CERS2

Summary

CERS2 (ceramide synthase 2, HGNC:14076) is a protein-coding gene on chromosome 1q21.3, encoding Ceramide synthase 2 (Q96G23). Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very-long-chain fatty acyl-CoA (chain length C22-C27). It is a selective cancer dependency (DepMap: 23.0% of cell lines).

This gene encodes a protein that has sequence similarity to yeast longevity assurance gene 1. Mutation or overexpression of the related gene in yeast has been shown to alter yeast lifespan. The human protein may play a role in the regulation of cell growth. Alternatively spliced transcript variants encoding the same protein have been described.

Source: NCBI Gene 29956 — RefSeq curated summary.

At a glance

• GWAS associations: 19
• Clinical variants (ClinVar): 66 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 23.0% of screened cell lines
• MANE Select transcript: NM_022075

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14076
Approved symbol	CERS2
Name	ceramide synthase 2
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	SP260, FLJ10243
Ensembl gene	ENSG00000143418
Ensembl biotype	protein_coding
OMIM	606920
Entrez	29956

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 39 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000271688, ENST00000345896, ENST00000361419, ENST00000368949, ENST00000368954, ENST00000421609, ENST00000457392, ENST00000460664, ENST00000482825, ENST00000558062, ENST00000559020, ENST00000559660, ENST00000560793, ENST00000561294, ENST00000885835, ENST00000885836, ENST00000885837, ENST00000885838, ENST00000885839, ENST00000885840, ENST00000885841, ENST00000885842, ENST00000885843, ENST00000885844, ENST00000885845, ENST00000885846, ENST00000885847, ENST00000885848, ENST00000885849, ENST00000885850, ENST00000885851, ENST00000885852, ENST00000885853, ENST00000885854, ENST00000885855, ENST00000911844, ENST00000911845, ENST00000911846, ENST00000911847, ENST00000911848, ENST00000955081, ENST00000955082, ENST00000955083, ENST00000955084

RefSeq mRNA: 2 — MANE Select: NM_022075 NM_022075, NM_181746

CCDS: CCDS973

Canonical transcript exons

ENST00000368954 — 11 exons

Exon	Start	End
ENSE00001448431	150974619	150974835
ENSE00003472753	150967820	150967877
ENSE00003582507	150968083	150968201
ENSE00003662611	150968395	150968512
ENSE00003694859	150967664	150967714
ENSE00003694940	150966476	150966629
ENSE00003696158	150967392	150967484
ENSE00003696856	150966756	150966862
ENSE00003696919	150968918	150969091
ENSE00003702046	150967074	150967202
ENSE00003899427	150965186	150966288

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 68.0803 / max 434.1670, expressed in 1821 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14373	31.7818	1803
14376	23.6103	1811
14375	5.9546	1682
14377	3.3384	1426
14374	1.9971	1212
14372	0.8322	516
14370	0.5157	295
14371	0.0503	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	99.38	gold quality
right adrenal gland	UBERON:0001233	99.32	gold quality
left adrenal gland	UBERON:0001234	99.24	gold quality
right lobe of liver	UBERON:0001114	99.23	gold quality
left adrenal gland cortex	UBERON:0035825	99.21	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.18	gold quality
adrenal cortex	UBERON:0001235	99.13	gold quality
secondary oocyte	CL:0000655	99.04	gold quality
adrenal gland	UBERON:0002369	98.99	gold quality
spinal cord	UBERON:0002240	98.97	gold quality
metanephros cortex	UBERON:0010533	98.83	gold quality
liver	UBERON:0002107	98.80	gold quality
adrenal tissue	UBERON:0018303	98.80	gold quality
islet of Langerhans	UBERON:0000006	98.68	gold quality
oocyte	CL:0000023	98.61	gold quality
right lung	UBERON:0002167	98.51	gold quality
upper lobe of left lung	UBERON:0008952	98.43	gold quality
nerve	UBERON:0001021	98.40	gold quality
tibial nerve	UBERON:0001323	98.40	gold quality
peripheral nervous system	UBERON:0000010	98.39	gold quality
upper lobe of lung	UBERON:0008948	98.32	gold quality
adult mammalian kidney	UBERON:0000082	98.30	gold quality
gall bladder	UBERON:0002110	98.29	gold quality
right coronary artery	UBERON:0001625	98.24	gold quality
body of stomach	UBERON:0001161	98.18	gold quality
right lobe of thyroid gland	UBERON:0001119	98.17	gold quality
body of pancreas	UBERON:0001150	98.16	gold quality
left lobe of thyroid gland	UBERON:0001120	98.15	gold quality
endocervix	UBERON:0000458	98.09	gold quality
corpus callosum	UBERON:0002336	97.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF6, SP1

miRNA regulators (miRDB)

106 targeting CERS2, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-548AN	99.97	70.91	2817
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
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-106B-5P	99.88	74.72	2795

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 23.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• activity of CerS2 can be regulated by another bioactive sphingolipid, sphingosine 1-phosphate (PMID:18165233)
• TMSG-1 overexpression caused strong inhibition of proliferation and decreased clonogenicity of MDA-MB-231 cells, and promoted cell apoptosis. (PMID:18194600)
• CerS2 down-regulation had a broad effect on ceramide homoeostasis, not just on very-long-chain ceramides. (PMID:19728861)
• CerS2 and CerS6 mRNA was significantly elevated in breast cancer tissue compared to paired normal tissue, with approximately half of the individuals showing elevated CerS2 and CerS6 mRNA. (PMID:19912991)
• Overexpression of CerS2 resulted in partial protection from ionizing radiation-induced apoptosis (PMID:20406683)
• LASS2 expression may be correlated with the development and progression of human bladder carcinoma (PMID:21755371)
• Interaction of KLF6 and Sp1, together with their binding of elements in exon 1 are critical events in initiation of transcription of the tmsg-1 gene. (PMID:21928351)
• KLF6 and Sp1 may participate in the inducible transcriptional regulation of TMSG-1 in prostate carcinoma cells. (PMID:22169644)
• Silencing of LASS2 can promote invasion of prostate cancer cells in vitro through the increase of V-ATPase activity, extracellular hydrogen ion concentration and activation of secreted MMP-2. (PMID:22178826)
• There is a nucleolar localization signal within TMSG-1. (PMID:22336162)
• silencing of LASS2/TMSG1 can promote invasion of prostate cancer cell in vitro through increase of V-ATPase activity which accelerated tumor’s invasion and metastasis, indicating that LASS2/TMSG1 is a novel tumor metastasis suppressor gene (PMID:22573553)
• LASS2 is involved in chemotherapeutic outcomes and low LASS2 expression may predict chemoresistance. (PMID:22580606)
• results contribute to the conclusion that LASS2/TMSG1 could regulate V-ATPase activity and intracellular pH through the direct interaction of its homeodomain and the C subunit of V-ATPase (PMID:22991218)
• Co-expression of CerS2 with CerS4/CerS6 reversed the inhibitory effect of long chain ceramides on cell proliferation and the induction of apoptosis. we detected no effect on cell proliferation. (PMID:23538298)
• expression and role of ceramide synthase-2 in the lung (PMID:23690971)
• the inhibitory effect of the LASS2 on growth, invasion and metastasis of prostate cancer cells (PMID:24453046)
• Data show that CERS2 expression was markedly different between various breast cancer cells and inversely correlated with cell invasion. (PMID:25213553)
• the vacuolar ATPase (V-ATPase) activity and extracellular hydrogen ion concentration were significantly decreased and the activity of secreted matrix metalloproteinase-2 (MMP-2) was downregulated in MCF-7 cells overexpressing LASS2/TMSG1 (PMID:25501280)
• Results confirmed that TMSG1 is a potential metastasis suppressor gene, and suggested that the mechanism involved the induction of apoptosis and inhibition of cell proliferation via a caspase-dependent mitochondrial pathway. (PMID:25735224)
• silencing of TMSG1 increased V-ATPase activity, decreased extracellular pH and in turn the activation of secreted MMP-2, which ultimately promoted metastasis capacity of breast cancer cell. (PMID:25973015)
• Data show that 1-acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) inhibit cell growth by regulating expression of KLF4/LASS2/V-ATPase proteins in breast cancer. (PMID:26110566)
• these results indicate that miR-9 upregulation might be associated with malignant phenotype of bladder cancer. miR-9 promotes chemoresistance of bladder cancer cells by target LASS2. (PMID:26150338)
• These results suggest that the phosphorylation of ceramide synthases may be a key regulatory point in the control of the distribution and levels of sphingolipids of various acyl-chain lengths. (PMID:26887952)
• ASGR1 can inhibit the activity of V-ATPase by interacting with LASS2, thereby suppressing the metastatic potential of hepatoma cells. (PMID:27241665)
• Low expression of LASS2 and TGFB1 contributes to the aggressiveness and poor prognosis of hepatocellular carcinoma, and may represent a novel prognostic biomarker for hepatocellular carcinoma patients. (PMID:27581744)
• CerS2-knockdown via CRISPR-Cas9 technology in cultured colon epithelial cells impaired barrier function. (PMID:28699686)
• Results show that silencing of ATP6V0C in highly metastatic prostate cancer (PC) cell lines, inhibited V-ATPase activity, which coincided with the inhibition of cell migration and invasion in vitro, as well as a marked decrease in the expression of LASS2/TMSG1 probably through positive feedback. (PMID:29138865)
• Data indicate that miR-3658 regulates tumor biological behavior and its downstream molecule signaling pathways through longevity assurance 2 protein (LASS2). (PMID:29739079)
• As potential molecular markers for bladder carcinoma, both TWIST1 and LASS2 transcripts seem to play role during the tumorigenesis and development of bladder cancer. (PMID:30213291)
• Data show that mRNA expression of Cer metabolizing enzyme CERS2 was significantly increased in multiple sclerosis (MS) patients. (PMID:30219773)
• The study demonstrates that miR-98 targets LASS2 and regulates bladder cancer chemoresistance through modulation of mitochondrial function. (PMID:30463687)
• In this study, we found that LASS2 protein level was positively related to International Federation of Gynecology and Obstetrics (FIGO) stage and LASS2-negative tumors showed significant association with longer disease-free survival (DFS) and overall survival (OS) in ovarian cancer patients (PMID:30537159)
• Study findings suggest that LASS2 inhibits proliferation and induces apoptosis in HepG2 hepatoblastoma cells through the mitochondrial apoptotic, NFkappaB and cell cycle signaling pathways. (PMID:30896811)
• results indicate that miR-3622a promotes the proliferation and invasion of bladder cancer cells by downregulating LASS2. (PMID:30898713)
• Studies indicate low level of ceramide synthase 2 (CerS-2) protein might suggest a bad prognosis and up-regulation of CerS-2 protein might act as a promising therapeutic strategy for malignant tumors [Review]. (PMID:30988071)
• G0/G1 ratio in LASS2/TMSG1 S248A group was obviously higher than that in LASS2/TMSG1 wild group (PMID:30996356)
• Association of rs8444 polymorphism in the LASS2 3’-UTR and bladder cancer risk in Chinese population. (PMID:31577563)
• CERS2 is differentially expressed in different types of bladder cancer cell lines and the siRNA-mediated downregulation of the expression of CERS2 reduces the migratory potential of UMUC1 bladder cancer cells (PMID:31636736)
• Activation of SIRT1 Enhances Epidermal Permeability Barrier Formation through Ceramide Synthase 2- and 3-Dependent Mechanisms. (PMID:31958434)
• Ceramide synthase 2-C24:1 -ceramide axis limits the metastatic potential of ovarian cancer cells. (PMID:33423335)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cers2a	ENSDARG00000013704
danio_rerio	cers2b	ENSDARG00000058992
mus_musculus	Cers2	ENSMUSG00000015714
rattus_norvegicus	Cers2	ENSRNOG00000021138
drosophila_melanogaster	schlank	FBGN0040918
caenorhabditis_elegans		WBGENE00002043
caenorhabditis_elegans		WBGENE00002044

Paralogs (5): CERS4 (ENSG00000090661), CERS5 (ENSG00000139624), CERS3 (ENSG00000154227), CERS6 (ENSG00000172292), CERS1 (ENSG00000223802)

Protein

Protein identifiers

Ceramide synthase 2 — Q96G23 (reviewed: Q96G23)

Alternative names: LAG1 longevity assurance homolog 2, SP260, Sphingosine N-acyltransferase CERS2, Tumor metastasis-suppressor gene 1 protein, Very-long-chain ceramide synthase CERS2

All UniProt accessions (8): Q96G23, H0YKH6, H0YLQ6, H0YNU7, Q5SZE1, Q5SZE2, Q5SZE3, Q5SZE4

UniProt curated annotations — full annotation on UniProt →

Function. Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very-long-chain fatty acyl-CoA (chain length C22-C27). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively. Plays a non-redundant role in the synthesis of ceramides with very-long-chain fatty acids in kidney, liver and brain. Regulates the abundance of myelin-specific sphingolipids galactosylceramide and sulfatide that affects myelin sheath architecture and motor neuron functions.

Subunit / interactions. Interacts with ATP6V0C, ASGR1, ASGR2 and SLC22A1/OCT1. Interacts with ELOV1, HSD17B12 and TECR. Interacts with NDUFS2. Interacts with PAQR4; the interaction regulates the stability and activity of CERS2 and is inhibited in presence of ceramides.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in kidney, liver, brain, heart, placenta and lung.

Post-translational modifications. Acetylated. Deacetylation by SIRT3 increases enzyme activity and promotes mitochondrial ceramide accumulation. Phosphorylated at the C-terminus by CK2, leading to increase the ceramide synthase activity.

Activity regulation. Ceramide synthase activity is inhibited by sphingosine-1-phosphate.

Domain organisation. The last loop motif confers selectivity toward behenoyl-CoA (docosanoyl-CoA; C22:0-CoA) and lignoceroyl-CoA (tetracosanoyl-CoA; C24:0-CoA) as acyl donors. The predicted Homeobox domain (Homeobox-like region) lacks important residues for DNA-binding. Moreover, the protein localizes to the endoplasmic reticulum membrane, strongly suggesting that it does not constitute a canonical homeobox domain.

Pathway. Lipid metabolism; sphingolipid metabolism.

Similarity. Belongs to the sphingosine N-acyltransferase family.

RefSeq proteins (2): NP_071358, NP_859530 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR006634	TLC-dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR016439	Lag1/Lac1-like	Family

Pfam: PF00046, PF03798

Enzyme classification (BRENDA):

• EC 2.3.1.24 — sphingosine N-acyltransferase (BRENDA: 14 organisms, 68 substrates, 31 inhibitors, 18 Km, 0 kcat entries)
• EC 2.3.1.297 — very-long-chain ceramide synthase (BRENDA: 7 organisms, 77 substrates, 27 inhibitors, 8 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
SPHINGOSINE	0.0011–0.171	3
PALMITOYL-COA	0.0124–0.141	2
SPHINGANINE	0.023–0.144	2
TETRACOSANOYL-COA	0.0546–0.0629	2
D-ERYTHRO-SPHINGANINE	0.0025–0.0032	2
PHYTOSPHINGOSINE	0.0069–0.023	2
BEHENOYL-COA	0.299	1
HEXANOYL-COA	0.522	1
LAUROYL-COA	0.358	1
OLEOYL-COA	0.18	1
STEAROYL-COA	0.146	1
BEHENOYL-COA	0.0001	1

Catalyzed reactions (Rhea), 12 shown:

• a fatty acyl-CoA + sphing-4-enine = an N-acylsphing-4-enine + CoA + H(+) (RHEA:23768)
• hexacosanoyl-CoA + sphinganine = N-hexacosanoylsphinganine + CoA + H(+) (RHEA:33351)
• tetracosanoyl-CoA + sphinganine = N-tetracosanoylsphinganine + CoA + H(+) (RHEA:33591)
• docosanoyl-CoA + sphinganine = N-docosanoylsphinganine + CoA + H(+) (RHEA:36535)
• sphinganine + hexadecanoyl-CoA = N-hexadecanoylsphinganine + CoA + H(+) (RHEA:36539)
• sphinganine + octadecanoyl-CoA = N-(octadecanoyl)-sphinganine + CoA + H(+) (RHEA:36547)
• eicosanoyl-CoA + sphinganine = N-eicosanoylsphinganine + CoA + H(+) (RHEA:36555)
• sphinganine + (9Z)-octadecenoyl-CoA = N-(9Z-octadecenoyl)-sphinganine + CoA + H(+) (RHEA:36575)
• 2-hydroxydocosanoyl-CoA + sphinganine = N-(2-hydroxydocosanoyl)-sphinganine + CoA + H(+) (RHEA:36619)
• 2-hydroxytetracosanoyl-CoA + sphinganine = N-(2-hydroxytetracosanoyl)-sphinganine + CoA + H(+) (RHEA:36627)
• (15Z)-tetracosenoyl-CoA + sphinganine = N-(15Z-tetracosenoyl)-sphinganine + CoA + H(+) (RHEA:36667)
• sphing-4-enine + hexadecanoyl-CoA = N-hexadecanoylsphing-4-enine + CoA + H(+) (RHEA:36687)

UniProt features (26 total): transmembrane region 6, modified residue 4, mutagenesis site 3, sequence conflict 3, topological domain 2, region of interest 2, chain 1, short sequence motif 1, compositionally biased region 1, glycosylation site 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96G23-F1	87.31	0.69

Functional residue map

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

Post-translational modifications (4): 341, 346, 348, 349

Glycosylation sites (1): 19

Mutagenesis-validated functional residues (3):

Position	Phenotype
230	abolished inhibition by sphingosine-1-phosphate; when associated with a-325.
325	abolished inhibition by sphingosine-1-phosphate; when associated with a-230.
341–349	strongly decreased phosphorylation leading to reduced ceramide synthase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis

MSigDB gene sets: 264 (showing top): GGGACCA_MIR133A_MIR133B, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_GLIOGENESIS, GOBP_VESICLE_ORGANIZATION, GOBP_REGENERATION, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_RESPONSE_TO_AXON_INJURY, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS

GO Biological Process (11): glycosphingolipid biosynthetic process (GO:0006688), regulation of lipid metabolic process (GO:0019216), sphingolipid biosynthetic process (GO:0030148), response to immobilization stress (GO:0035902), ceramide biosynthetic process (GO:0046513), negative regulation of axon regeneration (GO:0048681), negative regulation of Schwann cell migration (GO:1900148), obsolete negative regulation of Schwann cell proliferation involved in axon regeneration (GO:1905045), lipid metabolic process (GO:0006629), sphingolipid metabolic process (GO:0006665), negative regulation of Schwann cell proliferation (GO:0010626)

GO Molecular Function (5): DNA binding (GO:0003677), sphingosine N-acyltransferase activity (GO:0050291), protein binding (GO:0005515), obsolete N-acyltransferase activity (GO:0016410), transferase activity (GO:0016740)

GO Cellular Component (5): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sphingolipid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sphingolipid biosynthetic process	2
lipid metabolic process	2
intracellular membrane-bounded organelle	2
glycosphingolipid metabolic process	1
glycolipid biosynthetic process	1
regulation of primary metabolic process	1
sphingolipid metabolic process	1
lipid biosynthetic process	1
response to stress	1
ceramide metabolic process	1
axon regeneration	1
negative regulation of response to external stimulus	1
regulation of axon regeneration	1
negative regulation of neuron projection regeneration	1
negative regulation of response to wounding	1
Schwann cell migration	1
regulation of Schwann cell migration	1
negative regulation of glial cell migration	1
primary metabolic process	1
regulation of Schwann cell proliferation	1
Schwann cell proliferation	1
negative regulation of glial cell proliferation	1
nucleic acid binding	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
binding	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
endoplasmic reticulum membrane	1
cytoplasmic side of membrane	1

Protein interactions and networks

STRING

984 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CERS2	GDF1	P27539	934
CERS2	ATP6V0C	P27449	906
CERS2	SPTLC1	O15269	784
CERS2	ASGR1	P07306	784
CERS2	ASGR2	P07307	766
CERS2	SLC22A1	O15245	762
CERS2	SPTLC2	O15270	755
CERS2	ASAH1	Q13510	752
CERS2	SPTLC3	Q9NUV7	750
CERS2	ELOVL1	Q9BW60	728
CERS2	TLCD3B	Q71RH2	724
CERS2	UGCG	Q16739	716
CERS2	BCL2L13	Q9BXK5	701
CERS2	DEGS1	O15121	696
CERS2	SMPD1	P17405	691

IntAct

139 interactions, top by confidence:

A	B	Type	Score
CERS2	ATP6V0C	psi-mi:“MI:0915”(physical association)	0.730
CERS2	ATP6V0C	psi-mi:“MI:0407”(direct interaction)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ATP5PF	ATP5PD	psi-mi:“MI:0914”(association)	0.670
CERS2	ASGR1	psi-mi:“MI:0915”(physical association)	0.650
CERS2	ASGR2	psi-mi:“MI:0915”(physical association)	0.650
CERS2	SLC22A1	psi-mi:“MI:0915”(physical association)	0.650
CERS2	ASGR1	psi-mi:“MI:0407”(direct interaction)	0.650
CERS2	ASGR2	psi-mi:“MI:0407”(direct interaction)	0.650
SLC22A1	CERS2	psi-mi:“MI:0407”(direct interaction)	0.650
ASGR1	CERS2	psi-mi:“MI:0915”(physical association)	0.650
SLC22A1	CERS2	psi-mi:“MI:0915”(physical association)	0.650
ATP5PB	SLC19A2	psi-mi:“MI:0914”(association)	0.640
POMK	LRP5	psi-mi:“MI:0914”(association)	0.640
CERS2	ATP5F1B	psi-mi:“MI:0914”(association)	0.640
YIF1A	CERS2	psi-mi:“MI:0915”(physical association)	0.560
CERS2	IER3IP1	psi-mi:“MI:0915”(physical association)	0.560
CERS2	SLC19A2	psi-mi:“MI:0915”(physical association)	0.550
KPNB1	POM121C	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
POMK	TMEM120B	psi-mi:“MI:0914”(association)	0.530
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
RELL1	TCAF2	psi-mi:“MI:0914”(association)	0.530

BioGRID (292): CERS2 (Affinity Capture-MS), CERS2 (Affinity Capture-MS), CERS2 (Affinity Capture-MS), CERS2 (Affinity Capture-MS), CERS2 (Proximity Label-MS), CERS2 (Proximity Label-MS), CERS2 (Proximity Label-MS), CERS2 (Affinity Capture-MS), CERS2 (Affinity Capture-MS), CERS2 (Affinity Capture-MS), CERS2 (Affinity Capture-MS), CERS2 (Affinity Capture-MS), CERS2 (Affinity Capture-MS), CERS2 (Affinity Capture-MS), CERS2 (Affinity Capture-MS)

ESM2 similar proteins: A0PK00, A1L2R7, A2BIE7, A2VE61, A3KNK1, A6QPF8, A7XZ53, A8DZH4, B1AZA5, D3ZEH5, D3ZXD8, E1BD52, O35052, P58749, P98191, Q05B45, Q0VFK3, Q15035, Q17QL9, Q1LY80, Q3TA38, Q3UMR5, Q5EAX9, Q5EAY8, Q5FWV6, Q5HZE2, Q5R7B1, Q5U239, Q5ZMP3, Q63ZG0, Q68EY2, Q6DE21, Q6ZMG9, Q8BXA5, Q8C172, Q8C1E7, Q8CIF6, Q8N5B7, Q8NBJ9, Q8WVP7

Diamond homologs: A6ZSP9, G5ED45, P27545, P38703, P78970, Q3ZBF8, Q6EUN0, Q6NQI8, Q6YWS8, Q7Z139, Q84QC0, Q8IU89, Q8N5B7, Q8W4Y5, Q924Z4, Q96G23, Q9D6J1, Q9LDF2, Q9LJK3, Q9M6A3, Q1A3B0, Q5E9R6, Q6ZMG9, Q8C172, Q9D6K9, Q9HA82, O59735, P27544, Q15035, Q15629, Q5R7Z3, Q5XI41, Q91V04, Q924Z5, G1UJF5, Q8AYB8, Q9XWE9, Q8J2Q2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CERS2	“up-regulates quantity”	ceramide	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 138 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of ATP by chemiosmotic coupling	7	40.8×	1e-07
Cristae formation	7	24.7×	3e-06
Mitochondrial biogenesis	7	12.0×	3e-04
R-HSA-425366	6	11.1×	1e-03
Aerobic respiration and respiratory electron transport	8	7.2×	1e-03
Class A/1 (Rhodopsin-like receptors)	9	6.8×	9e-04
Organelle biogenesis and maintenance	9	6.1×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
proton motive force-driven ATP synthesis	7	46.0×	9e-08
proton motive force-driven mitochondrial ATP synthesis	8	17.3×	9e-06
amino acid transport	6	15.3×	3e-04
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	8	14.3×	2e-05
phospholipase C-activating G protein-coupled receptor signaling pathway	10	10.8×	1e-05
positive regulation of cytosolic calcium ion concentration	9	8.6×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2686 predictions. Top by Δscore:

Variant	Effect	Δscore
1:150962156:AGTG:A	donor_loss	1.0000
1:150962157:GT:G	donor_gain	1.0000
1:150962157:GTGT:G	donor_loss	1.0000
1:150962159:G:GG	donor_gain	1.0000
1:150962585:A:AG	acceptor_gain	1.0000
1:150962586:G:GG	acceptor_gain	1.0000
1:150962586:GA:G	acceptor_gain	1.0000
1:150962586:GAGTT:G	acceptor_gain	1.0000
1:150962717:GAT:G	donor_gain	1.0000
1:150962720:G:GG	donor_gain	1.0000
1:150963126:G:GT	donor_gain	1.0000
1:150963178:G:GG	donor_gain	1.0000
1:150963526:CCA:C	acceptor_loss	1.0000
1:150963527:CAGGT:C	acceptor_loss	1.0000
1:150963528:A:AG	acceptor_gain	1.0000
1:150963528:A:G	acceptor_loss	1.0000
1:150963529:G:A	acceptor_loss	1.0000
1:150963529:G:GG	acceptor_gain	1.0000
1:150963529:GGTCC:G	acceptor_gain	1.0000
1:150963720:C:T	donor_gain	1.0000
1:150963742:G:GG	donor_gain	1.0000
1:150964080:GCAA:G	donor_gain	1.0000
1:150964084:G:GG	donor_gain	1.0000
1:150966284:ACCAG:A	acceptor_gain	1.0000
1:150966285:CCAG:C	acceptor_gain	1.0000
1:150966285:CCAGC:C	acceptor_gain	1.0000
1:150966286:CAG:C	acceptor_gain	1.0000
1:150966286:CAGC:C	acceptor_gain	1.0000
1:150966287:AG:A	acceptor_gain	1.0000
1:150966288:GCT:G	acceptor_loss	1.0000

AlphaMissense

2489 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:150966523:A:G	W319R	1.000
1:150966523:A:T	W319R	1.000
1:150966788:A:C	F272L	1.000
1:150966788:A:T	F272L	1.000
1:150966790:A:G	F272L	1.000
1:150966854:C:A	K250N	1.000
1:150966854:C:G	K250N	1.000
1:150967121:C:A	G232W	1.000
1:150967181:G:C	H212D	1.000
1:150966273:G:T	R340S	0.999
1:150966279:C:G	D338H	0.999
1:150966521:C:A	W319C	0.999
1:150966521:C:G	W319C	0.999
1:150966534:A:G	L315P	0.999
1:150966543:A:G	L312P	0.999
1:150966777:C:G	R276P	0.999
1:150966789:A:G	F272S	0.999
1:150966790:A:T	F272I	0.999
1:150966800:G:C	F268L	0.999
1:150966800:G:T	F268L	0.999
1:150966802:A:G	F268L	0.999
1:150966809:G:C	F265L	0.999
1:150966809:G:T	F265L	0.999
1:150966811:A:G	F265L	0.999
1:150967087:T:A	D243V	0.999
1:150967087:T:C	D243G	0.999
1:150967087:T:G	D243A	0.999
1:150967088:C:A	D243Y	0.999
1:150967088:C:G	D243H	0.999
1:150967096:T:A	D240V	0.999

dbSNP variants (sampled 300 via entrez): RS1000107487 (1:150965780 T>C), RS1000373232 (1:150967635 A>C,T), RS1000405833 (1:150967297 G>A,T), RS1000826372 (1:150976656 ACT>A), RS1000882540 (1:150973347 G>A), RS1000934399 (1:150973047 G>A), RS1000972930 (1:150974189 C>A,T), RS1001601030 (1:150970349 C>T), RS1001893967 (1:150968261 G>C), RS1002108658 (1:150974286 C>G), RS1002187824 (1:150964711 A>C), RS1002448001 (1:150975772 G>C), RS1002483820 (1:150974987 G>T), RS1002778640 (1:150973422 T>C), RS1003292800 (1:150968740 G>A,T)

Disease associations

OMIM: gene MIM:606920 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000649_7	Chronic kidney disease	1.000000e-12
GCST001266_1	Melanoma	9.000000e-11
GCST001966_1	Rhegmatogenous retinal detachment	1.000000e-07
GCST002222_16	LDL cholesterol	5.000000e-09
GCST003372_8	Glomerular filtration rate (creatinine)	4.000000e-13
GCST003401_1	Glomerular filtration rate in non diabetics (creatinine)	3.000000e-12
GCST004233_60	LDL cholesterol levels	4.000000e-08
GCST004619_179	Reticulocyte fraction of red cells	4.000000e-09
GCST005951_38	Body mass index	4.000000e-09
GCST006611_141	HDL cholesterol	6.000000e-12
GCST007821_1	Facial attractiveness (female raters)	6.000000e-07
GCST007876_141	Estimated glomerular filtration rate	3.000000e-20
GCST007954_10	Glycated hemoglobin levels	3.000000e-09
GCST008058_159	Estimated glomerular filtration rate	1.000000e-48
GCST008059_122	Estimated glomerular filtration rate	2.000000e-48
GCST010241_102	Apolipoprotein A1 levels	1.000000e-47
GCST010242_433	HDL cholesterol levels	1.000000e-20
GCST011126_7	Caffeine consumption from coffee or tea	1.000000e-26
GCST90020028_623	Hip circumference adjusted for BMI	4.000000e-09

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007986	reticulocyte count
EFO:0004340	body mass index
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009892	facial attractiveness measurement
EFO:0004541	HbA1c measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0006781	coffee consumption measurement
EFO:0010091	tea consumption measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291553 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 16,015 (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
CHEMBL314854	FINGOLIMOD	4	16,015

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Ceramide synthase

ChEMBL bioactivities

7 potent at pChembl≥5 of 7 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.17	Kd	68.31	nM	CHEMBL3752910
7.17	ED50	68.31	nM	CHEMBL3752910
5.67	Ki	2150	nM	FINGOLIMOD
5.44	Kd	3595	nM	CHEMBL5653589
5.44	ED50	3595	nM	CHEMBL5653589
5.19	IC50	6400	nM	FINGOLIMOD
5.16	IC50	7000	nM	CHEMBL5268405

PubChem BioAssay actives

5 with measured affinity, of 7 total; 4 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148062: Binding affinity to human CERS2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0683	uM
Fingolimod	1923485: Competitive inhibition of CerS2 in HPAC cells using DHSph as substrate by LC/MS/MS analysis	ki	2.1500	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148062: Binding affinity to human CERS2 incubated for 45 mins by Kinobead based pull down assay	kd	3.5954	uM
(2S)-2-amino-4-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2-methylbutan-1-ol	1923492: Inhibition of human CerS2	ic50	7.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
Tobacco Smoke Pollution	increases expression	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
thermozymocidin	decreases reaction, increases expression	1
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression, decreases reaction	1
deoxynivalenol	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases abundance, increases expression, affects cotreatment	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
ICG 001	decreases expression	1
1-(4-chlorophenyl)-3-(3-(4-chlorophenyl)-5,5-dimethyl-1-(3-(5-nitrofuran-2-yl)allyldienehydrazinocarbonylmethyl)-2-oxoimidazolidin-4-yl)-1-hydroxyurea	decreases reaction, affects expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Bortezomib	affects expression, decreases reaction	1
Resveratrol	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	decreases expression	1
Aerosols	increases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Vehicle Emissions	decreases expression, increases abundance	1
Biological Factors	decreases expression	1
Carbamazepine	affects expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Smoke	decreases expression	1
Dronabinol	increases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5226568	Binding	Inhibition of CerS2 in HPAC cells using DHSph as substrate	Small Molecule Inhibitors Targeting Biosynthesis of Ceramide, the Central Hub of the Sphingolipid Network. — J Med Chem

Cellosaurus cell lines

10 cell lines: 6 cancer cell line, 3 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A0Q5	SEES3-1V human CERS2, clone1	Embryonic stem cell	Male
CVCL_A0Q6	SEES3-1V human CERS2, clone2	Embryonic stem cell	Male
CVCL_A0Q7	SEES3-1V human CERS2, clone3	Embryonic stem cell	Male
CVCL_B2U5	Abcam HEK293T CERS2 KO	Transformed cell line	Female
CVCL_B3SV	HeLa-mCAT#8 TAL-CERS2#13	Cancer cell line	Female
CVCL_B3SW	HeLa-mCAT#8 TAL-CERS2#16	Cancer cell line	Female
CVCL_B3SX	HeLa-mCAT#8 TAL-CERS2#18	Cancer cell line	Female
CVCL_B3T1	HeLa-mCAT#8 TAL-CERS2#18-CERT#10	Cancer cell line	Female
CVCL_DX09	HAP1 CERS2 (-) 2	Cancer cell line	Male
CVCL_XM74	HAP1 CERS2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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