0	0
MIR4709	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NABUMETONE	4	NPC1
PHENELZINE	4	NPC1
AMLEXANOX	4	NPC1
IDARUBICIN	4	NPC1
RABEPRAZOLE SODIUM	4	NPC1
NITAZOXANIDE	4	NPC1
NICLOSAMIDE	4	NPC1
NITROXOLINE	4	NPC1
NICARDIPINE	4	NPC1
DAUNORUBICIN HYDROCHLORIDE	4	NPC1
INDOPROFEN	4	NPC1
CYCLOSPORINE	4	NPC1
TERFENADINE	4	NPC1
DIGOXIN	4	NPC1
PRAZOSIN	4	NPC1
MAPROTILINE	4	NPC1
DIGITOXIN	4	NPC1
HYDRALAZINE	4	NPC1
EBASTINE	4	NPC1
DEQUALINIUM	4	NPC1
DOXORUBICIN HYDROCHLORIDE	4	NPC1
VINBLASTINE SULFATE	4	NPC1
FLUOXETINE	4	NPC1
DITHIAZANINE IODIDE	4	NPC1
TRIFLUOPERAZINE	4	NPC1
PACLITAXEL	4	NPC1
NORTRIPTYLINE	4	NPC1
MIBEFRADIL	4	NPC1
FLUSPIRILENE	4	NPC1
KETOROLAC	4	NPC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SMPD1	42	Binding:40, Functional:2
NPC1	18	Binding:13, Functional:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SMPD1	3.1.4.12	sphingomyelin phosphodiesterase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
NABUMETONE	4	NPC1
PHENELZINE	4	NPC1
AMLEXANOX	4	NPC1
IDARUBICIN	4	NPC1
RABEPRAZOLE SODIUM	4	NPC1
NITAZOXANIDE	4	NPC1
NICLOSAMIDE	4	NPC1
NITROXOLINE	4	NPC1
NICARDIPINE	4	NPC1
DAUNORUBICIN HYDROCHLORIDE	4	NPC1
INDOPROFEN	4	NPC1
CYCLOSPORINE	4	NPC1
TERFENADINE	4	NPC1
DIGOXIN	4	NPC1
PRAZOSIN	4	NPC1
MAPROTILINE	4	NPC1
DIGITOXIN	4	NPC1
HYDRALAZINE	4	NPC1
EBASTINE	4	NPC1
DEQUALINIUM	4	NPC1
DOXORUBICIN HYDROCHLORIDE	4	NPC1
VINBLASTINE SULFATE	4	NPC1
FLUOXETINE	4	NPC1
DITHIAZANINE IODIDE	4	NPC1
TRIFLUOPERAZINE	4	NPC1
PACLITAXEL	4	NPC1
NORTRIPTYLINE	4	NPC1
MIBEFRADIL	4	NPC1
FLUSPIRILENE	4	NPC1
KETOROLAC	4	NPC1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	NPC1, SMPD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ACYP1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	NPC2, ANKRD29, SYNDIG1L, MIR4709

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NPC2	0	NPC1
ACYP1	0	—
ANKRD29	0	—
SYNDIG1L	0	—
MIR4709	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	3
PHASE1/PHASE2	2
Not specified	2
PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
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
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
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
NCT03201627	EARLY_PHASE1	UNKNOWN	Study of Lithium Carbonate to Treat Niemann-Pick Type C1 Disease
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05642221	Not specified	COMPLETED	Functional Near-Infrared Spectroscopy (fNIRS) Combined With Diffuse Correlation Spectroscopy (DCS) in Neurocognitive Disease as Compared to Healthy Neurotypical Controls

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LITHIUM CARBONATE	4	1
2-HYDROXYPROPYL-BETA-CYCLODEXTRIN	3	3
ADRABETADEX	3	2
CHEMBL4303326	0	3