SMPDL3B

Summary

SMPDL3B (sphingomyelin phosphodiesterase acid like 3B, HGNC:21416) is a protein-coding gene on chromosome 1p35.3, encoding Acid sphingomyelinase-like phosphodiesterase 3b (Q92485). Lipid-modulating phosphodiesterase.

Enables phosphoric diester hydrolase activity. Predicted to be involved in membrane lipid catabolic process; negative regulation of inflammatory response; and negative regulation of toll-like receptor signaling pathway. Located in extracellular exosome.

Source: NCBI Gene 27293 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 96 total
• MANE Select transcript: NM_014474

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21416
Approved symbol	SMPDL3B
Name	sphingomyelin phosphodiesterase acid like 3B
Location	1p35.3
Locus type	gene with protein product
Status	Approved
Aliases	ASML3B
Ensembl gene	ENSG00000130768
Ensembl biotype	protein_coding
OMIM	617737
Entrez	27293

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000373888, ENST00000373894, ENST00000411604, ENST00000466793, ENST00000548116, ENST00000549094, ENST00000910805, ENST00000910806, ENST00000910807, ENST00000917789

RefSeq mRNA: 3 — MANE Select: NM_014474 NM_001009568, NM_001304579, NM_014474

CCDS: CCDS30655, CCDS30656

Canonical transcript exons

ENST00000373894 — 8 exons

Exon	Start	End
ENSE00000896298	27949065	27949162
ENSE00001461850	27935000	27935244
ENSE00003488406	27955684	27955864
ENSE00003561105	27958476	27959152
ENSE00003578488	27953215	27953358
ENSE00003597871	27955949	27956082
ENSE00003605807	27945232	27945445
ENSE00003674900	27954354	27954526

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 90.56.

FANTOM5 (CAGE): breadth broad, TPM avg 2.7336 / max 104.9047, expressed in 548 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1763	1.5052	404
1762	0.9822	309
1761	0.2202	113
1764	0.0260	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	90.56	gold quality
body of pancreas	UBERON:0001150	88.90	gold quality
rectum	UBERON:0001052	88.67	gold quality
pancreas	UBERON:0001264	83.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.66	gold quality
left lobe of thyroid gland	UBERON:0001120	80.12	gold quality
islet of Langerhans	UBERON:0000006	80.04	gold quality
right lobe of thyroid gland	UBERON:0001119	79.92	gold quality
thyroid gland	UBERON:0002046	78.54	gold quality
transverse colon	UBERON:0001157	78.28	gold quality
duodenum	UBERON:0002114	77.82	gold quality
body of stomach	UBERON:0001161	75.32	gold quality
mucosa of paranasal sinus	UBERON:0005030	74.25	gold quality
right uterine tube	UBERON:0001302	74.09	gold quality
minor salivary gland	UBERON:0001830	73.91	gold quality
saliva-secreting gland	UBERON:0001044	73.80	gold quality
stomach	UBERON:0000945	73.33	gold quality
right lung	UBERON:0002167	72.45	gold quality
small intestine Peyer’s patch	UBERON:0003454	71.79	gold quality
upper lobe of left lung	UBERON:0008952	71.61	gold quality
colonic mucosa	UBERON:0000317	71.51	gold quality
upper lobe of lung	UBERON:0008948	71.38	gold quality
mouth mucosa	UBERON:0003729	71.34	gold quality
small intestine	UBERON:0002108	71.26	gold quality
parotid gland	UBERON:0001831	70.60	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	70.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.58	gold quality
oocyte	CL:0000023	69.10	gold quality
tonsil	UBERON:0002372	68.82	gold quality
lower lobe of lung	UBERON:0008949	68.81	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting SMPDL3B, 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-627-3P	99.90	71.42	3316
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-4424	98.91	70.33	1145
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-5087	98.01	69.09	965
HSA-MIR-676-3P	97.86	65.70	668
HSA-MIR-6082	96.40	70.86	216
HSA-MIR-6879-3P	93.93	64.00	759

Literature-anchored findings (GeneRIF, showing 8)

• These results demonstrate that radiation injury induces early cytoskeletal remodeling, down-regulation of SMPDL3b, and elevation of cellular ceramide levels. Overexpression of SMPDL3b and pretreatment with rituximab confer a radioprotective effect in cultured podocytes. (PMID:27836988)
• Glomerular immunoreactivity and urinary excretion of SMPDL3b in proteinuric nephrotic syndrome patients decreased compared with controls. (PMID:29081073)
• Study reports that SMPDL3b excess, as observed in podocytes in diabetic kidney disease, impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in the plasma membrane. (PMID:31217420)
• Modulation of radiation-induced damage of human glomerular endothelial cells by SMPDL3B. (PMID:32293077)
• Phosphodiesterase SMPDL3B Gene Expression as Independent Outcome Prediction Marker in Localized Prostate Cancer. (PMID:32575490)
• Sphingomyelin Phosphodiesterase Acid-Like 3b is Essential for Toll-Like Receptor 3 Signaling in Human Podocytes. (PMID:34739556)
• SMPDL3b modulates radiation-induced DNA damage response in renal podocytes. (PMID:36094323)
• SMPDL3B contributes to gastric adenocarcinoma cells progression by promoting the infiltration of M2 macrophages. (PMID:38813495)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	smpdl3b	ENSDARG00000010130
mus_musculus	Smpdl3b	ENSMUSG00000028885
rattus_norvegicus	Smpdl3b	ENSRNOG00000042326
drosophila_melanogaster	CG32052	FBGN0044328
caenorhabditis_elegans		WBGENE00014106

Paralogs (2): SMPD1 (ENSG00000166311), SMPDL3A (ENSG00000172594)

Protein

Protein identifiers

Acid sphingomyelinase-like phosphodiesterase 3b — Q92485 (reviewed: Q92485)

All UniProt accessions (4): Q92485, F8VWW8, F8VXS3, Q5T0Y8

UniProt curated annotations — full annotation on UniProt →

Function. Lipid-modulating phosphodiesterase. Active on the surface of macrophages and dendritic cells and strongly influences macrophage lipid composition and membrane fluidity. Acts as a negative regulator of Toll-like receptor signaling. Has in vitro phosphodiesterase activity, but the physiological substrate is unknown. Lacks activity with phosphocholine-containing lipids, but can cleave CDP-choline, and can release phosphate from ATP and ADP (in vitro).

Subunit / interactions. Interacts with TLR4, TLR7, TLR8 and TLR9.

Subcellular location. Secreted. Cell membrane.

Post-translational modifications. N-glycosylated.

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

Similarity. Belongs to the acid sphingomyelinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92485-1	1	yes
Q92485-2	2

RefSeq proteins (3): NP_001009568, NP_001291508, NP_055289* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004843	Calcineurin-like_PHP	Domain
IPR017064	ASM-like_Pdiesterase_prd	Family
IPR029052	Metallo-depent_PP-like	Homologous_superfamily
IPR041805	ASMase/PPN1_MPP	Domain
IPR045473	ASM_C	Domain

Pfam: PF00149, PF19272

UniProt features (22 total): binding site 8, glycosylation site 3, disulfide bond 3, splice variant 2, sequence conflict 2, signal peptide 1, chain 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92485-F1	93.11	0.89

Functional residue map

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

Ligand- & substrate-binding residues (8): 28; 30; 93; 93; 134; 236; 277; 279

Disulfide bonds (3): 45–64, 405–409, 415–428

Glycosylation sites (3): 72, 164, 343

Mutagenesis-validated functional residues (1):

Position	Phenotype
135	reduced phosphodiesterase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 194 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_SPHINGOMYELIN_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MODULE_16, CHANDRAN_METASTASIS_DN, GOBP_MEMBRANE_LIPID_CATABOLIC_PROCESS, GOBP_REGULATION_OF_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GOBP_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM2

GO Biological Process (9): sphingomyelin catabolic process (GO:0006685), inflammatory response (GO:0006954), negative regulation of toll-like receptor signaling pathway (GO:0034122), innate immune response (GO:0045087), obsolete membrane lipid catabolic process (GO:0046466), negative regulation of inflammatory response (GO:0050728), immune system process (GO:0002376), lipid metabolic process (GO:0006629), lipid catabolic process (GO:0016042)

GO Molecular Function (7): sphingomyelin phosphodiesterase activity (GO:0004767), phosphoric diester hydrolase activity (GO:0008081), zinc ion binding (GO:0008270), hydrolase activity, acting on glycosyl bonds (GO:0016798), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (6): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), side of membrane (GO:0098552), extracellular region (GO:0005576), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
membrane	2
sphingomyelin metabolic process	1
phospholipid catabolic process	1
sphingolipid catabolic process	1
defense response	1
toll-like receptor signaling pathway	1
negative regulation of immune system process	1
negative regulation of signal transduction	1
regulation of toll-like receptor signaling pathway	1
immune response	1
defense response to symbiont	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
biological_process	1
primary metabolic process	1
lipid metabolic process	1
catabolic process	1
phosphoric diester hydrolase activity	1
sphingophospholipase activity	1
phosphoric ester hydrolase activity	1
transition metal ion binding	1
hydrolase activity	1
binding	1
catalytic activity	1
cation binding	1
cell periphery	1
extracellular vesicle	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

736 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMPDL3B	CERK	Q8TCT0	640
SMPDL3B	SMPD2	O60906	574
SMPDL3B	NPHS2	Q9NP85	573
SMPDL3B	SPTLC1	O15269	512
SMPDL3B	SYNPO	Q8N3V7	507
SMPDL3B	NPHS1	O60500	476
SMPDL3B	UGCG	Q16739	463
SMPDL3B	ASAH2	Q9NR71	452
SMPDL3B	SMPD4	Q9NXE4	452
SMPDL3B	PDE3B	Q13370	451
SMPDL3B	MRPS11	P82912	443
SMPDL3B	MRPL35	Q9NZE8	443
SMPDL3B	TMEM259	Q4ZIN3	437
SMPDL3B	CACHD1	Q5VU97	436
SMPDL3B	ACER2	Q5QJU3	423

IntAct

33 interactions, top by confidence:

A	B	Type	Score
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
SMPDL3B	HFE	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
L1TD1	MYO1C	psi-mi:“MI:0914”(association)	0.350
PRKD1		psi-mi:“MI:0914”(association)	0.350
ZDHHC5	HACD3	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
HASPIN	MYO1C	psi-mi:“MI:0914”(association)	0.350
PSMC5	PSMD1	psi-mi:“MI:0914”(association)	0.350
CERS2	VPS37C	psi-mi:“MI:0914”(association)	0.350
CEP15	POTEF	psi-mi:“MI:0914”(association)	0.350
ZDHHC23	VPS37C	psi-mi:“MI:0914”(association)	0.350
NDUFS5	METTL15	psi-mi:“MI:0914”(association)	0.350
YIPF3	EI24	psi-mi:“MI:0914”(association)	0.350
CST6	ATP2A1	psi-mi:“MI:0914”(association)	0.350
CBFB	RP2	psi-mi:“MI:0914”(association)	0.350
ZPBP2	PALM	psi-mi:“MI:0914”(association)	0.350
SMAD2	FLOT1	psi-mi:“MI:0914”(association)	0.350
SDHA	FLOT1	psi-mi:“MI:0914”(association)	0.350
TUBD1	FLOT1	psi-mi:“MI:0914”(association)	0.350
CSRP3	NME2	psi-mi:“MI:0914”(association)	0.350
LEAP2	GNB2	psi-mi:“MI:0914”(association)	0.350
RHCG	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC16A10	STXBP3	psi-mi:“MI:0914”(association)	0.350
SLC19A1	TAPBP	psi-mi:“MI:0914”(association)	0.350
SLC2A1	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
SLC34A2	SNAP23	psi-mi:“MI:0914”(association)	0.350
SLC7A2	SCAMP3	psi-mi:“MI:0914”(association)	0.350
SLCO1B3	SNAP23	psi-mi:“MI:0914”(association)	0.350

BioGRID (46): SMPDL3B (Affinity Capture-MS), SMPDL3B (Affinity Capture-MS), SMPDL3B (Affinity Capture-MS), SMPDL3B (Affinity Capture-MS), SMPDL3B (Affinity Capture-MS), SMPDL3B (Affinity Capture-MS), SMPDL3B (Affinity Capture-MS), SMPDL3B (Affinity Capture-RNA), SMPDL3B (Affinity Capture-MS), SMPDL3B (Affinity Capture-MS), SMPDL3B (Affinity Capture-MS), SMPDL3B (Affinity Capture-MS), SMPDL3B (Affinity Capture-MS), SMPDL3B (Reconstituted Complex), HFE (Affinity Capture-MS)

ESM2 similar proteins: A0A2I4HXH5, A5D6U8, B3A0N5, B6EWW8, E0D877, F8S0Z7, O00462, O35409, P05089, P15693, P19492, P21588, P21589, P29240, P31422, P42263, P49614, P49900, P50635, P52307, P70627, P83456, P83852, Q05927, Q14832, Q1ZZH1, Q29444, Q2KJ64, Q4FZV0, Q561R9, Q5R979, Q5RAL3, Q5RFI5, Q5TVM9, Q5XGR8, Q61503, Q641Z7, Q6AYS4, Q6PCE3, Q8CAA7

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	9
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1418 predictions. Top by Δscore:

Variant	Effect	Δscore
1:27935168:G:GT	donor_gain	1.0000
1:27935168:G:T	donor_gain	1.0000
1:27949063:A:AG	acceptor_gain	1.0000
1:27949064:G:GG	acceptor_gain	1.0000
1:27954523:CATGG:C	donor_loss	1.0000
1:27954527:GTAAG:G	donor_loss	1.0000
1:27954528:T:A	donor_loss	1.0000
1:27955860:TGCAG:T	donor_loss	1.0000
1:27955863:AGGT:A	donor_loss	1.0000
1:27955864:GG:G	donor_loss	1.0000
1:27955865:G:C	donor_loss	1.0000
1:27955866:T:G	donor_loss	1.0000
1:27955943:T:A	acceptor_gain	1.0000
1:27955945:ACAGG:A	acceptor_loss	1.0000
1:27955946:CA:C	acceptor_loss	1.0000
1:27955947:A:AG	acceptor_gain	1.0000
1:27955948:G:GG	acceptor_gain	1.0000
1:27955948:GGT:G	acceptor_gain	1.0000
1:27956081:AGGT:A	donor_loss	1.0000
1:27956082:GGTC:G	donor_loss	1.0000
1:27956083:G:A	donor_loss	1.0000
1:27956084:T:G	donor_loss	1.0000
1:27958470:TTCCA:T	acceptor_loss	1.0000
1:27958472:CCAG:C	acceptor_loss	1.0000
1:27958473:CAG:C	acceptor_loss	1.0000
1:27958474:A:AG	acceptor_gain	1.0000
1:27958474:A:AT	acceptor_loss	1.0000
1:27958475:G:GG	acceptor_gain	1.0000
1:27958475:GGAC:G	acceptor_gain	1.0000
1:27958475:GGACA:G	acceptor_gain	1.0000

AlphaMissense

2996 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:27949067:A:T	D93V	0.994
1:27945360:T:A	C64S	0.993
1:27945361:G:C	C64S	0.993
1:27953239:G:T	G133V	0.993
1:27953243:T:A	N134K	0.993
1:27953243:T:G	N134K	0.993
1:27956045:G:C	R323P	0.993
1:27958535:G:C	W355C	0.993
1:27958535:G:T	W355C	0.993
1:27945258:C:G	H30D	0.992
1:27955844:G:C	R284P	0.992
1:27945361:G:A	C64Y	0.991
1:27954415:C:A	N193K	0.991
1:27954415:C:G	N193K	0.991
1:27945438:T:A	W90R	0.990
1:27945438:T:C	W90R	0.990
1:27949068:T:A	D93E	0.990
1:27949068:T:G	D93E	0.990
1:27955837:A:C	S282R	0.990
1:27955839:C:A	S282R	0.990
1:27955839:C:G	S282R	0.990
1:27955824:C:A	H277Q	0.989
1:27955824:C:G	H277Q	0.989
1:27958533:T:A	W355R	0.989
1:27958533:T:C	W355R	0.989
1:27945303:T:A	C45S	0.988
1:27945304:G:C	C45S	0.988
1:27945364:A:T	D65V	0.988
1:27945445:G:T	G92V	0.988
1:27953246:T:A	H135Q	0.988

dbSNP variants (sampled 300 via entrez): RS1000106172 (1:27955086 G>A), RS1000116390 (1:27936024 C>A), RS1000128062 (1:27946542 C>T), RS1000175325 (1:27935669 A>C), RS1000333192 (1:27942194 G>A,C), RS1000422287 (1:27949670 C>T), RS1000516531 (1:27953928 C>T), RS1000960147 (1:27940712 G>A), RS1001026723 (1:27955961 G>A), RS1001106375 (1:27934353 T>C), RS1001176041 (1:27937146 A>G), RS1001394194 (1:27950738 C>G), RS1001413979 (1:27940987 T>C), RS1001531251 (1:27958854 T>C), RS1001629287 (1:27957652 G>A)

Disease associations

OMIM: gene MIM:617737 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Sphingomyelin phosphodiesterase

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
Estradiol	affects cotreatment, decreases expression, affects binding, increases reaction	2
aristolochic acid I	increases expression	1
glycidyl methacrylate	decreases expression	1
sulforaphane	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Glyphosate	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	increases expression	1
Methapyrilene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Triclosan	increases expression	1

Clinical trials (associated diseases)

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