SGMS2

Summary

SGMS2 (sphingomyelin synthase 2, HGNC:28395) is a protein-coding gene on chromosome 4q25, encoding Phosphatidylcholine:ceramide cholinephosphotransferase 2 (Q8NHU3). Sphingomyelin synthase that primarily contributes to sphingomyelin synthesis and homeostasis at the plasma membrane.

Sphingomyelin, a major component of cell and Golgi membranes, is made by the transfer of phosphocholine from phosphatidylcholine onto ceramide, with diacylglycerol as a side product. The protein encoded by this gene is an enzyme that catalyzes this reaction primarily at the cell membrane. The synthesis is reversible, and this enzyme can catalyze the reaction in either direction. The encoded protein is required for cell growth. Three transcript variants encoding the same protein have been found for this gene. There is evidence for more variants, but the full-length nature of their transcripts has not been determined.

Source: NCBI Gene 166929 — RefSeq curated summary.

At a glance

• Gene–disease (curated): calvarial doughnut lesions-bone fragility syndrome (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 16 total
• Phenotypes (HPO): 13
• Druggable target: yes
• MANE Select transcript: NM_001375905

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28395
Approved symbol	SGMS2
Name	sphingomyelin synthase 2
Location	4q25
Locus type	gene with protein product
Status	Approved
Aliases	MGC26963, SMS2
Ensembl gene	ENSG00000164023
Ensembl biotype	protein_coding
OMIM	611574
Entrez	166929

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 19 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000359079, ENST00000394684, ENST00000394686, ENST00000503385, ENST00000503862, ENST00000504754, ENST00000506462, ENST00000506993, ENST00000515332, ENST00000690982, ENST00000856649, ENST00000856650, ENST00000856651, ENST00000856652, ENST00000856653, ENST00000856654, ENST00000856655, ENST00000856656, ENST00000944788, ENST00000944789, ENST00000944790, ENST00000944791

RefSeq mRNA: 9 — MANE Select: NM_001375905 NM_001136257, NM_001136258, NM_001375905, NM_001375906, NM_001375907, NM_001375908, NM_001375910, NM_001375911, NM_152621

CCDS: CCDS3677

Canonical transcript exons

ENST00000690982 — 7 exons

Exon	Start	End
ENSE00001080611	107903233	107903386
ENSE00001136427	107895310	107896008
ENSE00001431931	107858472	107858553
ENSE00001764500	107910350	107915047
ENSE00003519530	107899575	107899692
ENSE00003789730	107908565	107908731
ENSE00003935765	107824932	107825253

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 99.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.9678 / max 250.3138, expressed in 1545 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49187	2.5238	1096
49181	2.1833	822
49186	1.9607	924
49183	1.7697	585
49184	1.4994	833
49185	0.6033	354
49190	0.4101	167
49195	0.2669	47
49182	0.2231	93
49188	0.2021	75

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.35	gold quality
secondary oocyte	CL:0000655	97.22	gold quality
epithelial cell of pancreas	CL:0000083	97.04	gold quality
germinal epithelium of ovary	UBERON:0001304	96.63	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.42	gold quality
jejunal mucosa	UBERON:0000399	96.00	gold quality
bronchial epithelial cell	CL:0002328	95.93	gold quality
oocyte	CL:0000023	95.79	gold quality
ileal mucosa	UBERON:0000331	94.81	gold quality
bronchus	UBERON:0002185	94.57	gold quality
palpebral conjunctiva	UBERON:0001812	93.18	gold quality
lower lobe of lung	UBERON:0008949	92.97	gold quality
parietal pleura	UBERON:0002400	92.12	gold quality
islet of Langerhans	UBERON:0000006	91.97	gold quality
buccal mucosa cell	CL:0002336	91.47	gold quality
cauda epididymis	UBERON:0004360	91.25	gold quality
gall bladder	UBERON:0002110	90.88	gold quality
smooth muscle tissue	UBERON:0001135	90.57	gold quality
esophagus squamous epithelium	UBERON:0006920	90.47	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.09	gold quality
amniotic fluid	UBERON:0000173	89.28	gold quality
nasal cavity mucosa	UBERON:0001826	89.24	gold quality
cartilage tissue	UBERON:0002418	89.18	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.96	gold quality
duodenum	UBERON:0002114	88.91	gold quality
visceral pleura	UBERON:0002401	88.83	gold quality
nasal cavity epithelium	UBERON:0005384	88.45	gold quality
gingival epithelium	UBERON:0001949	88.10	gold quality
stromal cell of endometrium	CL:0002255	87.97	gold quality
colonic mucosa	UBERON:0000317	87.66	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	15.85
E-GEOD-124858	no	289.79
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

169 targeting SGMS2, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 29)

• Data show that sphingomyelin synthases SMS1 and SMS2 are co-expressed in a variety of cell types and function as the key Golgi- and plasma membrane-associated SM synthases in human cervical carcinoma HeLa cells, respectively. (PMID:17449912)
• Results indicate that both synthase (SMS)1 and 2 contribute to sphingomyelin (SM) de novo synthesis and control SM levels in the cells and on the cell membrane including plasma membrane. (PMID:17616479)
• SMS2 is a key factor in control of sphingomyelin and diacylglycerol metabolism within the cell, and thus it influences apoptosis. (PMID:17982138)
• SMS2 regulates subcellular pools of diacylglycerol-binding proteins in the Golgi apparatus. (PMID:18370930)
• SMS2 (Sphingomyelin synthase 2) physiologically contributes to de novo Sphingomyelin biosynthesis and plasma membrane Sphingomyelin levels (PMID:18566297)
• Both SMS1 and SMS2 contain two histidines and one aspartic acid which are conserved within the lipid phosphate phosphatase superfamily. Site-directed mutagenesis of these amino acids abolished SMS activity without altering cellular distribution. (PMID:18694848)
• These results suggested that posttranslational palmitoylation is important for determination of the subcellular localization of SMS2. (PMID:19233134)
• Sphingomyelin synthase 2 is one of the determinants for plasma and liver sphingomyelin levels in mice. (PMID:19286635)
• Data show that SMS2 acting as a bifunctional enzyme with both SM and CPE synthase activity. (PMID:19454763)
• direct morphological evidence for the pro-atherogenic capabilities of sphingomyelin synthase 2 (PMID:21235823)
• SMS1 and SMS2 are capable of regulating TGN-mediated protein trafficking and secretion (PMID:21980337)
• Data indicate that the increased sphingomyelin mass was due to a rapid and highly specific activation of sphingomyelin synthases SMS1 and SMS2. (PMID:22106271)
• F-actin polymerization in the region of HIV-1 membrane fusion was more prominent in Sms2-expressing cells than Sms-deficient cells. (PMID:25231990)
• PPARdelta activation may be a potential risk of atherosclerosis through enhancing activity of SMS2 (PMID:27278004)
• SMS regulates the expression and function of drug transporters P-gp and MRP2. (PMID:27394416)
• findings suggest that the C-terminal tails of SMSs are involved in homodimer formation, which is required for efficient transport from the ER. (PMID:27927984)
• SGMS2 increased the expression of TGF-beta1 by upregulating ceramide, which subsequently activated the TGF-beta/Smad signalling pathway and promoted epithelial-to-mesenchymal transition in breast cancer cells, thus increasing the migration and invasiveness of breast cancer cells. (PMID:30770781)
• Study in 6 families with rare skeletal phenotypes and osteoporosis identified a heterozygous variant in SGMS2, a gene prominently expressed in cortical bone and encoding the plasma membrane-resident sphingomyelin synthase SMS2. Four unrelated families shared the same nonsense variant, c.148C>T (p.Arg50*), whereas the other families had a missense variant, c.185T>G (p.Ile62Ser) or c.191T>G (p.Met64Arg). (PMID:30779713)
• our results demonstrate that SMS2 can activate the Wnt/beta-catenin pathway and promote intracellular cholesterol accumulation, both of which can contribute to the induction of ER stress and finally lead to ED. (PMID:31212751)
• SGMS2-dependent signaling was investigated in human monocyte-derived macrophages of nonsmokers and human bronchial epithelial (HBE) cells isolated from healthy nonsmokers and subjects with COPD. Reduced SGMS2 expression was seen in HBE cells isolated from subjects with COPD. SGMS2 overexpression reduced the production of several matrix metalloproteinases in HBE cells and monocyte-derived macrophages. (PMID:31517509)
• Chlamydia trachomatis-infected human cells convert ceramide to sphingomyelin without sphingomyelin synthases 1 and 2. (PMID:31596951)
• Sphingomyelin synthase 2 facilitates M2-like macrophage polarization and tumor progression in a mouse model of triple-negative breast cancer. (PMID:32451413)
• Genome-wide association study of serum prostate-specific antigen levels based on 1000 Genomes imputed data in Japanese: the Japan Multi-Institutional Collaborative Cohort Study. (PMID:33727749)
• LncRNA THAP9-AS1 accelerates cell growth of esophageal squamous cell carcinoma through sponging miR-335-5p to regulate SGMS2. (PMID:34273804)
• LARP6 suppresses colorectal cancer progression through ZNF267/SGMS2-mediated imbalance of sphingomyelin synthesis. (PMID:36691044)
• Clinical and Genetic Characteristics of Calvarial Doughnut Lesions with Bone Fragility in Three Families with a Reccurent SGMS2 Gene Variant. (PMID:37175737)
• Identification of SGMS2 as a molecule involved in natural killer cell recruitment and its in-deep analysis in the liver cancer microenvironment: Evidence from large populations cohort. (PMID:37849429)
• SGMS2 in primary osteoporosis with facial nerve palsy. (PMID:37886644)
• Sphingomyelin synthase 2 promotes the stemness of breast cancer cells via modulating NF-kappaB signaling pathway. (PMID:38285090)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sgms2b	ENSDARG00000036897
danio_rerio	sgms2a	ENSDARG00000052520
mus_musculus	Sgms2	ENSMUSG00000050931
rattus_norvegicus	Sgms2	ENSRNOG00000011284
caenorhabditis_elegans		WBGENE00004892

Paralogs (2): SAMD8 (ENSG00000156671), SGMS1 (ENSG00000198964)

Protein

Protein identifiers

Phosphatidylcholine:ceramide cholinephosphotransferase 2 — Q8NHU3 (reviewed: Q8NHU3)

Alternative names: Sphingomyelin synthase 2

All UniProt accessions (4): E5RGG5, E5RJ63, E5RJU3, Q8NHU3

UniProt curated annotations — full annotation on UniProt →

Function. Sphingomyelin synthase that primarily contributes to sphingomyelin synthesis and homeostasis at the plasma membrane. Catalyzes the reversible transfer of phosphocholine moiety in sphingomyelin biosynthesis: in the forward reaction transfers phosphocholine head group of phosphatidylcholine (PC) on to ceramide (CER) to form ceramide phosphocholine (sphingomyelin, SM) and diacylglycerol (DAG) as by-product, and in the reverse reaction transfers phosphocholine from SM to DAG to form PC and CER. The direction of the reaction appears to depend on the levels of CER and DAG in the plasma membrane. Does not use free phosphorylcholine or CDP-choline as donors. Can also transfer phosphoethanolamine head group of phosphatidylethanolamine (PE) on to ceramide (CER) to form ceramide phosphoethanolamine (CPE). Regulates receptor-mediated signal transduction via mitogenic DAG and proapoptotic CER, as well as via SM, a structural component of membrane rafts that serve as platforms for signal transduction and protein sorting. To a lesser extent, plays a role in secretory transport via regulation of DAG pool at the Golgi apparatus and its downstream effects on PRKD1. Required for normal bone matrix mineralization.

Subcellular location. Cell membrane. Golgi apparatus membrane.

Tissue specificity. Brain, heart, kidney, liver, muscle and stomach. Also expressed in a number of cell lines such as carcinoma HeLa cells, hepatoma Hep-G2 cells, and colon carcinoma Caco-2 cells.

Post-translational modifications. Palmitoylated on Cys-331, Cys-332, Cys-343 and Cys-348; which plays an important role in plasma membrane localization.

Disease relevance. Calvarial doughnut lesions with bone fragility (CDL) [MIM:126550] A rare autosomal dominant bone disease characterized by low bone density, distinctive X-ray translucencies of the skull, multiple fractures, elevated serum alkaline phosphatase, and dental caries. Patients present with childhood onset of primary osteoporosis and typical sclerotic doughnut-shaped lesions in the cranial bones. The disease may be caused by variants affecting the gene represented in this entry. Calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia (CDLSMD) [MIM:126550] A severe form of calvarial doughnut lesions with bone fragility, a rare autosomal dominant disease characterized by low bone density, distinctive X-ray translucencies of the skull, multiple fractures, elevated serum alkaline phosphatase, and dental caries. CDLSMD patients show neonatal onset of fractures, severe short stature, marked cranial sclerosis, and spondylometaphyseal dysplasia. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by bacterial PC-phospholipase C inhibitor D609.

Pathway. Sphingolipid metabolism.

Miscellaneous. Overexpression of the human protein in mouse causes increased non-HDL-sphingomyelin and non-HDL cholesterol levels, decreased HDL-sphingomyelin and HDL-cholesterol levels and increases the atherogenic potential of non-HDL lipoprotein particles.

Similarity. Belongs to the sphingomyelin synthase family.

RefSeq proteins (9): NP_001129729, NP_001129730, NP_001362834, NP_001362835, NP_001362836, NP_001362837, NP_001362839, NP_001362840, NP_689834 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR025749	Sphingomyelin_synth-like_dom	Domain
IPR045221	Sphingomyelin_synth-like	Family

Pfam: PF14360

Enzyme classification (BRENDA):

• EC 2.7.8.27 — sphingomyelin synthase (BRENDA: 12 organisms, 39 substrates, 97 inhibitors, 8 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
C6-CERAMIDE	0.0063–0.0072	2
C8-CERAMIDE	0.0054–0.0055	2
6-((N-(7-NITROBENZ-2-OXA-1,3-DIAZOL-4-YL)AMINO)H	0.0075	1
C17-CERAMIDE	0.0003	1
DIACYLGLYCEROL	0.112	1
SPHINGOMYELIN	0.0356	1

Catalyzed reactions (Rhea), 12 shown:

• an N-acylsphing-4-enine + a 1,2-diacyl-sn-glycero-3-phosphocholine = a sphingomyelin + a 1,2-diacyl-sn-glycerol (RHEA:18765)
• an N-acylsphing-4-enine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine = an N-acylsphing-4-enine 1-phosphoethanolamine + a 1,2-diacyl-sn-glycerol (RHEA:36079)
• N-hexadecanoylsphinganine + a 1,2-diacyl-sn-glycero-3-phosphocholine = N-hexadecanoyl-sphinganine-1-phosphocholine + a 1,2-diacyl-sn-glycerol (RHEA:41796)
• N-hexadecanoylsphinganine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine = N-hexadecanoyl-sphinganine-1-phosphoethanolamine + a 1,2-diacyl-sn-glycerol (RHEA:42128)
• an N-acylsphinganine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine = an N-acylsphinganine-1-phosphoethanolamine + a 1,2-diacyl-sn-glycerol (RHEA:42136)
• N-hexadecanoyl-(4R)-hydroxysphinganine + a 1,2-diacyl-sn-glycero-3-phosphocholine = N-hexadecanoyl-(4R)-hydroxysphinganine-phosphocholine + a 1,2-diacyl-sn-glycerol (RHEA:42140)
• N-hexadecanoyl-(4R)-hydroxysphinganine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine = N-hexadecanoyl-(4R)-hydroxysphinganine-1-phosphoethanolamine + a 1,2-diacyl-sn-glycerol (RHEA:42144)
• an N-acyl-(4R)-4-hydroxysphinganine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine = an N-acyl-(4R)-4-hydroxysphinganine-1-phosphoethanolamine + a 1,2-diacyl-sn-glycerol (RHEA:42148)
• an N-acyl-(4R)-4-hydroxysphinganine + a 1,2-diacyl-sn-glycero-3-phosphocholine = an N-acyl-(4R)-4-hydroxysphinganine-phosphocholine + a 1,2-diacyl-sn-glycerol (RHEA:42152)
• 1-(9Z-octadecenoyl)-2-acyl-sn-3-glycerol + a sphingomyelin = a 1-(9Z-octadecenoyl)-2-acyl-sn-glycero-3-phosphocholine + an N-acylsphing-4-enine (RHEA:43320)
• 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine + an N-acylsphing-4-enine = 1,2-dihexadecanoyl-sn-glycerol + a sphingomyelin (RHEA:43324)
• an N-acylsphinganine + a 1,2-diacyl-sn-glycero-3-phosphocholine = an N-acylsphinganine-1-phosphocholine + a 1,2-diacyl-sn-glycerol (RHEA:44620)

UniProt features (36 total): topological domain 7, mutagenesis site 7, transmembrane region 6, lipid moiety-binding region 4, sequence variant 4, active site 3, compositionally biased region 2, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NHU3-F1	77.54	0.47

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 (3): 229; 272; 276

Post-translational modifications (4): 331, 332, 343, 348

Mutagenesis-validated functional residues (7):

Position	Phenotype
227	abolishes enzyme activity by about 70%. no change in subcellular location.
229	completely abolishes enzyme activity. no change in subcellular location.
272	completely abolishes enzyme activity. no change in subcellular location.
276	completely abolishes enzyme activity. no change in subcellular location.
331–332	little effect on palmitoylation; when associated with a-343 or a-348. abolishes palmitoylation and dramatically reduces
343	strongly decreases palmitoylation; when associated with a-348. abolishes palmitoylation and dramatically reduces plasma
348	strongly decreases palmitoylation; when associated with a-343. abolishes palmitoylation and dramatically reduces plasma

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis
R-HSA-1430728	Metabolism
R-HSA-428157	Sphingolipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 209 (showing top): chr4q25, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_SPHINGOMYELIN_METABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_BONE_MINERALIZATION, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, INGRAM_SHH_TARGETS_UP

GO Biological Process (7): sphingomyelin biosynthetic process (GO:0006686), sphingolipid biosynthetic process (GO:0030148), regulation of bone mineralization (GO:0030500), ceramide biosynthetic process (GO:0046513), ceramide phosphoethanolamine biosynthetic process (GO:1905373), lipid metabolic process (GO:0006629), sphingolipid metabolic process (GO:0006665)

GO Molecular Function (7): ceramide phosphoethanolamine synthase activity (GO:0002950), kinase activity (GO:0016301), sphingomyelin synthase activity (GO:0033188), ceramide cholinephosphotransferase activity (GO:0047493), protein binding (GO:0005515), transferase activity (GO:0016740), phosphotransferase activity, for other substituted phosphate groups (GO:0016780)

GO Cellular Component (6): Golgi membrane (GO:0000139), nucleoplasm (GO:0005654), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Sphingolipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sphingolipid biosynthetic process	3
phosphotransferase activity, for other substituted phosphate groups	3
phospholipid biosynthetic process	2
transferase activity, transferring phosphorus-containing groups	2
cellular anatomical structure	2
sphingomyelin metabolic process	1
sphingolipid metabolic process	1
lipid biosynthetic process	1
regulation of ossification	1
bone mineralization	1
regulation of biomineral tissue development	1
ceramide metabolic process	1
primary metabolic process	1
lipid metabolic process	1
binding	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
nuclear lumen	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

590 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SGMS2	SMPD1	P17405	687
SGMS2	SMPD2	O60906	666
SGMS2	SPTLC1	O15269	645
SGMS2	UGCG	Q16739	627
SGMS2	CERS2	Q96G23	622
SGMS2	CERS6	Q6ZMG9	622
SGMS2	SPTLC2	O15270	603
SGMS2	CERS4	Q9HA82	595
SGMS2	CERK	Q8TCT0	580
SGMS2	SPTLC3	Q9NUV7	572
SGMS2	ASAH1	Q13510	570
SGMS2	SMPD3	Q9NY59	563
SGMS2	ACER1	Q8TDN7	556
SGMS2	KDSR	Q06136	554
SGMS2	SMPD4	Q9NXE4	552

IntAct

25 interactions, top by confidence:

A	B	Type	Score
PPGB	SGMS2	psi-mi:“MI:0915”(physical association)	0.560
ZFPL1	SGMS2	psi-mi:“MI:0915”(physical association)	0.560
SGMS2	LPAR3	psi-mi:“MI:0915”(physical association)	0.560
VAMP1	SGMS2	psi-mi:“MI:0915”(physical association)	0.560
SGMS2	GPX8	psi-mi:“MI:0915”(physical association)	0.560
KIF2C	WDR62	psi-mi:“MI:0914”(association)	0.350
AKAP5	MRPL43	psi-mi:“MI:0914”(association)	0.350
Tnks2	AMOTL2	psi-mi:“MI:0914”(association)	0.350
TMPO		psi-mi:“MI:0914”(association)	0.350
Bcl7c	SMARCD2	psi-mi:“MI:0914”(association)	0.350
Sinhcaf	BRMS1	psi-mi:“MI:0914”(association)	0.350
CENPO	CENPX	psi-mi:“MI:0914”(association)	0.350
CX3CL1	FAM171A2	psi-mi:“MI:0914”(association)	0.350
SGMS2	ZNF24	psi-mi:“MI:0914”(association)	0.350
PPGB	SGMS2	psi-mi:“MI:0915”(physical association)	0.000
ZFPL1	SGMS2	psi-mi:“MI:0915”(physical association)	0.000
LPAR3	SGMS2	psi-mi:“MI:0915”(physical association)	0.000
VAMP1	SGMS2	psi-mi:“MI:0915”(physical association)	0.000
SGMS2	GPX8	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): SGMS2 (Affinity Capture-MS), SGMS2 (Affinity Capture-MS), SGMS2 (Affinity Capture-MS), SGMS2 (Affinity Capture-MS), SGMS2 (Affinity Capture-MS), SGMS2 (Affinity Capture-MS), SGMS2 (Affinity Capture-MS), SGMS2 (Synthetic Lethality), SGMS2 (Two-hybrid), SGMS2 (Affinity Capture-RNA), SGMS2 (Two-hybrid), SGMS2 (Two-hybrid), SGMS2 (Two-hybrid), GPX8 (Two-hybrid), LPAR3 (Two-hybrid)

ESM2 similar proteins: A0A078H868, A0AAS4, A0JP80, A6X919, D4AD75, O70536, O77760, O77761, P23913, P35610, P53439, P56079, Q14739, Q20696, Q20735, Q28677, Q2PZI1, Q4JM44, Q4R763, Q5R7H4, Q5RK27, Q60457, Q61263, Q63632, Q63633, Q657W3, Q6AX73, Q6Z0E2, Q7T3T4, Q7TSX5, Q86VZ5, Q8IWX5, Q8NHU3, Q8VCQ6, Q91V14, Q924N4, Q965Q4, Q9D4B1, Q9FJB4, Q9H2X9

Diamond homologs: A0AAS4, Q20696, Q4JM44, Q4R763, Q56Y01, Q7T3T4, Q7TSX5, Q86VZ5, Q8NHU3, Q8VCQ6, Q96LT4, Q9D4B1, Q9DA37, Q9TYV2, Q9U3D4, Q9VS60, Q20735, B3A0L9, B3A0M0, B3A0M1, E9AFX2, Q38E53, Q38E55, Q38E56, Q965Q4, Q9M325, Q9SH93, B3A0M2, B8ACH9, Q5N7A7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	9
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1912 predictions. Top by Δscore:

Variant	Effect	Δscore
4:107824792:GG:G	donor_gain	1.0000
4:107824793:GG:G	donor_gain	1.0000
4:107903223:T:TA	acceptor_gain	1.0000
4:107903230:CAG:C	acceptor_loss	1.0000
4:107903231:A:AG	acceptor_gain	1.0000
4:107903231:A:T	acceptor_loss	1.0000
4:107903232:G:GA	acceptor_gain	1.0000
4:107903232:GCTC:G	acceptor_gain	1.0000
4:107903232:GCTCA:G	acceptor_gain	1.0000
4:107903382:AGAAT:A	donor_gain	1.0000
4:107903383:GAAT:G	donor_gain	1.0000
4:107903383:GAATG:G	donor_gain	1.0000
4:107903384:AAT:A	donor_gain	1.0000
4:107903385:AT:A	donor_gain	1.0000
4:107903385:ATGT:A	donor_loss	1.0000
4:107903386:TGT:T	donor_loss	1.0000
4:107903387:G:GG	donor_gain	1.0000
4:107903388:TAAG:T	donor_loss	1.0000
4:107908559:GTCCA:G	acceptor_loss	1.0000
4:107908560:TCCA:T	acceptor_loss	1.0000
4:107908561:CCA:C	acceptor_loss	1.0000
4:107908562:CAG:C	acceptor_loss	1.0000
4:107908563:A:AG	acceptor_gain	1.0000
4:107908563:AGAT:A	acceptor_loss	1.0000
4:107908564:G:GA	acceptor_gain	1.0000
4:107908564:G:GT	acceptor_loss	1.0000
4:107908564:GATTC:G	acceptor_gain	1.0000
4:107908727:AAAAG:A	donor_loss	1.0000
4:107908728:AAAG:A	donor_loss	1.0000
4:107908729:AAGGT:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS10000006 (4:107905227 T>C), RS1000039297 (4:107882134 G>A), RS1000080090 (4:107868974 A>G), RS10000815 (4:107874412 C>G,T), RS1000093745 (4:107898454 G>GT), RS1000096710 (4:107889964 T>C), RS1000140210 (4:107851442 C>G), RS1000140530 (4:107824581 G>T), RS1000145478 (4:107879072 A>G), RS1000149499 (4:107898800 A>C), RS1000177118 (4:107832347 G>A), RS1000180782 (4:107878825 G>A,T), RS1000232239 (4:107896602 G>A), RS1000238900 (4:107875839 C>T), RS1000336076 (4:107871587 TTCTG>T)

Disease associations

OMIM: gene MIM:611574 | disease phenotypes: MIM:126550

GenCC curated gene-disease

Disease	Classification	Inheritance
calvarial doughnut lesions-bone fragility syndrome	Strong	Autosomal dominant

Mondo (1): calvarial doughnut lesions-bone fragility syndrome (MONDO:0007470)

Orphanet (1): Calvarial doughnut lesions-bone fragility syndrome (Orphanet:85192)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000410	Mixed hearing impairment
HP:0000670	Carious teeth
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001270	Motor delay
HP:0002650	Scoliosis
HP:0002684	Thickened calvaria
HP:0002757	Recurrent fractures
HP:0002980	Femoral bowing
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003510	Severe short stature

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007824_4	Monoclonal gammopathy of undetermined significance	5.000000e-06
GCST009391_1916	Metabolite levels	6.000000e-07
GCST009391_73	Metabolite levels	3.000000e-06
GCST012194_5	Obsessive-compulsive traits	9.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010464	beta-aminoisobutyric acid measurement
EFO:0009767	glycine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565089	Doughnut Lesions of Skull, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3112379 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Sphingomyelin synthase

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

Ligand	Action	Affinity	Parameter
sphingomyelin synthase 2 inhibitor 15w	Inhibition	7.0	pIC50
compound D24 [PMID: 24374347]	Inhibition	4.91	pIC50

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL1161894	IC50	56000 nM

ChEMBL bioactivities

89 potent at pChembl≥5 of 123 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.19	IC50	6.5	nM	CHEMBL4172856
7.80	IC50	16	nM	CHEMBL4177314
7.55	Kd	28	nM	CHEMBL4172856
7.52	Kd	30	nM	CHEMBL4172856
7.52	IC50	30	nM	CHEMBL4646354
7.42	Kd	38	nM	CHEMBL4172856
7.35	IC50	45	nM	CHEMBL4645607
7.33	IC50	47	nM	CHEMBL4641888
7.05	IC50	90	nM	CHEMBL4203399
7.04	IC50	91	nM	CHEMBL4540510
7.04	IC50	91	nM	CHEMBL4638337
7.00	IC50	100	nM	CHEMBL4204352
7.00	IC50	100	nM	CHEMBL4214637
6.96	IC50	110	nM	CHEMBL4207944
6.92	IC50	120	nM	CHEMBL4634669
6.89	IC50	130	nM	CHEMBL4646540
6.82	IC50	150	nM	CHEMBL4202436
6.80	IC50	160	nM	CHEMBL4206801
6.72	IC50	190	nM	CHEMBL4205965
6.68	IC50	210	nM	CHEMBL4634697
6.62	Kd	240	nM	CHEMBL4172856
6.62	IC50	240	nM	CHEMBL4217275
6.62	IC50	240	nM	CHEMBL4211357
6.57	IC50	270	nM	CHEMBL4202973
6.52	IC50	300	nM	CHEMBL4644293
6.47	IC50	340	nM	CHEMBL4212291
6.46	IC50	350	nM	CHEMBL4637599
6.42	IC50	380	nM	CHEMBL4649105
6.42	IC50	380	nM	CHEMBL4639746
6.39	IC50	410	nM	CHEMBL4162182
6.37	IC50	430	nM	CHEMBL4544787
6.33	IC50	470	nM	CHEMBL4162182
6.33	IC50	470	nM	CHEMBL4217676
6.33	IC50	470	nM	CHEMBL4472866
6.32	IC50	480	nM	CHEMBL4638097
6.28	IC50	520	nM	CHEMBL4216327
6.28	IC50	520	nM	CHEMBL4452926
6.21	IC50	610	nM	CHEMBL4644982
6.17	IC50	670	nM	CHEMBL4211679
6.17	IC50	670	nM	CHEMBL4448125
6.17	IC50	670	nM	CHEMBL4558411
6.16	IC50	690	nM	CHEMBL4559796
6.13	IC50	740	nM	CHEMBL4210244
6.13	IC50	740	nM	CHEMBL4462317
6.13	IC50	740	nM	CHEMBL4565783
6.06	IC50	880	nM	CHEMBL4540510
6.05	IC50	890	nM	CHEMBL4568145
6.02	IC50	950	nM	CHEMBL4162182
6.02	IC50	960	nM	CHEMBL4203583
6.00	IC50	1000	nM	MALABARICONE A

PubChem BioAssay actives

89 with measured affinity, of 194 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-methylcyclopropyl) 4-[3-[3-[[3,5-bis(trifluoromethyl)phenyl]methyl-methylcarbamoyl]-1-methyl-2-oxoquinolin-4-yl]oxypropyl]piperidine-1-carboxylate	1507292: Inhibition of full length C-terminal FLAG tagged human SMS2 expressed in HEK293 cell membranes using DMPC-d72 and C17-ceramide as substrate preincubated for 60 mins followed by substrate addition measured after 30 mins by RapidFire/mass spectrometry assay	ic50	0.0065	uM
N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-N,1-dimethyl-2-oxo-4-[(2-phenyl-4-pyridinyl)methoxy]quinoline-3-carboxamide	1507292: Inhibition of full length C-terminal FLAG tagged human SMS2 expressed in HEK293 cell membranes using DMPC-d72 and C17-ceramide as substrate preincubated for 60 mins followed by substrate addition measured after 30 mins by RapidFire/mass spectrometry assay	ic50	0.0160	uM
tert-butyl 4-[3-[3-[[3,5-bis(trifluoromethyl)phenyl]methyl-methylcarbamoyl]-1-methyl-2-oxoquinolin-4-yl]oxypropyl]piperidine-1-carboxylate	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.0300	uM
(1-methylcyclopropyl) 4-[3-[[3-[[3-methoxy-5-(trifluoromethyl)phenyl]methyl-methylcarbamoyl]-1-methyl-2-oxo-1,8-naphthyridin-4-yl]oxy]propyl]piperidine-1-carboxylate	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.0450	uM
(1-methylcyclopropyl) 4-[3-[[3-[[3,5-bis(trifluoromethyl)phenyl]methyl-methylcarbamoyl]-1-methyl-2-oxo-1,8-naphthyridin-4-yl]oxy]propyl]piperidine-1-carboxylate	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.0470	uM
4-[(2,6-dichlorophenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.0900	uM
2-[(2-ethylphenyl)methoxy]-N-pyridin-3-ylbenzamide	1613308: Inhibition of purified SMS2 (unknown origin) using C6-NBD-Ceramide and DMPC as substrates preincubated for 5 mins followed by substrate addition and measured after 30 mins by TLC or HPLC method	ic50	0.0910	uM
tert-butyl 4-[3-[3-[(3,5-dimethoxyphenyl)methyl-methylcarbamoyl]-1-methyl-2-oxoquinolin-4-yl]oxypropyl]piperidine-1-carboxylate	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.0910	uM
4-[(2-chloro-5-fluorophenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.1000	uM
4-[(3-chlorophenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.1000	uM
N-pyridin-3-yl-4-[[2-(trifluoromethoxy)phenyl]methoxy]-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.1100	uM
N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-N,1-dimethyl-2-oxo-4-(4,4,4-trifluorobutoxy)quinoline-3-carboxamide	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.1200	uM
tert-butyl 4-[3-[[3-[(3,5-dimethoxyphenyl)methyl-methylcarbamoyl]-1-methyl-2-oxo-1,8-naphthyridin-4-yl]oxy]propyl]piperidine-1-carboxylate	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.1300	uM
4-[(2,6-dimethylphenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.1500	uM
4-[(3-fluorophenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.1600	uM
4-[(3-methylphenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.1900	uM
N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-N,1-dimethyl-2-oxo-4-(3-phenylpropoxy)quinoline-3-carboxamide	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.2100	uM
4-[(2-ethylphenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.2400	uM
4-[(2-methoxyphenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.2400	uM
4-[(2-chlorophenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.2700	uM
(1-methylcyclopropyl) 4-[3-[[3-[(3,5-dimethoxyphenyl)methyl-methylcarbamoyl]-1-methyl-2-oxo-1,8-naphthyridin-4-yl]oxy]propyl]piperidine-1-carboxylate	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.3000	uM
4-phenylmethoxy-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.3400	uM
N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-N,1-dimethyl-4-(3-methylbutoxy)-2-oxoquinoline-3-carboxamide	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.3500	uM
tert-butyl 4-[3-[3-[(3,5-diethoxyphenyl)methyl-methylcarbamoyl]-1-methyl-2-oxoquinolin-4-yl]oxypropyl]piperidine-1-carboxylate	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.3800	uM
N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-N,1-dimethyl-2-oxo-4-(2-phenylmethoxyethoxy)quinoline-3-carboxamide	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.3800	uM
N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-N,1-dimethyl-2-oxo-4-pyrrolidin-1-ylquinoline-3-carboxamide	1507282: Inhibition of human SMS2 expressed in HEK293T cells using C2-ceramide as substrate preincubated for 60 mins followed by substrate addition measured after 30 mins by RapidFire/mass spectrometry assay	ic50	0.4100	uM
2-[(5-chloro-2-heptoxyphenyl)methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	0.4300	uM
2-[[2-(6-chlorohexoxy)phenyl]methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	0.4700	uM
4-[(2-methylphenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.4700	uM
N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-4-(3-cyclohexylpropoxy)-N,1-dimethyl-2-oxoquinoline-3-carboxamide	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.4800	uM
2-[(5-chloro-2-hexoxyphenyl)methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	0.5200	uM
4-[(3-methoxyphenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.5200	uM
N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-N,1-dimethyl-2-oxo-4-(3-phenylmethoxypyrrolidin-1-yl)quinoline-3-carboxamide	1667228: Inhibition of human recombinant C-terminal FLAG-tagged SMS2 expressed in Freestyle293 cell membrane using C14-phosphatidylcholineD72 and C17-ceramide pre-incubated for 60 mins followed by incubation with substrate for 30 mins measured by RapidFire/MS assay	ic50	0.6100	uM
2-[(5-chloro-2-methoxyphenyl)methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	0.6700	uM
2-[[2-(5-chloropentoxy)phenyl]methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	0.6700	uM
4-[(2-fluorophenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.6700	uM
2-[(2,6-dichlorophenyl)methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	0.6900	uM
2-[(2-chloro-5-fluorophenyl)methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	0.7400	uM
2-[(5-fluoro-2-methylphenyl)methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	0.7400	uM
4-[(2,6-difluorophenyl)methoxy]-N-pyridin-3-yl-1,2-benzoxazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.7400	uM
2-[(2,6-dimethylphenyl)methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	0.8900	uM
3-[[3-(pyridin-3-ylamino)-1,2-benzoxazol-4-yl]oxymethyl]benzonitrile	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	0.9600	uM
2-[(2,5-dichlorophenyl)methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	0.9900	uM
1-(2,6-dihydroxyphenyl)-9-(3,4-dihydroxyphenyl)nonan-1-one	1600506: Noncompetitive inhibition of SMS2 (unknown origin) stably expressed in mouse ZS cells using 5 to 50 uM C6-NBD-ceramide as substrate preincubated for 30 mins followed by substrate addition and measured after 3 hrs by HPLC analysis	ic50	1.0000	uM
1-(2,6-dihydroxyphenyl)-9-(4-hydroxyphenyl)nonan-1-one	1600506: Noncompetitive inhibition of SMS2 (unknown origin) stably expressed in mouse ZS cells using 5 to 50 uM C6-NBD-ceramide as substrate preincubated for 30 mins followed by substrate addition and measured after 3 hrs by HPLC analysis	ic50	1.0000	uM
1-(2,6-dihydroxyphenyl)-9-phenylnonan-1-one	1600506: Noncompetitive inhibition of SMS2 (unknown origin) stably expressed in mouse ZS cells using 5 to 50 uM C6-NBD-ceramide as substrate preincubated for 30 mins followed by substrate addition and measured after 3 hrs by HPLC analysis	ic50	1.0000	uM
2-[(5-chloro-2-methylphenyl)methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	1.1000	uM
2-[(2-chlorophenyl)methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	1.1000	uM
4-phenylmethoxy-N-pyridin-3-yl-1,2-benzothiazol-3-amine	1385502: Inhibition of human SMS2 using C6-NBD-ceramide and DMPC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by HPLC analysis	ic50	1.2000	uM
2-[[2-(4-chlorobutoxy)phenyl]methoxy]-N-pyridin-3-ylbenzamide	1613307: Inhibition of SMS2 (unknown origin) over-expressed in H5 insect cell lysate using C6-NBD-Ceramide and DMPC as substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by TLC or HPLC method	ic50	1.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	7
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression	3
trichostatin A	affects cotreatment, increases expression, decreases expression	3
Cyclosporine	increases expression	3
sodium arsenite	increases expression, affects cotreatment, increases abundance	2
Arsenic	increases abundance, increases expression, affects cotreatment	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Nickel	increases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	decreases expression	1
TL8-506	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sodium arsenate	increases abundance, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
methylparaben	decreases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
bisphenol S	decreases methylation	1

ChEMBL screening assays

30 unique, capped per target: 30 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3119036	Binding	Inhibition of SMS2 (unknown origin) expressed in H5 insect cells using C6-NBD-Cer as substrate at 100 uM after 1 hr	Identification of small molecule sphingomyelin synthase inhibitors. — Eur J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8A7	Ubigene A-549 SGMS2 KO	Cancer cell line	Male
CVCL_E0UY	Ubigene Hep G2 SGMS2 KO	Cancer cell line	Male
CVCL_E0ZP	Ubigene NCI-H1299 SGMS2 KO	Cancer cell line	Male
CVCL_E2K0	HAP1 SGMS2 (-) 1	Cancer cell line	Male
CVCL_E2K1	HAP1 SGMS2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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