CERS6

Summary

CERS6 (ceramide synthase 6, HGNC:23826) is a protein-coding gene on chromosome 2q24.3, encoding Ceramide synthase 6 (Q6ZMG9). Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward palmitoyl-CoA (hexadecanoyl-CoA; C16:0-CoA).

Enables sphingosine N-acyltransferase activity. Involved in ceramide biosynthetic process. Located in membrane.

Source: NCBI Gene 253782 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 57 total
• Druggable target: yes
• MANE Select transcript: NM_203463

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23826
Approved symbol	CERS6
Name	ceramide synthase 6
Location	2q24.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000172292
Ensembl biotype	protein_coding
OMIM	615336
Entrez	253782

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000305747, ENST00000392687, ENST00000947121, ENST00000947122, ENST00000947123

RefSeq mRNA: 2 — MANE Select: NM_203463 NM_001256126, NM_203463

CCDS: CCDS2228, CCDS58734

Canonical transcript exons

ENST00000305747 — 10 exons

Exon	Start	End
ENSE00000964715	168765592	168765748
ENSE00001187508	168717872	168717978
ENSE00001187518	168715001	168715129
ENSE00001257886	168769510	168775134
ENSE00001411280	168547596	168547701
ENSE00001421925	168561192	168561322
ENSE00001425068	168630985	168631042
ENSE00001425408	168691034	168691084
ENSE00002364667	168694959	168695051
ENSE00002561332	168456272	168456618

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 96.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.4483 / max 1177.0745, expressed in 1772 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23512	32.2199	1767
23511	1.0185	528
23510	0.2099	102

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hair follicle	UBERON:0002073	96.81	gold quality
corpus epididymis	UBERON:0004359	96.62	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.56	gold quality
adrenal tissue	UBERON:0018303	96.35	gold quality
cortical plate	UBERON:0005343	96.22	gold quality
decidua	UBERON:0002450	95.75	gold quality
colonic mucosa	UBERON:0000317	95.71	gold quality
jejunal mucosa	UBERON:0000399	95.07	gold quality
ganglionic eminence	UBERON:0004023	95.01	gold quality
orbitofrontal cortex	UBERON:0004167	94.86	gold quality
middle temporal gyrus	UBERON:0002771	94.78	gold quality
epithelium of bronchus	UBERON:0002031	94.68	gold quality
bronchial epithelial cell	CL:0002328	94.64	gold quality
skin of hip	UBERON:0001554	94.41	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.40	gold quality
embryo	UBERON:0000922	94.25	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.25	gold quality
bronchus	UBERON:0002185	94.23	gold quality
upper leg skin	UBERON:0004262	94.04	gold quality
ventricular zone	UBERON:0003053	93.70	gold quality
mammary duct	UBERON:0001765	93.57	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.53	gold quality
heart right ventricle	UBERON:0002080	93.52	gold quality
postcentral gyrus	UBERON:0002581	93.29	gold quality
parietal lobe	UBERON:0001872	93.26	gold quality
entorhinal cortex	UBERON:0002728	93.13	gold quality
cauda epididymis	UBERON:0004360	93.12	gold quality
pylorus	UBERON:0001166	92.98	gold quality
epithelium of nasopharynx	UBERON:0001951	92.66	gold quality
nasopharynx	UBERON:0001728	92.64	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	4559.65
E-CURD-119	yes	29.06
E-ANND-3	yes	5.45
E-CURD-88	yes	4.74

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

340 targeting CERS6, 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-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6740-5P	100.00	65.64	932

Literature-anchored findings (GeneRIF, showing 34)

• Mechanistically, regulation of ER-stress-induced apoptosis by CerS6/C(16)-ceramide was linked to the activation of a specific arm, ATF6/CHOP, of the unfolded protein response pathway. (PMID:19723703)
• 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)
• Findings indicate that mda-7/IL-24 induces PERK activation that triggers production of ceramide, ceramide synthase 6 and thioredoxin, which in turn promote glioma cell autophagy and cell death. (PMID:20103619)
• ionizing radiation induces de novo synthesis of ceramide to influence HeLa cell apoptosis by specifically activating CerS isoforms 2, 5, and 6 that generate opposing anti- and pro-apoptotic ceramides in mitochondrial membranes. (PMID:20406683)
• Alteration of ceramide synthase 6/C16-ceramide induces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2+ and ER/Golgi membrane network (PMID:22013072)
• The transiently increased expression of ceramide synthase (CerS6) correlates to the clinical finding that C(16:0)-Cer levels are increased 1.9-fold in cerebrospinal fluid of multiple sclerosis patients. (PMID:22544924)
• folate withdrawal also induced CerS6/C16-ceramide elevation accompanied by p53 accumulation. Overall, these novel findings link folate and de novo ceramide pathways in cellular stress response. (PMID:23519469)
• 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)
• CerS6 as a novel epithelial-mesenchymal transition-regulated gene that has a pivotal role in the regulation of cell migration. (PMID:24632610)
• Upregulation of CERS6 in an experimental autoimmune encephalomyelitis model is sex dependent. (PMID:25173988)
• On the basis of its pivotal role in regulating cell death upon COX dysfunction, CerS6 might potentially represent a novel target for therapeutic intervention in mitochondrial diseases caused by COX dysfunction. (PMID:25766330)
• Data indicate that ceramide synthase 6 (CerS6) expression is upregulated in leukocytes from multiple sclerosis (MS) patients. (PMID:25833068)
• Taken together, these results suggest that increased expression of CerS6 can mediate transcriptional activation of acid ceramidase in a JNK-dependent manner that is independent of CerS6 activity. (PMID:25839235)
• stichoposide D inhibits growth of experimental leukemia by activating Fas/ceramide synthase 6/p38 kinase in lipid rafts (PMID:26318294)
• Identification of CerS6 and ceramide pathways as a novel Methotrexate target. (PMID:26783755)
• 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)
• silencing of CerS6 induced the increased expression of GLUT1, which downregulated the expression of WNT5A and enhanced the invasion and proliferation of melanoma cells. (PMID:26934938)
• This study has shown that by direct transcriptional activation of CerS6, p53 can regulate specific ceramide biosynthesis, which contributes to the pro-apoptotic cellular response. (PMID:27302066)
• ceramide synthase (CerS)6 was specifically up-regulated in zone 3 hepatocytes in alcoholic steatosis (PMID:28864659)
• CerS6 could mediate an effective response to cisplatin in chemoresistant oral squamous cell carcinoma. (PMID:30054909)
• Study found that overexpression of CERS6 in gastric cancer (GC) cells facilitated cell proliferation and spread as well as xenograft proliferation, resulting in a significantly worse prognosis of the patients with GC. These findings suggest that CERS6 overexpression can be a useful biomarker for predicting the outcomes of GC patients. (PMID:30129684)
• CERS6 interferes with Fas-Fas-associated protein with death domain death-inducing signaling complex assembly. CERS6 may serve as a biomarker in determining the effectiveness of anticancer agents acting via the extrinsic pathway in T-cell acute lymphoblastic leukemia. (PMID:30206207)
• both SphK1 overexpression and S1P addition increased mTOR phosphorylation as shown by ELISA, while S1PR2 inhibition had the inverse effect. These data suggest that CerS6 and SphK1 regulate mTOR signaling in breast cancer cell proliferation. Moreover, mTOR activity can be regulated by the balance between S1P and C16ceramide, which is generated by CerS6. (PMID:30226616)
• The human CERS6 gene promoter harbors a large CpG island (94 CpGs) and multiple transcription factor binding sites (TFBS), which support precise transcriptional regulation and signaling functions. Additional regulation is conferred by 15 microRNA (miRNA) target sites identified in the CERS6 3’-UTR region (PMID:30297675)
• These associations were successfully replicated in an independent collection of Indigenous Australian T2D cases and controls. These SNPs all lie within the gene encoding ceramide synthase 6 (CERS6) and thus may regulate ceramide synthesis. (PMID:31012404)
• Long noncoding RNA CERS6-AS1 functions as a malignancy promoter in breast cancer by binding to IGF2BP3 to enhance the stability of CERS6 mRNA. (PMID:31701672)
• CERS6 required for cell migration and metastasis in lung cancer. (PMID:32902157)
• CEBPgamma facilitates lamellipodia formation and cancer cell migration through CERS6 upregulation. (PMID:33934437)
• AKT1/FOXP3 axis-mediated expression of CerS6 promotes p53 mutant pancreatic tumorigenesis. (PMID:34343636)
• Comprehensive analysis of LASS6 expression and prognostic value in ovarian cancer. (PMID:34488809)
• Dependence of ABCB1 transporter expression and function on distinct sphingolipids generated by ceramide synthases-2 and -6 in chemoresistant renal cancer. (PMID:34915026)
• CircCERS6 Suppresses the Development of Epithelial Ovarian Cancer Through Mediating miR-630/RASSF8. (PMID:35676548)
• CerS6 triggered by high glucose activating the TLR4/IKKbeta pathway regulates ferroptosis of LO2 cells through mitochondrial oxidative stress. (PMID:37230220)
• Ceramide synthase 6 (CerS6) is upregulated in alcohol-associated liver disease and exhibits sex-based differences in the regulation of energy homeostasis and lipid droplet accumulation. (PMID:37714377)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cers6	ENSDARG00000053583
mus_musculus	Cers6	ENSMUSG00000027035
rattus_norvegicus	Cers6	ENSRNOG00000024595
drosophila_melanogaster	schlank	FBGN0040918
caenorhabditis_elegans		WBGENE00002043
caenorhabditis_elegans		WBGENE00002044

Paralogs (5): CERS4 (ENSG00000090661), CERS5 (ENSG00000139624), CERS2 (ENSG00000143418), CERS3 (ENSG00000154227), CERS1 (ENSG00000223802)

Protein

Protein identifiers

Ceramide synthase 6 — Q6ZMG9 (reviewed: Q6ZMG9)

Alternative names: LAG1 longevity assurance homolog 6, Sphingoid base N-palmitoyltransferase CERS6

All UniProt accessions (1): Q6ZMG9

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 palmitoyl-CoA (hexadecanoyl-CoA; C16:0-CoA). Can use other acyl donors, but with less efficiency. N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively. Ceramides generated by CERS6 play a role in inflammatory response. Acts as a regulator of metabolism and hepatic lipid accumulation. Under high fat diet, palmitoyl- (C16:0-) ceramides generated by CERS6 specifically bind the mitochondrial fission factor MFF, thereby promoting mitochondrial fragmentation and contributing to the development of obesity.

Subunit / interactions. Monomer and homodimer. The monomer has an acyl-binding tunnel that selects for a palmitoyl chain by limiting the number of carbons that can fit in the tunnel.

Subcellular location. Endoplasmic reticulum membrane.

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

Induction. Up-regulated in adipose tissues in obese patients.

Pathway. Lipid metabolism; sphingolipid metabolism.

Similarity. Belongs to the sphingosine N-acyltransferase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6ZMG9-1	1	yes
Q6ZMG9-2	2

RefSeq proteins (2): NP_001243055, NP_982288* (*=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)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. 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
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

Catalyzed reactions (Rhea), 6 shown:

• sphinganine + hexadecanoyl-CoA = N-hexadecanoylsphinganine + CoA + H(+) (RHEA:36539)
• sphinganine + octadecanoyl-CoA = N-(octadecanoyl)-sphinganine + CoA + H(+) (RHEA:36547)
• sphinganine + tetradecanoyl-CoA = N-(tetradecanoyl)-sphinganine + CoA + H(+) (RHEA:36571)
• sphing-4-enine + hexadecanoyl-CoA = N-hexadecanoylsphing-4-enine + CoA + H(+) (RHEA:36687)
• hexadecasphinganine + hexadecanoyl-CoA = N-hexadecanoylhexadecasphinganine + CoA + H(+) (RHEA:43040)
• a sphingoid base + hexadecanoyl-CoA = an N-hexadecanoyl-sphingoid base + CoA + H(+) (RHEA:61472)

UniProt features (52 total): helix 18, topological domain 8, mutagenesis site 8, transmembrane region 7, turn 4, chain 1, domain 1, region of interest 1, compositionally biased region 1, active site 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8QZ7	ELECTRON MICROSCOPY	3
9EOT	ELECTRON MICROSCOPY	3.02
8QZ6	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZMG9-F1	87.97	0.80

Antibody-complex structures (SAbDab): 3 — 8QZ6, 8QZ7, 9EOT

Functional residue map

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

Catalytic / active sites (1): 211 (nucleophile; for acyl transferase activity)

Glycosylation sites (1): 18

Mutagenesis-validated functional residues (8):

Position	Phenotype
131	abolished ceramide synthase activity.
131	does not affect ceramide synthase activity.
211	abolishes ceramide synthase activity.
212	abolishes ceramide synthase activity.
238	impairs ceramide synthase activity.
275	impairs ceramide synthase activity.
315	impairs ceramide synthase activity.
341–347	decreased phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis

MSigDB gene sets: 358 (showing top): YANG_BREAST_CANCER_ESR1_LASER_UP, GOBP_INFLAMMATORY_RESPONSE, GOZGIT_ESR1_TARGETS_DN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, WEI_MYCN_TARGETS_WITH_E_BOX, ONKEN_UVEAL_MELANOMA_UP, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, chr2q24, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN

GO Biological Process (7): inflammatory response (GO:0006954), oligodendrocyte development (GO:0014003), sphingolipid biosynthetic process (GO:0030148), ceramide biosynthetic process (GO:0046513), positive regulation of oligodendrocyte apoptotic process (GO:1900143), lipid metabolic process (GO:0006629), sphingolipid metabolic process (GO:0006665)

GO Molecular Function (4): DNA binding (GO:0003677), sphingosine N-acyltransferase activity (GO:0050291), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (3): endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), endoplasmic reticulum (GO:0005783)

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
defense response	1
glial cell development	1
oligodendrocyte differentiation	1
sphingolipid metabolic process	1
lipid biosynthetic process	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
positive regulation of glial cell apoptotic process	1
oligodendrocyte apoptotic process	1
regulation of oligodendrocyte apoptotic process	1
primary metabolic process	1
lipid metabolic process	1
nucleic acid binding	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
binding	1
catalytic activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

776 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CERS6	GDF1	P27539	876
CERS6	SPTLC1	O15269	819
CERS6	SPTLC2	O15270	797
CERS6	SPTLC3	Q9NUV7	762
CERS6	DEGS1	O15121	740
CERS6	ASAH1	Q13510	737
CERS6	UGCG	Q16739	726
CERS6	TLCD3B	Q71RH2	723
CERS6	CERK	Q8TCT0	706
CERS6	SMPD2	O60906	701
CERS6	SGPL1	O95470	699
CERS6	SMPD1	P17405	697
CERS6	KDSR	Q06136	693
CERS6	SPHK1	Q9NYA1	676
CERS6	ASAH2	Q9NR71	670

IntAct

107 interactions, top by confidence:

A	B	Type	Score
ATP5F1B	ATP5PD	psi-mi:“MI:0914”(association)	0.670
ATP5PF	ATP5PD	psi-mi:“MI:0914”(association)	0.670
RETREG3	PLSCR1	psi-mi:“MI:0914”(association)	0.640
ATP5PB	SLC19A2	psi-mi:“MI:0914”(association)	0.640
OPRL1	CERS6	psi-mi:“MI:0915”(physical association)	0.630
CERS6	OPRL1	psi-mi:“MI:0915”(physical association)	0.630
GPR84	CERS6	psi-mi:“MI:0915”(physical association)	0.560
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
GPR21	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
SLC7A1	TMEM223	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC2A12	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC22A9	GPR89A	psi-mi:“MI:0914”(association)	0.530
VSIG1	TNPO2	psi-mi:“MI:0914”(association)	0.530
CHRM3	PLD2	psi-mi:“MI:0914”(association)	0.530
ATP6V0A2	B4GALT3	psi-mi:“MI:0914”(association)	0.530
CERS6	ATP5F1B	psi-mi:“MI:0914”(association)	0.530
AGTR1	CERS6	psi-mi:“MI:0915”(physical association)	0.510
CERS6	AGTR1	psi-mi:“MI:0915”(physical association)	0.510

BioGRID (144): CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CERS6 (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, P27544, P27545, P38703, Q1A3B0, Q5E9R6, Q6EUN0, Q6NQI8, Q6YWS8, Q6ZMG9, Q7Z139, Q84QC0, Q8C172, Q8N5B7, Q8W4Y5, Q9D6K9, Q9HA82, Q9LJK3, Q9XWE9, W7LKY5, Q3ZBF8, Q8IU89, Q924Z4, Q96G23, Q9D6J1, Q9LDF2, G5ED45, Q9M6A3, O59735, P78970, Q15035, Q15629, Q5R7Z3, Q5XI41, Q91V04, Q924Z5, G1UJF5, Q8AYB8, Q8J2Q2

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CSNK2A1	“up-regulates activity”	CERS6	phosphorylation
CERS6	“up-regulates quantity”	ceramide	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 124 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	5	32.1×	2e-05
Cristae formation	5	19.4×	2e-04
Class A/1 (Rhodopsin-like receptors)	15	12.5×	2e-10
GPCR ligand binding	15	10.8×	1e-09
Mitochondrial biogenesis	5	9.4×	5e-03
Signaling by GPCR	15	6.8×	5e-07
GPCR downstream signalling	13	6.3×	7e-06
G alpha (i) signalling events	14	6.1×	4e-06

GO biological processes:

GO term	Partners	Fold	FDR
proton motive force-driven ATP synthesis	5	33.7×	4e-05
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	10	18.4×	6e-08
calcium-mediated signaling	8	12.3×	4e-05
phospholipase C-activating G protein-coupled receptor signaling pathway	11	12.2×	4e-07
proton motive force-driven mitochondrial ATP synthesis	5	11.1×	8e-03
positive regulation of cytosolic calcium ion concentration	10	9.8×	1e-05
adenylate cyclase-activating G protein-coupled receptor signaling pathway	9	8.6×	1e-04
G protein-coupled receptor signaling pathway	25	7.6×	1e-12

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3166 predictions. Top by Δscore:

Variant	Effect	Δscore
2:168547587:A:AG	acceptor_gain	1.0000
2:168547588:A:G	acceptor_gain	1.0000
2:168547594:A:AG	acceptor_gain	1.0000
2:168547595:G:GG	acceptor_gain	1.0000
2:168547595:GA:G	acceptor_gain	1.0000
2:168547595:GAT:G	acceptor_gain	1.0000
2:168547595:GATTT:G	acceptor_gain	1.0000
2:168547698:AAAGG:A	donor_loss	1.0000
2:168547699:AAGG:A	donor_loss	1.0000
2:168547701:GGTAT:G	donor_loss	1.0000
2:168547703:T:G	donor_loss	1.0000
2:168561182:T:TA	acceptor_gain	1.0000
2:168561187:CATAG:C	acceptor_loss	1.0000
2:168561188:ATAGC:A	acceptor_loss	1.0000
2:168561189:T:G	acceptor_gain	1.0000
2:168561189:TA:T	acceptor_loss	1.0000
2:168561190:A:AG	acceptor_gain	1.0000
2:168561190:AGCAT:A	acceptor_loss	1.0000
2:168561191:G:GT	acceptor_gain	1.0000
2:168561191:GC:G	acceptor_gain	1.0000
2:168561191:GCA:G	acceptor_gain	1.0000
2:168561191:GCAT:G	acceptor_gain	1.0000
2:168561191:GCATC:G	acceptor_gain	1.0000
2:168561318:AGCAT:A	donor_gain	1.0000
2:168561319:GCAT:G	donor_gain	1.0000
2:168561319:GCATG:G	donor_gain	1.0000
2:168561320:CAT:C	donor_gain	1.0000
2:168561321:AT:A	donor_gain	1.0000
2:168561322:TGTA:T	donor_loss	1.0000
2:168561323:G:GA	donor_loss	1.0000

AlphaMissense

2533 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:168561261:T:A	W116R	1.000
2:168561261:T:C	W116R	1.000
2:168456488:T:A	W14R	0.999
2:168456488:T:C	W14R	0.999
2:168456511:G:C	W21C	0.999
2:168456511:G:T	W21C	0.999
2:168547673:T:A	L83Q	0.999
2:168547673:T:C	L83P	0.999
2:168547684:T:C	F87L	0.999
2:168547686:C:A	F87L	0.999
2:168547686:C:G	F87L	0.999
2:168561195:C:T	P94S	0.999
2:168561196:C:A	P94H	0.999
2:168561220:T:C	L102P	0.999
2:168561227:G:C	K104N	0.999
2:168561227:G:T	K104N	0.999
2:168561232:T:C	L106P	0.999
2:168561262:G:C	W116S	0.999
2:168561263:G:C	W116C	0.999
2:168561263:G:T	W116C	0.999
2:168561274:G:C	R120T	0.999
2:168561275:A:C	R120S	0.999
2:168561275:A:T	R120S	0.999
2:168456492:T:C	L15P	0.998
2:168561216:G:C	G101R	0.998
2:168561220:T:A	L102H	0.998
2:168561264:T:C	F117L	0.998
2:168561265:T:C	F117S	0.998
2:168561266:T:A	F117L	0.998
2:168561266:T:G	F117L	0.998

dbSNP variants (sampled 300 via entrez): RS1000001760 (2:168586457 A>G), RS1000010841 (2:168627448 C>T), RS1000020918 (2:168684578 T>A), RS1000022069 (2:168731976 G>T), RS1000043957 (2:168597588 A>G), RS1000045923 (2:168691170 G>A,C), RS1000055045 (2:168732180 T>C), RS1000075521 (2:168634036 G>C), RS1000088248 (2:168476748 GA>G), RS1000088932 (2:168671897 C>T), RS1000099149 (2:168746364 T>C), RS1000100126 (2:168605025 C>T), RS1000101089 (2:168770318 G>A), RS1000111506 (2:168627961 A>G), RS1000114280 (2:168610191 A>C,G)

Disease associations

OMIM: gene MIM:615336 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000211_2	Response to TNF antagonist treatment	4.000000e-06
GCST003984_5	Parkinson’s disease	3.000000e-16
GCST004574_2	Skin aging (microtopography measurement)	9.000000e-06
GCST004621_52	Red cell distribution width	5.000000e-14
GCST006804_60	Red cell distribution width	1.000000e-12
GCST008103_96	Bipolar disorder	2.000000e-06
GCST010244_211	Triglyceride levels	2.000000e-08
GCST010653_7	Thyroid stimulating hormone levels	2.000000e-11
GCST012302_1	Recurrent major depressive disorder	8.000000e-07
GCST012303_3	Recurrent major depressive disorder x sex interaction	2.000000e-06
GCST012465_45	Bipolar disorder	2.000000e-08
GCST90002404_27	Red cell distribution width	7.000000e-43
GCST90002404_28	Red cell distribution width	6.000000e-20

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004653	response to TNF antagonist
EFO:0009188	Red cell distribution width
EFO:0004530	triglyceride measurement
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291517 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs13393173	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Rheumatoid arthritis

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs13393173	CERS6	3	2.25	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs13022792	CERS6		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Ceramide synthase

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.16	IC50	7000	nM	CHEMBL5268405

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
(2S)-2-amino-4-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2-methylbutan-1-ol	1923496: Inhibition of human CerS6	ic50	7.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression, affects expression	4
bisphenol A	increases expression, decreases expression, increases reaction, decreases reaction, affects cotreatment (+1 more)	3
Benzo(a)pyrene	decreases expression	3
Cisplatin	decreases expression, increases expression	2
Doxorubicin	affects response to substance, decreases expression	2
Estradiol	increases expression, affects expression	2
Tamoxifen	affects expression, affects cotreatment, decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
geldanamycin	increases expression	1
thermozymocidin	decreases reaction, increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects expression, decreases reaction	1
perfluoro-n-nonanoic acid	increases 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	affects expression, decreases reaction	1
abrine	decreases expression	1
jinfukang	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Bortezomib	decreases reaction, affects expression	1
Resveratrol	increases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Arsenic	increases abundance, increases expression, affects cotreatment	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5226573	Binding	Inhibition of CerS6 (unknown origin) at 10 uM relative to control	Small Molecule Inhibitors Targeting Biosynthesis of Ceramide, the Central Hub of the Sphingolipid Network. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2U6	Abcam HEK293T CERS6 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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