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SMPD3 sphingomyelin phosphodiesterase 3 [ Homo sapiens (human) ]

Gene ID: 55512, updated on 3-Mar-2026
Official Symbol
SMPD3provided by HGNC
Official Full Name
sphingomyelin phosphodiesterase 3provided by HGNC
Primary source
HGNC:HGNC:14240
See related
Ensembl:ENSG00000103056 MIM:605777; AllianceGenome:HGNC:14240
Gene type
protein coding
RefSeq status
VALIDATED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
NSMASE2
Summary
Enables sphingomyelin phosphodiesterase activity. Involved in sphingomyelin catabolic process. Predicted to be located in plasma membrane. Predicted to be active in cytoplasm. Biomarker of pulmonary emphysema. [provided by Alliance of Genome Resources, Jul 2025]
Expression
Biased expression in duodenum (RPKM 22.0), small intestine (RPKM 21.4) and 11 other tissues See more
Orthologs
all
Try the new Gene page
Try the new Transcripts and proteins table
See SMPD3 in Genome Data Viewer
Location:
16q22.1
Exon count:
13
Annotation release Status Assembly Chr Location
RS_2025_08 current GRCh38.p14 (GCF_000001405.40) 16 NC_000016.10 (68358327..68448508, complement)
RS_2025_08 current T2T-CHM13v2.0 (GCF_009914755.1) 16 NC_060940.1 (74154167..74244330, complement)
RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 16 NC_000016.9 (68392230..68482411, complement)

Chromosome 16 - NC_000016.10Genomic Context describing neighboring genes Neighboring gene small nucleolar RNA U13 Neighboring gene protein arginine methyltransferase 7 Neighboring gene RNA, U4 small nuclear 30, pseudogene Neighboring gene H3K27ac hESC enhancer GRCh37_chr16:68382607-68383107 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 11013 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68396471-68397283 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68397284-68398095 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68400892-68401445 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68401446-68401998 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 11014 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 11015 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68413436-68413938 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68413939-68414439 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68415806-68416642 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68416643-68417477 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68422765-68423592 Neighboring gene Sharpr-MPRA regulatory region 9240 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68431713-68432213 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:68432795-68433424 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:68433425-68434052 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:68442570-68443549 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:68444678-68445630 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:68445631-68446581 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7646 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 11016 Neighboring gene uncharacterized LOC124903705 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68504627-68505126 Neighboring gene ribosomal protein L35a pseudogene 33

Go to nucleotide: Graphics FASTA GenBank

  • Project title: Tissue-specific circular RNA induction during human fetal development
  • Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
  • BioProject: PRJNA270632
  • Publication: PMID 26076956
  • Analysis date: Mon Apr 2 22:54:59 2018

Related articles in PubMed

  1. The Role of Neutral Sphingomyelinase-2 (NSM2) in the Control of Neutral Lipid Storage in T Cells. Schempp R, et al. Int J Mol Sci, 2024 Mar 13. PMID 38542220, Free PMC Article
  2. nSMase2 activation and trafficking are modulated by oxidative stress to induce apoptosis. Levy M, et al. Biochem Biophys Res Commun, 2006 Jun 9. PMID 16631623, Free PMC Article
  3. Analysis of membrane topology of neutral sphingomyelinase 2. Tani M, et al. FEBS Lett, 2007 Apr 3. PMID 17349629, Free PMC Article
  4. Neutral sphingomyelinase 2 (nSMase2) is a phosphoprotein regulated by calcineurin (PP2B). Filosto S, et al. J Biol Chem, 2010 Apr 2. PMID 20106976, Free PMC Article
  5. Neutral sphingomyelinase 2 (nSMase2) is the primary neutral sphingomyelinase isoform activated by tumour necrosis factor-α in MCF-7 cells. Clarke CJ, et al. Biochem J, 2011 Apr 15. PMID 21303347, Free PMC Article

See all (57) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. The Role of Neutral Sphingomyelinase-2 (NSM2) in the Control of Neutral Lipid Storage in T Cells.
    Title: The Role of Neutral Sphingomyelinase-2 (NSM2) in the Control of Neutral Lipid Storage in T Cells.
  2. Regulated translocation of neutral sphingomyelinase-2 to the plasma membrane drives insulin resistance in steatotic hepatocytes.
    Title: Regulated translocation of neutral sphingomyelinase-2 to the plasma membrane drives insulin resistance in steatotic hepatocytes.
  3. Inhibition of Neutral Sphingomyelinase 2 by Novel Small Molecule Inhibitors Results in Decreased Release of Extracellular Vesicles by Vascular Smooth Muscle Cells and Attenuated Calcification.
    Title: Inhibition of Neutral Sphingomyelinase 2 by Novel Small Molecule Inhibitors Results in Decreased Release of Extracellular Vesicles by Vascular Smooth Muscle Cells and Attenuated Calcification.
  4. Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects.
    Title: Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects.
  5. Activation of neutral sphingomyelinase 2 through hyperglycemia contributes to endothelial apoptosis via vesicle-bound intercellular transfer of ceramides.
    Title: Activation of neutral sphingomyelinase 2 through hyperglycemia contributes to endothelial apoptosis via vesicle-bound intercellular transfer of ceramides.
  6. Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti-PD-1 Therapy Efficacy.
    Title: Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti-PD-1 Therapy Efficacy.
  7. Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis.
    Title: Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis.
  8. demonstrate that PS binding at the N-terminal and juxtamembrane regions of nSMase2 rather acts as a conformational switch leading to interdomain interactions that are critical to enzyme activation
    Title: The juxtamembrane linker in neutral sphingomyelinase-2 functions as an intramolecular allosteric switch that activates the enzyme.
  9. Compounds against human nSMase2 we identified.
    Title: DPTIP, a newly identified potent brain penetrant neutral sphingomyelinase 2 inhibitor, regulates astrocyte-peripheral immune communication following brain inflammation.
  10. These findings identify neutral sphingomyelinase 2 as essential in TCR signaling when dynamic cytoskeletal reorganization promotes continued lateral and vertical supply of TCR signaling components
    Title: The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling.
Submit: New GeneRIF Correction See all GeneRIFs (40)

Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

Protein interactions

Protein Gene Interaction Pubs
Envelope surface glycoprotein gp120 env A redox-regulated translocation of neutral sphingomyelinase-2 to the plasma membrane is required for HIV-1 gp120-induced enlargement and stabilization of the structure of lipid microdomains on dendrites PubMed
env HIV-1 gp120 binding to CXCR4 induces NADPH oxidase-mediated production of superoxide radicals in neurons, which is involved in the activation of neutral sphingomyelinase PubMed
env In human primary neurons, HIV-1 gp120 induces the activation of sphingomyelinases (primarily neutral sphingomyelinase); antisense knockdown of neutral sphingomyelinase markedly inhibits gp120-mediated apoptosis and cell death of primary neurons PubMed
Nef nef HIV-1 Nef inhibits sphingomyelinase activity in human podocyte PubMed

Go to the HIV-1, Human Interaction Database

Products Interactant Other Gene Complex Source Pubs Description

Markers

Homology

Clone Names

  • FLJ22593, MGC138443

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables catalytic activity IEA
Inferred from Electronic Annotation
more info
  
enables hydrolase activity IEA
Inferred from Electronic Annotation
more info
  
enables identical protein binding IEA
Inferred from Electronic Annotation
more info
  
enables metal ion binding IEA
Inferred from Electronic Annotation
more info
  
enables neutral sphingomyelin phosphodiesterase activity IEA
Inferred from Electronic Annotation
more info
  
enables phosphatidic acid binding IEA
Inferred from Electronic Annotation
more info
  
enables phosphatidic acid binding ISS
Inferred from Sequence or Structural Similarity
more info
  
enables phosphatidylserine binding IEA
Inferred from Electronic Annotation
more info
  
enables phosphatidylserine binding ISS
Inferred from Sequence or Structural Similarity
more info
  
enables phosphoric diester hydrolase activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables phosphoric diester hydrolase activity IEA
Inferred from Electronic Annotation
more info
  
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
enables sphingomyelin phosphodiesterase activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables sphingomyelin phosphodiesterase activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables sphingomyelin phosphodiesterase activity IEA
Inferred from Electronic Annotation
more info
  
enables sphingomyelin phosphodiesterase activity ISS
Inferred from Sequence or Structural Similarity
more info
  
Process Evidence Code Pubs
involved_in lipid metabolic process IEA
Inferred from Electronic Annotation
more info
  
involved_in positive regulation of exosomal secretion ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in sphingolipid metabolic process IEA
Inferred from Electronic Annotation
more info
  
involved_in sphingomyelin catabolic process IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in sphingomyelin catabolic process TAS
Traceable Author Statement
more info
 PubMed 
involved_in sphingomyelin metabolic process IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in sphingomyelin metabolic process ISS
Inferred from Sequence or Structural Similarity
more info
  
Component Evidence Code Pubs
located_in Golgi apparatus IEA
Inferred from Electronic Annotation
more info
  
located_in Golgi cis cisterna IEA
Inferred from Electronic Annotation
more info
  
located_in Golgi membrane IEA
Inferred from Electronic Annotation
more info
  
is_active_in cytoplasm IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in endoplasmic reticulum IDA
Inferred from Direct Assay
more info
  
located_in extracellular region IEA
Inferred from Electronic Annotation
more info
  
located_in plasma membrane IEA
Inferred from Electronic Annotation
more info
  
located_in plasma membrane ISS
Inferred from Sequence or Structural Similarity
more info
  
located_in plasma membrane TAS
Traceable Author Statement
more info
  
Preferred Names
sphingomyelin phosphodiesterase 3
Names
nSMase-2
neutral sphingomyelinase 2
neutral sphingomyelinase II
NP_061137.1
XP_005256089.1
XP_011521509.1
XP_011521512.1
XP_016878895.1
XP_047290292.1
XP_047290293.1
XP_047290294.1
XP_047290295.1
XP_047290296.1
XP_047290297.1
XP_054169385.1
XP_054169386.1
XP_054169387.1
XP_054169388.1
XP_054169389.1
XP_054169390.1
XP_054169391.1
XP_054169392.1
XP_054169393.1
XP_054169394.1
XP_054169395.1

NEW Try the new Transcript table

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

  1. NM_018667.4 → NP_061137.1  sphingomyelin phosphodiesterase 3

    See identical proteins and their annotated locations for NP_061137.1

    Status: VALIDATED

    Source sequence(s)
    AC099521, AK289651, BC112238
    Consensus CDS
    CCDS10867.1
    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6
    Related
    ENSP00000219334.5, ENST00000219334.10
    Conserved Domains (2) summary
    cd09078
    Location:338 → 646
    nSMase; Neutral sphingomyelinases (nSMase) catalyze the hydrolysis of sphingomyelin in biological membranes to ceramide and phosphorylcholine
    PHA03307
    Location:171 → 321
    PHA03307; transcriptional regulator ICP4; Provisional

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2025_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000016.10 Reference GRCh38.p14 Primary Assembly

    Range
    68358327..68448508 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_011523207.2 → XP_011521509.1  sphingomyelin phosphodiesterase 3 isoform X1

    See identical proteins and their annotated locations for XP_011521509.1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6
    Conserved Domains (2) summary
    cd09078
    Location:338 → 646
    nSMase; Neutral sphingomyelinases (nSMase) catalyze the hydrolysis of sphingomyelin in biological membranes to ceramide and phosphorylcholine
    PHA03307
    Location:171 → 321
    PHA03307; transcriptional regulator ICP4; Provisional

  2. XM_047434339.1 → XP_047290295.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6
    Related
    ENSP00000549658.1, ENST00000879599.1

  3. XM_017023406.2 → XP_016878895.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6
    Conserved Domains (2) summary
    cd09078
    Location:338 → 646
    nSMase; Neutral sphingomyelinases (nSMase) catalyze the hydrolysis of sphingomyelin in biological membranes to ceramide and phosphorylcholine
    PHA03307
    Location:171 → 321
    PHA03307; transcriptional regulator ICP4; Provisional

  4. XM_047434340.1 → XP_047290296.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6

  5. XM_047434338.1 → XP_047290294.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6
    Related
    ENSP00000549657.1, ENST00000879598.1

  6. XM_047434336.1 → XP_047290292.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6
    Related
    ENSP00000549654.1, ENST00000879595.1

  7. XM_047434337.1 → XP_047290293.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6
    Related
    ENSP00000549655.1, ENST00000879596.1

  8. XM_005256032.4 → XP_005256089.1  sphingomyelin phosphodiesterase 3 isoform X1

    See identical proteins and their annotated locations for XP_005256089.1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6
    Related
    ENSP00000549656.1, ENST00000879597.1
    Conserved Domains (2) summary
    cd09078
    Location:338 → 646
    nSMase; Neutral sphingomyelinases (nSMase) catalyze the hydrolysis of sphingomyelin in biological membranes to ceramide and phosphorylcholine
    PHA03307
    Location:171 → 321
    PHA03307; transcriptional regulator ICP4; Provisional

  9. XM_047434341.1 → XP_047290297.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6

  10. XM_011523210.3 → XP_011521512.1  sphingomyelin phosphodiesterase 3 isoform X2

    Conserved Domains (1) summary
    cl00490
    Location:338 → 441
    EEP; Exonuclease-Endonuclease-Phosphatase (EEP) domain superfamily

RNA

  1. XR_933371.3 RNA Sequence

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060940.1 Alternate T2T-CHM13v2.0

    Range
    74154167..74244330 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054313412.1 → XP_054169387.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6

  2. XM_054313415.1 → XP_054169390.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6

  3. XM_054313410.1 → XP_054169385.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6

  4. XM_054313416.1 → XP_054169391.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6

  5. XM_054313414.1 → XP_054169389.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6

  6. XM_054313418.1 → XP_054169393.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6

  7. XM_054313413.1 → XP_054169388.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6

  8. XM_054313411.1 → XP_054169386.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6

  9. XM_054313417.1 → XP_054169392.1  sphingomyelin phosphodiesterase 3 isoform X1

    UniProtKB/Swiss-Prot
    B7ZL82, Q2M1S8, Q9NY59
    UniProtKB/TrEMBL
    A8K0T6

  10. XM_054313420.1 → XP_054169395.1  sphingomyelin phosphodiesterase 3 isoform X2

  11. XM_054313419.1 → XP_054169394.1  sphingomyelin phosphodiesterase 3 isoform X2

RNA

  1. XR_008484705.1 RNA Sequence

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
Q9NY59.1 GenPept UniProtKB/Swiss-Prot:Q9NY59

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