SMPD1

Summary

SMPD1 (sphingomyelin phosphodiesterase 1, HGNC:11120) is a protein-coding gene on chromosome 11p15.4, encoding Sphingomyelin phosphodiesterase (P17405). Converts sphingomyelin to ceramide.

The protein encoded by this gene is a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide. The encoded protein also has phospholipase C activity. Defects in this gene are a cause of Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB). Multiple transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 6609 — RefSeq curated summary.

At a glance

• Gene–disease (curated): acid sphingomyelinase deficiency (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 1,172 total — 129 pathogenic, 172 likely-pathogenic
• Phenotypes (HPO): 91
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000543

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11120
Approved symbol	SMPD1
Name	sphingomyelin phosphodiesterase 1
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	ASM
Ensembl gene	ENSG00000166311
Ensembl biotype	protein_coding
OMIM	607608
Entrez	6609

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000342245, ENST00000526280, ENST00000527275, ENST00000530395, ENST00000531303, ENST00000531336, ENST00000532367, ENST00000533123, ENST00000533196, ENST00000534405, ENST00000880909, ENST00000880910, ENST00000880911

RefSeq mRNA: 5 — MANE Select: NM_000543 NM_000543, NM_001007593, NM_001318087, NM_001318088, NM_001365135

CCDS: CCDS31409, CCDS44531

Canonical transcript exons

ENST00000342245 — 6 exons

Exon	Start	End
ENSE00001372035	6391384	6392156
ENSE00001379501	6394198	6394996
ENSE00002184545	6390474	6390916
ENSE00003532835	6393216	6393387
ENSE00003552053	6393896	6394041
ENSE00003583142	6393617	6393693

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 97.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.4304 / max 277.7188, expressed in 1815 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112847	42.7641	1813
112848	0.6544	334
112849	0.5259	251
112856	0.4591	238
112855	0.3503	101
112851	0.3354	166
112853	0.1796	85
112854	0.1616	56

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	97.49	silver quality
stromal cell of endometrium	CL:0002255	96.64	gold quality
islet of Langerhans	UBERON:0000006	96.07	gold quality
apex of heart	UBERON:0002098	95.92	gold quality
right lobe of liver	UBERON:0001114	95.76	gold quality
adenohypophysis	UBERON:0002196	94.73	gold quality
metanephros cortex	UBERON:0010533	94.67	gold quality
tendon of biceps brachii	UBERON:0008188	94.56	silver quality
right hemisphere of cerebellum	UBERON:0014890	94.54	gold quality
olfactory bulb	UBERON:0002264	94.50	silver quality
right atrium auricular region	UBERON:0006631	94.26	gold quality
cerebellar hemisphere	UBERON:0002245	94.10	gold quality
cerebellar cortex	UBERON:0002129	94.08	gold quality
mucosa of transverse colon	UBERON:0004991	93.94	gold quality
heart left ventricle	UBERON:0002084	93.92	gold quality
cardiac ventricle	UBERON:0002082	93.70	gold quality
right lobe of thyroid gland	UBERON:0001119	93.69	gold quality
cardiac atrium	UBERON:0002081	93.66	gold quality
pituitary gland	UBERON:0000007	93.40	gold quality
adult mammalian kidney	UBERON:0000082	93.21	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.20	gold quality
left lobe of thyroid gland	UBERON:0001120	93.17	gold quality
left adrenal gland cortex	UBERON:0035825	93.10	gold quality
left adrenal gland	UBERON:0001234	93.07	gold quality
right adrenal gland	UBERON:0001233	93.01	gold quality
right adrenal gland cortex	UBERON:0035827	92.99	gold quality
skin of leg	UBERON:0001511	92.89	gold quality
spinal cord	UBERON:0002240	92.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.81	gold quality
granulocyte	CL:0000094	92.72	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.72

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, TFAP2A, TP53

miRNA regulators (miRDB)

26 targeting SMPD1, 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-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-155-3P	99.03	67.99	924
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-5699-3P	97.81	65.00	861
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-1289	97.46	65.37	655
HSA-MIR-612	97.26	65.95	1597
HSA-MIR-6860	97.21	66.31	1656
HSA-MIR-4288	97.11	67.23	1636
HSA-MIR-346	97.01	66.97	662
HSA-MIR-5586-5P	96.29	68.02	685

Literature-anchored findings (GeneRIF, showing 40)

• Up-regulation of acid sphingomyelinase during retinoic acid-induced myeloid differentiation (PMID:11788605)
• contribution of acidic sphingomyelinase (ASMase), a ceramide generating enzyme, in tumor necrosis factor (TNF)-mediated apoptosis in human colon HT-29 cells (PMID:12208520)
• first extensive demographic assessment of type B Niemann-Pick disease and several new mutations that can be used to predict phenotypic outcome and gain new insights into the structure and function of SMPD1 (PMID:12369017)
• SMPD1 mutation (r608del) is prevalent among Niemann-Pick disease type b patients from the North-African Maghreb region. (PMID:12556236)
• data report the identification of the disulfide bond pattern of human acid sphingomyelinase (PMID:12631268)
• human acid sphingomyelinase is activated through modification or deletion of C-terminal cysteine (PMID:12801930)
• biochemistry of acid ceramidase reaction with acid sphingomyelinase (PMID:12815059)
• Activity of Zn++-dependent acid sphingomyelinase in patients was nearly twice the activity in healty subjects. (PMID:12953170)
• reduction in SMase-generating ceramides and impaired differentiation are involved in the defective barrier function found in atopic dermatitis (PMID:15175033)
• Mutation analysis detected 14 novel SMPD1 mutations in Italian Niemann-Pick A patients. (PMID:15221801)
• Six novel base changes and three frameshift mutations were identified amoung 18 Italian Niemann Pick disease patients in SMPD1. (PMID:15241805)
• Activated acid sphingomyelinase (ASMase) plays a central role in dendritic cell (DC) apoptosis induced by Escherichia coli/lipopolysaccharide (LPS); protection by nitric oxide/cyclic GMP in vivo occurs through inhibition of ASMase activation. (PMID:15383576)
• results suggest that UV light-triggered acid sphingomyelinase activation is essentially required for Bax protein conformational change leading to mitochondrial release of pro-apoptotic factors (PMID:15743760)
• raft-associated acid sphingomyelinase and JNK activation and translocation are induced by UV-C light on a nuclear signal (PMID:15769735)
• acid sphingomyelinase activation within rafts involves a Fas-mediated mechanism dependent upon caspase 8 and FADD (PMID:15849201)
• broad phenotypic potential of ASM deficiency, suggesting the existence of still unknown factors independently controlling the storage level in the visceral and neuronal compartments (PMID:15877209)
• infection of human epithelial cells with rhinovirus triggers a rapid activation of the acid sphingomyelinase correlating with its microtubule- and microfilament-mediated translocation from an intracellular compartment onto the cell membrane (PMID:15888438)
• Data show that 93lysine residue plays a critical role in acid sphingomyelinase targeting since the K93A mutant had reduced intracellular activity, but enhanced secreted activity that was zinc responsive. (PMID:15997205)
• analysis of SMPD1 mutations in Italian patients affected by Niemann Pick Type B disease [case report] (PMID:16010684)
• sphingomyelinase has a role in apoptosis and organ failure in sepsis (PMID:16051685)
• In the major depression patient group, A-SMase activity was correlated to the score (n=17, r=0.64, P=0.005). The patient group exhibited higher A-SMase activity compared to healthy volunteers (T=2.09, df=21.33, P<0.05). (PMID:16245071)
• Six novel base changes and three frameshift mutations were identified amoung 18 Italian Niemann Pick disease patients in SMPD1. (PMID:16472269)
• These data thus demonstrate, for the first time, imprinting at the SMPD1 gene and reveal the influence of this epigenetic modification on the presentation of ASM-deficient NPD. (PMID:16642440)
• ASM uses sortilin as an alternative receptor to be targeted to the lysosomes (PMID:16787399)
• Assembly and activation of the TLR4 receptor following LPS binding to CD14 requires the production of ceramide by acid sphingomyelinase. (PMID:17381401)
• study provides key molecular insights into activation of ASMase in response to UV light, the role of PKCdelta in this activation, and the role of ASMase in mediating apoptotic responses (PMID:17698617)
• carboxyl-terminus of the ASM is crucial for its protein structure, which in turns dictates the enzymatic function and secretion (PMID:18052040)
• the two common coding variants at the SMPD1 gene locus are not associated with low HDL-cholesterol levels in the French Canadian population. (PMID:18088425)
• Since cisplatin activates acid sphingomyelinase (ASMase), we investigate the role of the ASMase/ceramide (Cer) pathway in mediating morphological changes in a breast cancer cell line. (PMID:18426979)
• Acid sphingomyelinase overexpression enhances the antineoplastic effects of irradiation in mouse melanomas. (PMID:18628757)
• Marked deficiencies of SMPD1 activity in primary skin fibroblasts harvested from Niemann-Pick disease patients. (PMID:18815062)
• Mycoplasma pneumoniae infection could affect the expression of SPT or the distribution of ASM at certain concentrations in A549 cells. (PMID:19059331)
• Results represent the first demonstration that activation of acid sphingomyelinase is necessary and sufficient for microparticle release from glial cells. (PMID:19300439)
• first exhaustive mutational analysis of Spanish Niemann-Pick A/B disease patients (PMID:19405096)
• inhibition of both A- and N1-Smase might explain the upregulatory effect of agLDL on TF activation, and suggest that this effect is related, at least in part, to membrane SM enrichment. (PMID:19817993)
• Alcohol-induced activation of sphingomyelin phosphodiesterase occured in human subjects who were alcohol dependent and appears to be responsible for the deleterious effects of ethanol intoxication. (PMID:19860808)
• In amnion cells EGFR clustering induced by 50-Hz MF depends on acid sphingomyelinase activity. (PMID:20137294)
• Report the identification, characterization and genotype/phenotype correlations of eight novel SMPD1 mutations in six unrelated Types A and B Niemann-Pick disease (NPD) patients. (PMID:20386867)
• Data support a crucial role for Ser(508) in the regulation of S-SMase secretion, and they suggest distinct metabolic roles for S-SMase and L-SMase. (PMID:20807762)
• Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function. (PMID:20956541)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	smpd1	ENSDARG00000076121
mus_musculus	Smpd1	ENSMUSG00000037049
rattus_norvegicus	Smpd1	ENSRNOG00000017977
drosophila_melanogaster	CG15533	FBGN0039768
drosophila_melanogaster	CG15534	FBGN0039769
caenorhabditis_elegans		WBGENE00000211
caenorhabditis_elegans		WBGENE00000212
caenorhabditis_elegans		WBGENE00000213

Paralogs (2): SMPDL3B (ENSG00000130768), SMPDL3A (ENSG00000172594)

Protein

Protein identifiers

Sphingomyelin phosphodiesterase — P17405 (reviewed: P17405)

Alternative names: Acid sphingomyelinase

All UniProt accessions (6): P17405, E9PL59, E9PPK6, E9PQT3, G3V1E1, H0YEP5

UniProt curated annotations — full annotation on UniProt →

Function. Converts sphingomyelin to ceramide. Exists as two enzymatic forms that arise from alternative trafficking of a single protein precursor, one that is targeted to the endolysosomal compartment, whereas the other is released extracellularly. However, in response to various forms of stress, lysosomal exocytosis may represent a major source of the secretory form. In the lysosomes, converts sphingomyelin to ceramide. Plays an important role in the export of cholesterol from the intraendolysosomal membranes. Also has phospholipase C activities toward 1,2-diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol. Modulates stress-induced apoptosis through the production of ceramide. When secreted, modulates cell signaling with its ability to reorganize the plasma membrane by converting sphingomyelin to ceramide. Secreted form is increased in response to stress and inflammatory mediators such as IL1B, IFNG or TNF as well as upon infection with bacteria and viruses. Produces the release of ceramide in the outer leaflet of the plasma membrane playing a central role in host defense. Ceramide reorganizes these rafts into larger signaling platforms that are required to internalize P.aeruginosa, induce apoptosis and regulate the cytokine response in infected cells. In wounded cells, the lysosomal form is released extracellularly in the presence of Ca(2+) and promotes endocytosis and plasma membrane repair. This form is generated following cleavage by CASP7 in the extracellular milieu in response to bacterial infection. It shows increased ability to convert sphingomyelin to ceramide and promotes plasma membrane repair. Plasma membrane repair by ceramide counteracts the action of gasdermin-D (GSDMD) perforin (PRF1) pores that are formed in response to bacterial infection. (Microbial infection) Secretion is activated by bacteria such as P.aeruginosa, N.gonorrhoeae and others, this activation results in the release of ceramide in the outer leaflet of the plasma membrane which facilitates the infection. (Microbial infection) Secretion is activated by human coronaviruses SARS-CoV and SARS-CoV-2 as well as Zaire ebolavirus, this activation results in the release of ceramide in the outer leaflet of the plasma membrane which facilitates the infection. Lacks residues that bind the cofactor Zn(2+) and has no enzyme activity. Lacks residues that bind the cofactor Zn(2+) and has no enzyme activity.

Subunit / interactions. Monomer. Interacts with SORT1; the interaction is required for SMPD1 targeting to lysosomes.

Subcellular location. Lysosome. Lipid droplet. Secreted Secreted. Extracellular space.

Post-translational modifications. Proteolytically processed. Mature lysosomal form arises from C-terminal proteolytic processing of pro-sphingomyelin phosphodiesterase. This form is generated following cleavage by CASP7 in the extracellular milieu. It shows increased activity. Both lysosomal and secreted forms are glycosylated but they show a differential pattern of glycosylation. Phosphorylated at Ser-510 by PRKCD upon stress stimuli. Phosphorylation is required for secretion.

Disease relevance. Niemann-Pick disease A (NPDA) [MIM:257200] An early-onset lysosomal storage disorder caused by failure to hydrolyze sphingomyelin to ceramide. It results in the accumulation of sphingomyelin and other metabolically related lipids in reticuloendothelial and other cell types throughout the body, leading to cell death. Niemann-Pick disease type A is a primarily neurodegenerative disorder characterized by onset within the first year of life, intellectual disability, digestive disorders, failure to thrive, major hepatosplenomegaly, and severe neurologic symptoms. The severe neurological disorders and pulmonary infections lead to an early death, often around the age of four. Clinical features are variable. A phenotypic continuum exists between type A (basic neurovisceral) and type B (purely visceral) forms of Niemann-Pick disease, and the intermediate types encompass a cluster of variants combining clinical features of both types A and B. The disease is caused by variants affecting the gene represented in this entry. Niemann-Pick disease B (NPDB) [MIM:607616] A late-onset lysosomal storage disorder caused by failure to hydrolyze sphingomyelin to ceramide. It results in the accumulation of sphingomyelin and other metabolically related lipids in reticuloendothelial and other cell types throughout the body, leading to cell death. Clinical signs involve only visceral organs. The most constant sign is hepatosplenomegaly which can be associated with pulmonary symptoms. Patients remain free of neurologic manifestations. However, a phenotypic continuum exists between type A (basic neurovisceral) and type B (purely visceral) forms of Niemann-Pick disease, and the intermediate types encompass a cluster of variants combining clinical features of both types A and B. In Niemann-Pick disease type B, onset of the first symptoms occurs in early childhood and patients can survive into adulthood. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Hydrolysis of liposomal sphingomyelin is stimulated by incorporation of diacylglycerol (DAG), ceramide and free fatty acids into the liposomal membranes. Phosphatidylcholine hydrolysis is inhibited by incorporation of cholesterol, ceramide, DAG, monoacylglycerol and fatty acids. Antidepressants, namely amitriptyline, imipramine, desipramine, fluoxetine, sertraline, escitalopram, and maprotiline inhibit sphingomyelin phosphodiesterase activity. (Microbial infection) The secretory form is activated by P.aeruginosa, this activation results in the release of ceramide in the outer leaflet of the plasma membrane. (Microbial infection) The secretory form is activated by human coronavirus SARS-CoV-2, this activation results in the release of ceramide in the outer leaflet of the plasma membrane.

Cofactor. Binds 2 Zn(2+) ions per subunit.

Polymorphism. A common polymorphism arises from a variable number of hexanucleotide repeat sequence within the signal peptide region.

Miscellaneous. There are two types of sphingomyelinases: ASM (acid), and NSM (neutral). Most abundant (90%). Intermediate abundance (10%). Low abundance (<1%).

Similarity. Belongs to the acid sphingomyelinase family.

Isoforms (4)

UniProt ID	Names	Canonical?
P17405-1	1, ASM-1	yes
P17405-2	2, ASM-2
P17405-3	3, ASM-3
P17405-4	4

RefSeq proteins (5): NP_000534, NP_001007594, NP_001305016, NP_001305017, NP_001352064 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004843	Calcineurin-like_PHP	Domain
IPR008139	SaposinB_dom	Domain
IPR011001	Saposin-like	Homologous_superfamily
IPR011160	Sphingomy_PDE	Family
IPR029052	Metallo-depent_PP-like	Homologous_superfamily
IPR041805	ASMase/PPN1_MPP	Domain
IPR045473	ASM_C	Domain

Pfam: PF00149, PF19272

Enzyme classification (BRENDA):

• EC 3.1.4.12 — sphingomyelin phosphodiesterase (BRENDA: 30 organisms, 220 substrates, 319 inhibitors, 54 Km, 10 kcat entries)

Substrate kinetics (BRENDA)

18 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
SPHINGOMYELIN	0.0006–13	30
2-N-HEXADECANOYLAMINO-4-NITROPHENYLPHOSPHORYLCHO	0.034–0.34	2
4-(4-NITROPHENOXY)-2-HYDROXY-BUTYL-1-PHOSPHORYLC	12.6–39.6	2
1-ALKYL-LYSO-PLATELET ACTIVATING FACTOR	0.048	1
2-(N-HEXADECANOYLAMINO)-4-NITROPHENYLPHOSPHORYLC	1.7	1
2N-HEXADECANOYLAMINO-4-NITROPHENYLPHOSPHORYLCHOL	0.027	1
4-NITROPHENYL PHOSPHORYLCHOLINE	11.6	1
ADP	0.306	1
ADP-RIBOSE	0.348	1
ATP	0.327	1
BIS-P-NITROPHENYL PHOSPHATE	14.5	1
BODIPYFL-C12-SPHINGOMYELIN	0.06	1
CDP-CHOLINE	0.262	1
CDP-ETHANOLAMINE	0.391	1
HEXADECANOYL-P-NITROPHENYL PHOSPHORYLCHOLINE	0.174	1

Catalyzed reactions (Rhea), 4 shown:

• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = phosphocholine + a 1,2-diacyl-sn-glycerol + H(+) (RHEA:10604)
• a sphingomyelin + H2O = phosphocholine + an N-acylsphing-4-enine + H(+) (RHEA:19253)
• 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1,2-dihexadecanoyl-sn-glycerol + phosphocholine + H(+) (RHEA:45304)
• N-(octadecanoyl)-sphing-4-enine-1-phosphocholine + H2O = N-octadecanoylsphing-4-enine + phosphocholine + H(+) (RHEA:54284)

UniProt features (220 total): sequence variant 127, helix 22, strand 17, mutagenesis site 12, binding site 8, turn 8, disulfide bond 8, glycosylation site 6, splice variant 4, chain 2, signal peptide 1, site 1, modified residue 1, sequence conflict 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5I81	X-RAY DIFFRACTION	2.25
5I85	X-RAY DIFFRACTION	2.5
5JG8	X-RAY DIFFRACTION	2.8
5I8R	X-RAY DIFFRACTION	3.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17405-F1	88.37	0.83

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): 253–254 (cleavage; by casp7)

Ligand- & substrate-binding residues (8): 427; 459; 461; 208; 210; 280; 280; 320

Post-translational modifications (1): 510

Disulfide bonds (8): 91–167, 94–159, 122–133, 223–228, 229–252, 387–433, 586–590, 596–609

Glycosylation sites (6): 88, 177, 337, 397, 505, 522

Mutagenesis-validated functional residues (12):

Position	Phenotype
88	no effect on sphingomyelin phosphodiesterase activity. no effect on secretion.
151	no effect on sphingomyelin phosphodiesterase activity. no effect on subcellular location. no effect on phosphorylation b
177	reduces protein levels. reduces sphingomyelin phosphodiesterase activity. no effect on secretion.
225	does not affect cleavage by casp7.
233	no effect on sphingomyelin phosphodiesterase activity. no effect on endolysosome location. no effect on phosphorylation
250	no effect on sphingomyelin phosphodiesterase activity. no effect on endolysosome location. no effect on phosphorylation
253	abolished cleavage by casp7.
337	no effect on sphingomyelin phosphodiesterase activity. no effect on secretion.
397	reduces sphingomyelin phosphodiesterase activity. no effect on secretion.
505	loss of sphingomyelin phosphodiesterase activity. loss of secretion.
510	abolishes constitutive secretion and decreases secretion in response to il1b. no effect on lysosomal targeting. no effec
522	loss of sphingomyelin phosphodiesterase activity. loss of secretion.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-9769739	Regulation of clotting cascade
R-HSA-9840310	Glycosphingolipid catabolism
R-HSA-1430728	Metabolism
R-HSA-1660662	Glycosphingolipid metabolism
R-HSA-428157	Sphingolipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 456 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_RESPONSE_TO_COCAINE, BIOCARTA_EDG1_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_RESPONSE_TO_PEPTIDE, FISCHER_G1_S_CELL_CYCLE, GOCC_SECRETORY_GRANULE, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_SPHINGOMYELIN_METABOLIC_PROCESS, GOBP_PLASMA_MEMBRANE_ORGANIZATION

GO Biological Process (28): plasma membrane repair (GO:0001778), sphingomyelin metabolic process (GO:0006684), sphingomyelin catabolic process (GO:0006685), signal transduction (GO:0007165), nervous system development (GO:0007399), cholesterol metabolic process (GO:0008203), response to xenobiotic stimulus (GO:0009410), response to virus (GO:0009615), response to ionizing radiation (GO:0010212), termination of signal transduction (GO:0023021), response to type I interferon (GO:0034340), response to tumor necrosis factor (GO:0034612), cellular response to UV (GO:0034644), wound healing (GO:0042060), response to cocaine (GO:0042220), positive regulation of apoptotic process (GO:0043065), negative regulation of MAPK cascade (GO:0043409), positive regulation of endocytosis (GO:0045807), glycosphingolipid catabolic process (GO:0046479), ceramide biosynthetic process (GO:0046513), positive regulation of viral entry into host cell (GO:0046598), symbiont entry into host cell (GO:0046718), response to interleukin-1 (GO:0070555), cellular response to calcium ion (GO:0071277), lipid metabolic process (GO:0006629), ceramide metabolic process (GO:0006672), cholesterol efflux (GO:0033344), pyroptotic inflammatory response (GO:0070269)

GO Molecular Function (8): sphingomyelin phosphodiesterase activity (GO:0004767), zinc ion binding (GO:0008270), hydrolase activity, acting on glycosyl bonds (GO:0016798), phosphatidylcholine phospholipase C activity (GO:0034480), acid sphingomyelin phosphodiesterase activity (GO:0061750), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (11): obsolete extracellular space (GO:0005615), lysosome (GO:0005764), endosome (GO:0005768), lipid droplet (GO:0005811), plasma membrane (GO:0005886), endolysosome (GO:0036019), lamellar body (GO:0042599), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Coagulation pathway	1
Glycosphingolipid metabolism	1
Sphingolipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sphingolipid catabolic process	2
response to cytokine	2
lysosome	2
cellular anatomical structure	2
plasma membrane organization	1
wound healing	1
phospholipid metabolic process	1
sphingolipid metabolic process	1
sphingomyelin metabolic process	1
phospholipid catabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
sterol metabolic process	1
secondary alcohol metabolic process	1
response to chemical	1
response to other organism	1
response to radiation	1
negative regulation of signal transduction	1
innate immune response	1
response to UV	1
cellular response to light stimulus	1
response to wounding	1
tissue regeneration	1
response to alkaloid	1
response to oxygen-containing compound	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
endocytosis	1
regulation of endocytosis	1
positive regulation of transport	1
positive regulation of cellular component organization	1
glycosphingolipid metabolic process	1

Protein interactions and networks

STRING

1666 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMPD1	SMPD2	O60906	947
SMPD1	ASAH1	Q13510	909
SMPD1	SMPD3	Q9NY59	903
SMPD1	KLRB1	Q12918	898
SMPD1	SPTLC1	O15269	817
SMPD1	TLCD3B	Q71RH2	807
SMPD1	SPTLC2	O15270	798
SMPD1	SPTLC3	Q9NUV7	794
SMPD1	MAT1A	Q00266	785
SMPD1	GBA1	P04062	781
SMPD1	SORT1	Q99523	774
SMPD1	PSAP	P07292	757
SMPD1	GALC	P54803	729
SMPD1	SGMS1	Q86VZ5	728
SMPD1	UGCG	Q16739	711

IntAct

24 interactions, top by confidence:

A	B	Type	Score
CASP7	SMPD1	psi-mi:“MI:0403”(colocalization)	0.540
SMPD1	CASP7	psi-mi:“MI:0403”(colocalization)	0.540
SMPD1	CASP7	psi-mi:“MI:0914”(association)	0.540
CASP7	SMPD1	psi-mi:“MI:0915”(physical association)	0.540
SMPD1	CASP7	psi-mi:“MI:0915”(physical association)	0.540
SMPD1	CLGN	psi-mi:“MI:0914”(association)	0.530
INSL5	COCH	psi-mi:“MI:0914”(association)	0.530
CASP8	SMPD1	psi-mi:“MI:0403”(colocalization)	0.430
	TK2	psi-mi:“MI:0915”(physical association)	0.400
ANXA4	SMPD1	psi-mi:“MI:0915”(physical association)	0.370
ANXA7	SMPD1	psi-mi:“MI:0915”(physical association)	0.370
SMPD1	DUSP23	psi-mi:“MI:0915”(physical association)	0.370
NR1H2	SMPD1	psi-mi:“MI:0915”(physical association)	0.370
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
IGF2R	MANBA	psi-mi:“MI:0914”(association)	0.350
CLGN	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SMPD1	TNFRSF1A	psi-mi:“MI:0403”(colocalization)	0.270

BioGRID (39): SMPD1 (Affinity Capture-RNA), OS9 (Affinity Capture-MS), ALDH3A2 (Affinity Capture-MS), ALG11 (Affinity Capture-MS), SLC27A2 (Affinity Capture-MS), CNTNAP3B (Affinity Capture-MS), SMPD1 (Affinity Capture-MS), CANX (Affinity Capture-MS), CNTNAP3B (Affinity Capture-MS), SEL1L (Affinity Capture-MS), SMPD1 (Affinity Capture-RNA), SMPD1 (Negative Genetic), SMPD1 (Affinity Capture-MS), CANX (Affinity Capture-MS), SMPD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0D3QS98, A0A0D3QS99, A4D0V7, C5H5C4, F6Q1T7, O70309, O75354, P17405, P18084, P18424, P22413, P50747, P52850, P58242, P61642, P80747, Q04519, Q0VBD0, Q0VD19, Q13219, Q52KP5, Q58CQ9, Q5QQ51, Q5STE3, Q64687, Q6DFZ6, Q6KFX9, Q6MZW2, Q6P988, Q6UWX4, Q6YGZ1, Q6ZXD2, Q71RP1, Q812F8, Q8BJQ9, Q8C1F4, Q8C419, Q8N5D6, Q8N6G5, Q8R116

Diamond homologs: P17405, P70158, Q04519, Q0VD19, Q10916, Q23498, Q54C16, Q54SR8, Q55C09, Q641Z7, Q92484, Q92485, Q9UAY4, P58242, Q3ZC91

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKCD	up-regulates	SMPD1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1172 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	129
Likely pathogenic	172
Uncertain significance	272
Likely benign	363
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100731	NM_000543.5(SMPD1):c.739G>A (p.Gly247Ser)	Pathogenic
1013298	NM_000543.5(SMPD1):c.1486+5G>A	Pathogenic
1076908	NM_000543.5(SMPD1):c.839A>C (p.Asp280Ala)	Pathogenic
1173964	NM_000543.5(SMPD1):c.257G>A (p.Trp86Ter)	Pathogenic
1173967	NM_000543.5(SMPD1):c.647T>G (p.Leu216Arg)	Pathogenic
1173979	NM_000543.5(SMPD1):c.1699C>T (p.Gln567Ter)	Pathogenic
1173981	NM_000543.5(SMPD1):c.1151del (p.Met384fs)	Pathogenic
1173982	NM_000543.5(SMPD1):c.504dup (p.His169fs)	Pathogenic
1173983	NM_000543.5(SMPD1):c.1071_1081del (p.Glu358fs)	Pathogenic
1173984	NM_000543.5(SMPD1):c.933_936delinsGAC (p.Val312fs)	Pathogenic
1323631	NM_000543.5(SMPD1):c.318+1G>C	Pathogenic
1370114	NM_000543.5(SMPD1):c.1032T>G (p.Tyr344Ter)	Pathogenic
1372840	NM_000543.5(SMPD1):c.1216C>T (p.Gln406Ter)	Pathogenic
1399082	NM_000543.5(SMPD1):c.1576del (p.Ala526fs)	Pathogenic
1420134	NM_000543.5(SMPD1):c.820del (p.Met274fs)	Pathogenic
1427800	NM_000543.5(SMPD1):c.742G>T (p.Glu248Ter)	Pathogenic
1430049	NM_000543.5(SMPD1):c.1643_1644insA (p.Asn549fs)	Pathogenic
1451535	NM_000543.5(SMPD1):c.193dup (p.Ser65fs)	Pathogenic
1452305	NM_000543.5(SMPD1):c.742G>C (p.Glu248Gln)	Pathogenic
1452689	NM_000543.5(SMPD1):c.477_483dup (p.Leu162fs)	Pathogenic
1456733	NM_000543.5(SMPD1):c.208_227del (p.Pro70fs)	Pathogenic
1475471	NM_000543.5(SMPD1):c.1497_1498inv (p.Tyr500His)	Pathogenic
167710	NM_000543.5(SMPD1):c.573del (p.Ser192fs)	Pathogenic
1684031	NM_000543.5(SMPD1):c.668G>A (p.Cys223Tyr)	Pathogenic
188840	NM_000543.5(SMPD1):c.96G>A (p.Trp32Ter)	Pathogenic
188853	NM_000543.5(SMPD1):c.1111_1112del (p.Leu371fs)	Pathogenic
188955	NM_000543.5(SMPD1):c.1805G>A (p.Arg602His)	Pathogenic
189096	NM_000543.5(SMPD1):c.538_539del (p.Leu180fs)	Pathogenic
195086	NM_000543.5(SMPD1):c.785_807del (p.Leu262fs)	Pathogenic
195089	NM_000543.5(SMPD1):c.558_559insT (p.Pro187fs)	Pathogenic

SpliceAI

1049 predictions. Top by Δscore:

Variant	Effect	Δscore
11:6391983:G:GT	donor_gain	1.0000
11:6393289:C:A	acceptor_gain	1.0000
11:6393291:T:TA	acceptor_gain	1.0000
11:6393388:G:GG	donor_gain	1.0000
11:6393894:AGGTA:A	acceptor_loss	1.0000
11:6393895:G:A	acceptor_loss	1.0000
11:6394037:TCCTG:T	donor_gain	1.0000
11:6394038:CCTG:C	donor_gain	1.0000
11:6394039:CTG:C	donor_gain	1.0000
11:6394040:TG:T	donor_gain	1.0000
11:6394041:GG:G	donor_gain	1.0000
11:6394041:GGT:G	donor_loss	1.0000
11:6394042:G:GA	donor_loss	1.0000
11:6394042:G:GG	donor_gain	1.0000
11:6394043:T:A	donor_loss	1.0000
11:6391380:GCA:G	acceptor_loss	0.9900
11:6391381:CAGAA:C	acceptor_loss	0.9900
11:6391382:A:AG	acceptor_gain	0.9900
11:6391382:AGAAG:A	acceptor_gain	0.9900
11:6391383:G:A	acceptor_loss	0.9900
11:6391383:G:GG	acceptor_gain	0.9900
11:6391383:GA:G	acceptor_gain	0.9900
11:6391383:GAA:G	acceptor_gain	0.9900
11:6391383:GAAGG:G	acceptor_gain	0.9900
11:6393364:GCTGC:G	donor_gain	0.9900
11:6393386:AAGTG:A	donor_loss	0.9900
11:6393387:AGTG:A	donor_loss	0.9900
11:6393388:G:GA	donor_loss	0.9900
11:6393413:T:TA	donor_gain	0.9900
11:6393414:G:GA	donor_gain	0.9900

AlphaMissense

4066 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:6391593:G:C	W176C	0.998
11:6391593:G:T	W176C	0.998
11:6391904:A:T	D280V	0.998
11:6392025:C:A	N320K	0.998
11:6392025:C:G	N320K	0.998
11:6393297:C:A	N391K	0.998
11:6393297:C:G	N391K	0.998
11:6393359:T:C	L412P	0.998
11:6393632:C:G	H427D	0.998
11:6393652:T:G	C433W	0.998
11:6391688:A:T	D208V	0.997
11:6392021:G:T	G319V	0.997
11:6393273:T:A	N383K	0.997
11:6393273:T:G	N383K	0.997
11:6393279:T:A	N385K	0.997
11:6393279:T:G	N385K	0.997
11:6393285:T:G	C387W	0.997
11:6393347:T:C	L408P	0.997
11:6393624:T:A	I424K	0.997
11:6393634:C:A	H427Q	0.997
11:6393634:C:G	H427Q	0.997
11:6393651:G:A	C433Y	0.997
11:6393942:G:C	D463H	0.997
11:6394011:A:C	S486R	0.997
11:6394013:T:A	S486R	0.997
11:6394013:T:G	S486R	0.997
11:6394204:G:C	R498P	0.997
11:6391685:C:T	T207I	0.996
11:6391901:G:T	G279V	0.996
11:6391904:A:C	D280A	0.996

dbSNP variants (sampled 300 via entrez): RS1000298240 (11:6395130 G>A), RS1000327510 (11:6395429 T>C), RS1000886448 (11:6391070 C>G), RS1001589747 (11:6391362 C>G,T), RS1001668925 (11:6390323 G>A,T), RS1001763813 (11:6390163 G>A), RS1002771366 (11:6391196 A>C), RS1003669312 (11:6390223 C>T), RS1003681756 (11:6392623 T>A,G), RS1003775121 (11:6392180 A>G), RS1003856335 (11:6394618 C>T), RS1003887233 (11:6395034 C>A,T), RS1004520503 (11:6392475 C>A), RS1005166836 (11:6389559 T>A,G), RS1006165094 (11:6391033 A>G)

Disease associations

OMIM: gene MIM:607608 | disease phenotypes: MIM:257200, MIM:601780, MIM:607616, MIM:257220

GenCC curated gene-disease

Disease	Classification	Inheritance
Niemann-Pick disease type A	Definitive	Autosomal recessive
Niemann-Pick disease	Definitive	Autosomal recessive
Niemann-Pick disease type B	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
acid sphingomyelinase deficiency	Definitive	AR

Mondo (9): Niemann-Pick disease (MONDO:0001982), Niemann-Pick disease type A (MONDO:0009756), ceroid lipofuscinosis, neuronal, 6A (MONDO:0011144), Niemann-Pick disease type B (MONDO:0011871), lysosomal storage disease (MONDO:0002561), acid sphingomyelinase deficiency (MONDO:0100464), intellectual disability (MONDO:0001071), Gaucher disease (MONDO:0018150), Niemann-Pick disease, type C1 (MONDO:0009757)

Orphanet (9): OBSOLETE: Late infantile neuronal ceroid lipofuscinosis (Orphanet:168491), CLN6 disease (Orphanet:228363), Infantile neurovisceral acid sphingomyelinase deficiency (Orphanet:77292), Chronic visceral acid sphingomyelinase deficiency (Orphanet:77293), Lysosomal disease (Orphanet:68366), Acid sphingomyelinase deficiency (Orphanet:618899), Gaucher disease (Orphanet:355), Niemann-Pick disease type C (Orphanet:646), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

91 total (30 of 91 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000256	Macrocephaly
HP:0000639	Nystagmus
HP:0000707	Abnormality of the nervous system
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000737	Irritability
HP:0000823	Delayed puberty
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000991	Xanthomatosis
HP:0001081	Cholelithiasis
HP:0001103	Abnormal macular morphology
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001317	Abnormal cerebellum morphology
HP:0001324	Muscle weakness
HP:0001328	Specific learning disability
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001410	Decreased liver function
HP:0001508	Failure to thrive
HP:0001538	Protuberant abdomen
HP:0001541	Ascites
HP:0001654	Abnormal heart valve morphology

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002875_69	Diisocyanate-induced asthma	2.000000e-07
GCST006585_2643	Blood protein levels	2.000000e-31
GCST008478_34	Neurological blood protein biomarker levels	4.000000e-13
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D005776	Gaucher Disease	C10.228.140.163.100.435.825.400; C16.320.565.189.435.825.400; C16.320.565.398.641.803.441; C16.320.565.595.554.825.400; C18.452.132.100.435.825.400; C18.452.584.563.641.803.441; C18.452.648.189.435.825.400; C18.452.648.398.641.803.441; C18.452.648.595.554.825.400
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
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
D052537	Niemann-Pick Disease, Type B	C10.228.140.163.100.435.825.700.750; C15.604.250.410.625.750; C16.320.565.189.435.825.700.750; C16.320.565.398.641.803.730.750; C16.320.565.595.554.825.700.750; C18.452.132.100.435.825.700.750; C18.452.584.563.641.803.730.750; C18.452.648.189.435.825.700.750; C18.452.648.398.641.803.730.750; C18.452.648.595.554.825.700.750
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
C566627	Ceroid Lipofuscinosis, Neuronal, 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2760 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 100,427 (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
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL71	CHLORPROMAZINE	4	45,827
CHEMBL254832	FENDILINE	2	5,707

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Sphingomyelin phosphodiesterase

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 21b [PMID: 31944697]	Inhibition	6.49	pIC50
WJYK50	Inhibition	6.05	pIC50

ChEMBL bioactivities

84 potent at pChembl≥5 of 157 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.70	IC50	20	nM	CHEMBL4163007
7.70	IC50	20	nM	CHEMBL4553570
7.70	IC50	20	nM	CHEMBL5288063
7.16	IC50	70	nM	CHEMBL4176817
6.54	IC50	290	nM	CHEMBL4167088
6.52	IC50	300	nM	CHEMBL4161092
6.52	IC50	300	nM	CHEMBL5434322
6.51	IC50	310	nM	CHEMBL4172326
6.50	IC50	320	nM	CHEMBL4551503
6.47	IC50	340	nM	CHEMBL4464117
6.46	IC50	350	nM	CHEMBL4169019
6.44	IC50	360	nM	CHEMBL4464068
6.44	IC50	360	nM	CHEMBL4517596
6.41	IC50	390	nM	CHEMBL5559723
6.36	IC50	440	nM	CHEMBL4175277
6.36	IC50	440	nM	CHEMBL5556497
6.33	IC50	470	nM	CHEMBL5409988
6.32	IC50	480	nM	CHEMBL4167681
6.30	IC50	500	nM	CHEMBL5542512
6.29	IC50	510	nM	CHEMBL5413803
6.28	Ki	530	nM	CHEMBL5279916
6.19	IC50	640	nM	CHEMBL5566028
6.09	IC50	810	nM	CHEMBL5401959
6.08	IC50	830	nM	CHEMBL5416755
6.06	IC50	880	nM	CHEMBL4471880
6.06	IC50	870	nM	CHEMBL5559942
6.05	IC50	890	nM	CHEMBL4167681
6.00	IC50	1000	nM	CHEMBL5421810
5.94	IC50	1140	nM	CHEMBL5273649
5.92	IC50	1200	nM	CHEMBL4167681
5.85	IC50	1420	nM	CHEMBL4167496
5.82	IC50	1500	nM	CHEMBL5395183
5.77	IC50	1700	nM	CHEMBL5542640
5.76	IC50	1730	nM	CHEMBL4449978
5.76	IC50	1750	nM	CHEMBL5273927
5.74	IC50	1820	nM	CHEMBL5271590
5.73	IC50	1860	nM	CHEMBL5276301
5.71	IC50	1960	nM	CHEMBL4588641
5.68	IC50	2110	nM	CHEMBL4465034
5.66	IC50	2200	nM	CHEMBL4464068
5.63	IC50	2340	nM	CHEMBL600442
5.57	IC50	2710	nM	CHEMBL5542655
5.52	IC50	3030	nM	CHEMBL5568173
5.51	IC50	3100	nM	CHEMBL4175734
5.51	IC50	3100	nM	CHEMBL5556653
5.48	IC50	3300	nM	CHEMBL5440976
5.47	IC50	3380	nM	CHEMBL4465034
5.47	IC50	3370	nM	CHEMBL4551503
5.46	IC50	3500	nM	CHEMBL4175734
5.44	IC50	3630	nM	CHEMBL4446879

PubChem BioAssay actives

83 with measured affinity, of 393 total; 50 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
(1-amino-1-phosphonodecyl)phosphonic acid	2078208: Inhibition of ASM (unknown origin)	ic50	0.0200	uM
(1-amino-1-phosphonooxydecyl) dihydrogen phosphate	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	0.0200	uM
(1-amino-1-phosphonooctyl)phosphonic acid	1583193: Inhibition of acid sphingomyelinase (unknown origin)	ic50	0.0200	uM
(1-hydroxy-1-phosphonooxydodecyl) dihydrogen phosphate	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	0.0700	uM
(1-amino-1-phosphonooxydodecyl) dihydrogen phosphate	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	0.2900	uM
1-phosphonooxydecyl dihydrogen phosphate	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	0.3000	uM
5-[[4-(4-chlorophenyl)phenoxy]methyl]-N-hydroxy-1,2,4-oxadiazole-3-carboxamide	2028546: Inhibition of recombinant human aSMase (62 to 628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based assay	ic50	0.3000	uM
1-phosphonooxyundecyl dihydrogen phosphate	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	0.3100	uM
3-[[4-(4-chlorophenyl)phenyl]methoxy]-N-hydroxy-1,2-oxazole-5-carboxamide	1583167: Inhibition of human Huh7 cell derived acid sphingomyelinase using NBD-sphingomyelin as substrate after 30 mins by fluorescence based assay	ic50	0.3200	uM
3-[[4-(4-chlorophenyl)phenyl]methoxy]-N-hydroxy-4-methoxybenzamide	1583167: Inhibition of human Huh7 cell derived acid sphingomyelinase using NBD-sphingomyelin as substrate after 30 mins by fluorescence based assay	ic50	0.3400	uM
1-phosphonooxyoctyl dihydrogen phosphate	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	0.3500	uM
3-decoxy-N-hydroxy-1,2-oxazole-5-carboxamide	1583167: Inhibition of human Huh7 cell derived acid sphingomyelinase using NBD-sphingomyelin as substrate after 30 mins by fluorescence based assay	ic50	0.3600	uM
3-[[4-(4-chlorophenyl)phenyl]methoxy]-N-hydroxybenzamide	1583192: Inhibition of recombinant human acid sphingomyelinase (His62 to Pro628 residues) using NBD-sphingomyelin as substrate after 30 mins by fluorescence based assay	ic50	0.3600	uM
1-decyl-N-hydroxy-5-[4-(2-methylpropoxy)phenyl]pyrazole-3-carboxamide	2078148: Inhibition of human recombinant ASM (His62 to Pro628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based analysis	ic50	0.3900	uM
[(2R,3S,4R,5R)-4,6-dihydroxy-3,5-diphosphonooxyoxan-2-yl] dodecane-1-sulfonate	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	0.4400	uM
(2-hydroxy-4-phosphanyl-3,5-diphosphonooxycyclohexyl) dodecane-1-sulfonate	2078208: Inhibition of ASM (unknown origin)	ic50	0.4400	uM
3-[[4-(4-chlorophenyl)phenoxy]methyl]-N-hydroxy-1,2,4-oxadiazole-5-carboxamide	2028546: Inhibition of recombinant human aSMase (62 to 628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based assay	ic50	0.4700	uM
3-decoxy-N-hydroxy-4-methoxybenzamide	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	0.4800	uM
1-decyl-5-(4-fluorophenyl)-N-hydroxypyrazole-3-carboxamide	2078148: Inhibition of human recombinant ASM (His62 to Pro628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based analysis	ic50	0.5000	uM
5-[4-(4-chlorophenyl)phenyl]-N-hydroxy-1,3,4-oxadiazole-2-carboxamide	2028546: Inhibition of recombinant human aSMase (62 to 628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based assay	ic50	0.5100	uM
[(2R)-3-[hydroxy-[(2R,3R,5S,6R)-2,4,6-trihydroxy-3,5-diphosphonooxycyclohexyl]oxyphosphoryl]oxy-2-octanoyloxypropyl] octanoate	1923499: Inhibition of recombinant human aSMase assessed as inhibition constant	ki	0.5300	uM
1-decyl-N-hydroxy-5-phenylpyrazole-3-carboxamide	2078148: Inhibition of human recombinant ASM (His62 to Pro628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based analysis	ic50	0.6400	uM
N-hydroxy-5-[4-(2-methylpropoxy)phenyl]-1,3,4-oxadiazole-2-carboxamide	2028546: Inhibition of recombinant human aSMase (62 to 628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based assay	ic50	0.8100	uM
N-hydroxy-3-[(4-phenylphenoxy)methyl]-1,2,4-oxadiazole-5-carboxamide	2028546: Inhibition of recombinant human aSMase (62 to 628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based assay	ic50	0.8300	uM
5-(4-bromophenyl)-1-(4-chlorophenyl)-N-hydroxypyrazole-3-carboxamide	2078148: Inhibition of human recombinant ASM (His62 to Pro628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based analysis	ic50	0.8700	uM
N-hydroxy-3-[(4-phenylphenyl)methoxy]-1,2-oxazole-5-carboxamide	1583167: Inhibition of human Huh7 cell derived acid sphingomyelinase using NBD-sphingomyelin as substrate after 30 mins by fluorescence based assay	ic50	0.8800	uM
5-(4-butoxyphenyl)-N-hydroxy-1,2-oxazole-3-carboxamide	2028546: Inhibition of recombinant human aSMase (62 to 628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based assay	ic50	1.0000	uM
2-amino-2-(1-nonyltriazol-4-yl)propane-1,3-diol	1923504: Inhibition of aSMase (unknown origin)	ic50	1.1400	uM
3-decoxy-N-hydroxybenzamide	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	1.4200	uM
3-[4-[(4-bromophenoxy)methyl]phenyl]-N-hydroxy-1,2,4-oxadiazole-5-carboxamide	2028546: Inhibition of recombinant human aSMase (62 to 628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based assay	ic50	1.5000	uM
1-decyl-N-hydroxy-5-(4-methoxyphenyl)pyrazole-3-carboxamide	2078148: Inhibition of human recombinant ASM (His62 to Pro628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based analysis	ic50	1.7000	uM
N-hydroxy-3-[[4-[5-(2-phenylethyl)-1,2,4-oxadiazol-3-yl]phenyl]methoxy]benzamide	1583167: Inhibition of human Huh7 cell derived acid sphingomyelinase using NBD-sphingomyelin as substrate after 30 mins by fluorescence based assay	ic50	1.7300	uM
2-amino-2-(1-octyltriazol-4-yl)propane-1,3-diol	1923504: Inhibition of aSMase (unknown origin)	ic50	1.7500	uM
2-amino-2-(1-heptyltriazol-4-yl)propane-1,3-diol	1923504: Inhibition of aSMase (unknown origin)	ic50	1.8200	uM
2-amino-2-(1-hexyltriazol-4-yl)propane-1,3-diol	1923504: Inhibition of aSMase (unknown origin)	ic50	1.8600	uM
3-[(4-hexylphenyl)methoxy]-N-hydroxy-4-methoxybenzamide	1583167: Inhibition of human Huh7 cell derived acid sphingomyelinase using NBD-sphingomyelin as substrate after 30 mins by fluorescence based assay	ic50	1.9600	uM
3-[(4-hexylphenyl)methoxy]-N-hydroxybenzamide	1583167: Inhibition of human Huh7 cell derived acid sphingomyelinase using NBD-sphingomyelin as substrate after 30 mins by fluorescence based assay	ic50	2.1100	uM
[(2R,3S,4S,5R)-4,6-dihydroxy-3,5-diphosphonooxyoxan-2-yl]methyl octane-1-sulfonate	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	2.3400	uM
5-(4-chlorophenyl)-1-decyl-N-hydroxypyrazole-3-carboxamide	2078148: Inhibition of human recombinant ASM (His62 to Pro628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based analysis	ic50	2.7100	uM
5-(4-bromophenyl)-N-hydroxy-1-(4-methylphenyl)pyrazole-3-carboxamide	2078148: Inhibition of human recombinant ASM (His62 to Pro628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based analysis	ic50	3.0300	uM
2-(6-bromo-4H-1,3-benzodioxin-8-yl)-7-ethoxychromen-4-one	2078208: Inhibition of ASM (unknown origin)	ic50	3.1000	uM
3-amino-2-(6-bromo-4H-1,3-benzodioxin-8-yl)-6-ethoxychromen-4-one	1583193: Inhibition of acid sphingomyelinase (unknown origin)	ic50	3.1000	uM
N-hydroxy-3-[4-(phenoxymethyl)phenyl]-1,2,4-oxadiazole-5-carboxamide	2028546: Inhibition of recombinant human aSMase (62 to 628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based assay	ic50	3.3000	uM
N-hydroxy-4-methoxy-3-[(4-phenylphenyl)methoxy]benzamide	1583167: Inhibition of human Huh7 cell derived acid sphingomyelinase using NBD-sphingomyelin as substrate after 30 mins by fluorescence based assay	ic50	3.6300	uM
N-hydroxy-4-methoxy-3-[(4-pyridin-3-ylphenyl)methoxy]benzamide	1583192: Inhibition of recombinant human acid sphingomyelinase (His62 to Pro628 residues) using NBD-sphingomyelin as substrate after 30 mins by fluorescence based assay	ic50	3.8300	uM
[(2R,3S,4S,5R)-4,6-dihydroxy-3,5-diphosphonooxyoxan-2-yl]methyl hexane-1-sulfonate	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	4.1600	uM
3-[4-[(4-chlorophenoxy)methyl]phenyl]-N-hydroxy-1,2,4-oxadiazole-5-carboxamide	2028546: Inhibition of recombinant human aSMase (62 to 628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based assay	ic50	4.2000	uM
1,5-bis(4-chlorophenyl)-N-hydroxypyrazole-3-carboxamide	2078148: Inhibition of human recombinant ASM (His62 to Pro628 residues) using HMU-PC as substrate incubated for 2 hrs by fluorescence based analysis	ic50	4.7100	uM
(E)-4-(2,8-dihydroxy-3,6-dimethoxy-9-oxoxanthen-1-yl)-N-ethylbut-2-enamide	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	4.8900	uM
(E)-4-(2,8-dihydroxy-3,6-dimethoxy-9-oxoxanthen-1-yl)-N,N-diethylbut-2-enamide	1357899: Inhibition of acid sphingomyelinase in human HuH7 cell lysate using NBD-sphingomyelin as substrate after 30 mins by TLC based fluorescence assay	ic50	4.8900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
entinostat	decreases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	decreases activity, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
lasiocarpine	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
quercitrin	increases expression	1
diethyl maleate	decreases reaction, increases expression, affects binding, increases reaction, increases activity (+1 more)	1
beta-lapachone	increases expression	1
afimoxifene	decreases expression, decreases reaction	1
butyraldehyde	decreases expression	1
phenethyl isothiocyanate	increases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
yessotoxin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
N-butyrylglucosamine	increases expression	1
darinaparsin	increases expression, decreases reaction	1
dorsomorphin	affects cotreatment, decreases expression	1
5,7,3’-trihydroxy-3,4’-dimethoxyflavone	increases activity	1
PP242	increases expression	1
Sevoflurane	decreases activity	1
Sorafenib	affects cotreatment, affects localization, increases reaction, increases abundance	1
Temozolomide	decreases expression	1
Vorinostat	affects cotreatment, affects localization, increases reaction, increases abundance	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression	1
Amitriptyline	decreases activity	1

ChEMBL screening assays

42 unique, capped per target: 40 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1794495	Functional	PubChem BioAssay. Inhibitors of Secretory Acid Sphingomyelinase (S-ASM): qHTS. (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL2026165	Binding	Inhibition of aSMase expressed in human A549 cells using 6-hexadecanoylamino-4-methylumbelliferylphosphorylcholine as substrate at 10 uM after 2 hrs by spectrophotometry	3-Deoxy-3,4-dehydro analogs of XM462. Preparation and activity on sphingolipid metabolism and cell fate. — Bioorg Med Chem

Cellosaurus cell lines

31 cell lines: 16 induced pluripotent stem cell, 6 finite cell line, 6 cancer cell line, 2 transformed cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_7379	GM03252	Finite cell line	Female
CVCL_A8QQ	GM27463	Induced pluripotent stem cell	Male
CVCL_AX18	GM00559	Finite cell line	Female
CVCL_AX25	GM13205	Finite cell line	Female
CVCL_AX26	GM16195	Finite cell line	Male
CVCL_C0KJ	AIW002-02/SMPD1-KO	Induced pluripotent stem cell	Male
CVCL_C7DN	Abcam A-549 SMPD1 KO	Cancer cell line	Male
CVCL_C7ER	Abcam THP-1 SMPD1 KO	Cancer cell line	Male
CVCL_D5FK	HeLa::TMEM192-3xHA SMPD1 partial KO	Cancer cell line	Female
CVCL_D6A4	HyCyte HEK293T KO-hSMPD1	Transformed cell line	Female

Clinical trials (associated diseases)

275 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
NCT01132690	PHASE4	COMPLETED	A Safety and Efficacy Study of Two Dose Levels of Taliglucerase Alfa in Pediatric Subjects With Gaucher Disease
NCT02528617	PHASE4	WITHDRAWN	The Effect of Velaglucerase Alfa (Vpriv) on Skeletal Development in Pediatric Gaucher Disease
NCT02574286	PHASE4	COMPLETED	Study of the Effect of Velaglucerase Alfa (VPRIV®) on Bone-related Pathology in Treatment-naïve Participants With Type 1 Gaucher Disease
NCT03721627	PHASE4	UNKNOWN	Chronic Hepatitis C Treatment in Egyptian Children With Gaucher Disease.
NCT04718779	PHASE4	COMPLETED	A Study of Enzyme Replacement Therapy (VPRIV) in People With Type 1 Gaucher Disease Who Were Previously Treated With Substrate Reduction Therapy
NCT00654433	PHASE3	TERMINATED	ALD-101 Adjuvant Therapy of Unrelated Umbilical Cord Blood Transfusion (UCBT) in Patients With Inherited Metabolic Diseases
NCT04283227	PHASE3	ACTIVE_NOT_RECRUITING	OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD)
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
NCT00319046	PHASE3	COMPLETED	Clinical Study to Evaluate the Long Term Efficacy, Safety and Tolerability of Miglustat in Patients With Stable Type 1 Gaucher Disease
NCT00376168	PHASE3	COMPLETED	A Phase III Trial to Assess the Safety and Efficacy of Plant Cell Expressed GCD in Patients With Gaucher Disease
NCT00705939	PHASE3	COMPLETED	Plant Cell Expressed Recombinant Human Glucocerebrosidase Extension Trial
NCT00712348	PHASE3	COMPLETED	Switchover Trial From Imiglucerase to Plant Cell Expressed Recombinant Human Glucocerebrosidase
NCT01074944	PHASE3	COMPLETED	A Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease to Evaluate Once Daily Versus Twice Daily Dosing (EDGE)
NCT01161914	PHASE3	WITHDRAWN	The Safety and Efficacy Study of ISU302 in Patient With Type I Gaucher Disease
NCT01411228	PHASE3	COMPLETED	A Multicenter Extension Study of Taliglucerase Alfa in Pediatric Subjects With Gaucher Disease
NCT01422187	PHASE3	COMPLETED	A Multicenter Extension Study of Taliglucerase Alfa in Adult Subjects With Gaucher Disease
NCT00668564	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism
NCT03392987	PHASE2	COMPLETED	A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD)
NCT06130228	PHASE2	UNKNOWN	Nutritional Therapy in Late-onset Pompe Disease
NCT06949358	PHASE2	COMPLETED	A Study to Evaluate Safety and Tolerability of Olipudase Alfa in Pediatric and Adult Participants With Acid Sphingomyelinase Deficiency (ASMD) Who Completed the DFI12712 or the LTS13632 Study in France
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
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
NCT00215527	PHASE1	TERMINATED	Intrathecal Enzyme Replacement Therapy for Spinal Cord Compression in Mucopolysaccharidosis (MPS) I
NCT00744692	PHASE1	COMPLETED	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant in Pediatric Patients With Non-Malignant Disorders
NCT00786968	PHASE1	TERMINATED	Extension Study of Intrathecal Enzyme Replacement Therapy for MPS I
NCT01003912	PHASE1	WITHDRAWN	Fetal Umbilical Cord Blood (UCB) Transplant for Lysosomal Storage Diseases
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)