CERS3

Summary

CERS3 (ceramide synthase 3, HGNC:23752) is a protein-coding gene on chromosome 15q26.3, encoding Ceramide synthase 3 (Q8IU89). Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very- and ultra-long-chain fatty acyl-CoA (chain length greater than C22).

This gene is a member of the ceramide synthase family of genes. The ceramide synthase enzymes regulate sphingolipid synthesis by catalyzing the formation of ceramides from sphingoid base and acyl-coA substrates. This family member is involved in the synthesis of ceramides with ultra-long-chain acyl moieties (ULC-Cers), important to the epidermis in its role in creating a protective barrier from the environment. The protein encoded by this gene has also been implicated in modification of the lipid structures required for spermatogenesis. Mutations in this gene have been associated with male fertility defects, and epidermal defects, including ichthyosis. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 204219 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive congenital ichthyosis 9 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 163 total — 9 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 22
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001378789

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23752
Approved symbol	CERS3
Name	ceramide synthase 3
Location	15q26.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC27091
Ensembl gene	ENSG00000154227
Ensembl biotype	protein_coding
OMIM	615276
Entrez	204219

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000284382, ENST00000394113, ENST00000538112, ENST00000558884, ENST00000559023, ENST00000559639, ENST00000560348, ENST00000560944, ENST00000679737

RefSeq mRNA: 5 — MANE Select: NM_001378789 NM_001290341, NM_001290342, NM_001290343, NM_001378789, NM_178842

CCDS: CCDS10384

Canonical transcript exons

ENST00000679737 — 12 exons

Exon	Start	End
ENSE00001014714	100472924	100473052
ENSE00001014718	100469378	100469484
ENSE00001106664	100476086	100476178
ENSE00001275273	100490817	100490931
ENSE00001314962	100484550	100484668
ENSE00001316362	100479428	100479478
ENSE00001358424	100521667	100521756
ENSE00001404223	100455893	100456046
ENSE00001434272	100400395	100402865
ENSE00002623554	100479989	100480046
ENSE00003702008	100501677	100501850
ENSE00003910858	100528813	100528950

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 97.60.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.1081 / max 202.1951, expressed in 86 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151787	0.8924	79
151786	0.0853	36
151788	0.0472	24
151791	0.0393	3
151790	0.0130	7
151789	0.0095	3
207671	0.0094	3
151793	0.0061	3
151792	0.0059	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	97.60	gold quality
skin of abdomen	UBERON:0001416	94.39	gold quality
esophagus mucosa	UBERON:0002469	94.33	gold quality
skin of leg	UBERON:0001511	93.84	gold quality
zone of skin	UBERON:0000014	93.14	gold quality
gingiva	UBERON:0001828	92.26	gold quality
oral cavity	UBERON:0000167	91.93	gold quality
gingival epithelium	UBERON:0001949	91.87	gold quality
mammalian vulva	UBERON:0000997	91.45	gold quality
esophagus squamous epithelium	UBERON:0006920	90.21	gold quality
upper leg skin	UBERON:0004262	89.86	gold quality
buccal mucosa cell	CL:0002336	87.28	gold quality
penis	UBERON:0000989	86.53	gold quality
vagina	UBERON:0000996	83.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.82	gold quality
skin of hip	UBERON:0001554	82.57	gold quality
left testis	UBERON:0004533	80.30	gold quality
right testis	UBERON:0004534	79.71	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.51	gold quality
testis	UBERON:0000473	79.13	gold quality
esophagus	UBERON:0001043	72.20	gold quality
tonsil	UBERON:0002372	71.92	gold quality
pharyngeal mucosa	UBERON:0000355	71.31	gold quality
nipple	UBERON:0002030	69.19	gold quality
mouth mucosa	UBERON:0003729	68.12	gold quality
sperm	CL:0000019	68.02	silver quality
palpebral conjunctiva	UBERON:0001812	67.36	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	67.12	gold quality
adult organism	UBERON:0007023	67.08	gold quality
amniotic fluid	UBERON:0000173	67.02	silver 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

miRNA regulators (miRDB)

111 targeting CERS3, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
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-4262	100.00	73.26	3931
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4803	99.98	71.99	3117
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
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-1468-3P	99.96	72.74	3797
HSA-MIR-570-3P	99.96	72.41	4910

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 10)

• Our findings demonstrate that synthesis of very long chain ceramides by CerS3 is a crucial early step for the skin barrier formation and link disorders presenting with congenital ichthyosis to defects in sphingolipid metabolism and lipid architecture. (PMID:23549421)
• these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis. (PMID:23754960)
• testis-specific SLs, which we also link to CerS3 in human testis, are quintessential for male fertility. (PMID:26045466)
• 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)
• Novel mutations in CERS3 co-segregated with the ichthyosis phenotype in six Iranian families. (PMID:28875980)
• Activation of SIRT1 Enhances Epidermal Permeability Barrier Formation through Ceramide Synthase 2- and 3-Dependent Mechanisms. (PMID:31958434)
• Congenital ichthyosis in Prader-Willi syndrome associated with maternal chromosome 15 uniparental disomy: Case report and review of autosomal recessive conditions unmasked by UPD. (PMID:32815268)
• beta-Sitosterol 3-O-D-glucoside increases ceramide levels in the stratum corneum via the up-regulated expression of ceramide synthase-3 and glucosylceramide synthase in a reconstructed human epidermal keratinization model. (PMID:33684145)
• Ceramide synthase 3 affects invasion and metastasis of hepatocellular carcinoma via the SMAD6 gene.", trans “3SMAD6. (PMID:35753729)
• A novel homozygous splice site variant in CERS3 causes autosomal recessive congenital ichthyosis. (PMID:37128664)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cers3b	ENSDARG00000036337
danio_rerio	cers3a	ENSDARG00000078541
mus_musculus	Cers3	ENSMUSG00000030510
rattus_norvegicus	Cers3	ENSRNOG00000013823
drosophila_melanogaster	schlank	FBGN0040918
caenorhabditis_elegans		WBGENE00002043
caenorhabditis_elegans		WBGENE00002044

Paralogs (5): CERS4 (ENSG00000090661), CERS5 (ENSG00000139624), CERS2 (ENSG00000143418), CERS6 (ENSG00000172292), CERS1 (ENSG00000223802)

Protein

Protein identifiers

Ceramide synthase 3 — Q8IU89 (reviewed: Q8IU89)

Alternative names: Dihydroceramide synthase 3, LAG1 longevity assurance homolog 3, Sphingosine N-acyltransferase CERS3, Ultra-long-chain ceramide synthase CERS3, Very-long-chain ceramide synthase CERS3

All UniProt accessions (3): Q8IU89, H0YMG6, H0YN05

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- and ultra-long-chain fatty acyl-CoA (chain length greater than C22). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively. It is crucial for the synthesis of ultra-long-chain ceramides in the epidermis, to maintain epidermal lipid homeostasis and terminal differentiation.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in the epidermis, where it localizes at the interface between the stratum granulosum and the stratum corneum (at protein level).

Disease relevance. Ichthyosis, congenital, autosomal recessive 9 (ARCI9) [MIM:615023] A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Lipid metabolism; sphingolipid metabolism.

Similarity. Belongs to the sphingosine N-acyltransferase family.

RefSeq proteins (5): NP_001277270, NP_001277271, NP_001277272, NP_001365718, NP_849164 (=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 2.3.1.298 — ultra-long-chain ceramide synthase (BRENDA: 5 organisms, 55 substrates, 3 inhibitors, 0 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), 11 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 + octadecanoyl-CoA = N-(octadecanoyl)-sphinganine + CoA + H(+) (RHEA:36547)
• 2-hydroxyoctadecanoyl-CoA + sphinganine = N-(2-hydroxyoctadecanoyl)-sphinganine + CoA + H(+) (RHEA:36615)
• 2-hydroxydocosanoyl-CoA + sphinganine = N-(2-hydroxydocosanoyl)-sphinganine + CoA + H(+) (RHEA:36619)
• 2-hydroxytetracosanoyl-CoA + sphinganine = N-(2-hydroxytetracosanoyl)-sphinganine + CoA + H(+) (RHEA:36627)
• octacosanoyl-CoA + sphinganine = N-(octacosanoyl)-sphinganine + CoA + H(+) (RHEA:36675)
• a very long-chain fatty acyl-CoA + a sphingoid base = an N-(very-long-chain fatty acyl)-sphingoid base + CoA + H(+) (RHEA:61480)
• an ultra-long-chain fatty acyl-CoA + a sphingoid base = an N-(ultra-long-chain-acyl)-sphingoid base + CoA + H(+) (RHEA:61492)

UniProt features (19 total): transmembrane region 6, sequence variant 3, region of interest 2, sequence conflict 2, chain 1, compositionally biased region 1, modified residue 1, mutagenesis site 1, topological domain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IU89-F1	87.52	0.68

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 (1): 340

Mutagenesis-validated functional residues (1):

Position	Phenotype
340	decreased phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis

MSigDB gene sets: 128 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, NIKOLSKY_BREAST_CANCER_15Q26_AMPLICON, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_LIPID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOBP_CERAMIDE_METABOLIC_PROCESS, REACTOME_SPHINGOLIPID_METABOLISM, GOBP_SPHINGOLIPID_BIOSYNTHETIC_PROCESS, GOBP_KERATINIZATION

GO Biological Process (7): epidermis development (GO:0008544), sphingolipid biosynthetic process (GO:0030148), keratinocyte differentiation (GO:0030216), ceramide biosynthetic process (GO:0046513), cornification (GO:0070268), 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 (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), nucleus (GO:0005634), membrane (GO:0016020)

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
intracellular membrane-bounded organelle	2
tissue development	1
sphingolipid metabolic process	1
lipid biosynthetic process	1
epidermal cell differentiation	1
skin development	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
programmed cell death	1
keratinization	1
cornified envelope assembly	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
cytoplasm	1
endomembrane system	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

754 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CERS3	PNPLA1	Q8N8W4	807
CERS3	CYP4F22	Q6NT55	796
CERS3	GDF1	P27539	785
CERS3	SGMS1	Q86VZ5	763
CERS3	NIPAL4	Q0D2K0	742
CERS3	ALOXE3	Q9BYJ1	715
CERS3	ABCA12	Q86UK0	709
CERS3	SPTLC1	O15269	705
CERS3	ALOX12B	O75342	695
CERS3	SPTLC2	O15270	668
CERS3	UGCG	Q16739	659
CERS3	SPTLC3	Q9NUV7	657
CERS3	LIPN	Q5VXI9	655
CERS3	KDSR	Q06136	653
CERS3	ELOVL1	Q9BW60	646

IntAct

23 interactions, top by confidence:

A	B	Type	Score
	CERS3	psi-mi:“MI:0915”(physical association)	0.560
NEU1	CERS3	psi-mi:“MI:0915”(physical association)	0.560
CERS3		psi-mi:“MI:0915”(physical association)	0.560
CERS3	PCBD2	psi-mi:“MI:0915”(physical association)	0.560
CERS3	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560
CERS3	SLC39A9	psi-mi:“MI:0915”(physical association)	0.560
CERS3	NEU1	psi-mi:“MI:0915”(physical association)	0.560
OR2A4	A2ML1	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	A2ML1	psi-mi:“MI:0914”(association)	0.350
CERS3	ATP6V0C	psi-mi:“MI:0914”(association)	0.350
SSUH2	IGLC7	psi-mi:“MI:0914”(association)	0.350
CERS3	IGLC7	psi-mi:“MI:0914”(association)	0.350
PHF11	A2ML1	psi-mi:“MI:0914”(association)	0.350
MBNL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PCBD2	CERS3	psi-mi:“MI:0915”(physical association)	0.000
ORMDL3	CERS3	psi-mi:“MI:0915”(physical association)	0.000
SLC39A9	CERS3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (60): CERS3 (Affinity Capture-MS), CERS3 (Two-hybrid), CERS3 (Two-hybrid), ORMDL3 (Two-hybrid), SLC29A2 (Two-hybrid), NEU1 (Two-hybrid), ATP6V0C (Affinity Capture-MS), CERS3 (Affinity Capture-MS), EPPK1 (Affinity Capture-MS), VMA21 (Affinity Capture-MS), CERS3 (Affinity Capture-MS), KLK6 (Affinity Capture-MS), IL36RN (Affinity Capture-MS), HMGCS1 (Affinity Capture-MS), IGHG4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0C5PHQ7, A0JNC4, A1L3X0, B4QVX4, D4A612, D4ADY9, G5EEE5, O35949, P49191, Q03574, Q1A3B0, Q1HRV8, Q20300, Q20303, Q2KJD9, Q32NI8, Q3S8M4, Q4D321, Q4D5J7, Q4DHY3, Q4DUK4, Q4QJ85, Q4R516, Q54TC9, Q57UP6, Q57X51, Q5M8U1, Q5RFL5, Q6GLX2, Q6P4N1, Q6PC64, Q84QC0, Q8BHI7, Q8IU89, Q920L5, Q920L6, Q920L7, Q95K73, Q9BW60, Q9D2Y9

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, Q8AYB8, Q9XWE9, Q8J2Q2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CERS3	“up-regulates quantity”	ceramide	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	13
Uncertain significance	52
Likely benign	33
Benign	48

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
1451147	NM_001378789.1(CERS3):c.43T>A (p.Trp15Arg)	Pathogenic
1996888	NM_001378789.1(CERS3):c.662del (p.Phe221fs)	Pathogenic
2429320	NM_001378789.1(CERS3):c.686G>A (p.Arg229His)	Pathogenic
2691721	NM_001378789.1(CERS3):c.540G>A (p.Trp180Ter)	Pathogenic
3384753	NM_001378789.1(CERS3):c.685C>T (p.Arg229Cys)	Pathogenic
4734458	NM_001378789.1(CERS3):c.363del (p.Asn122fs)	Pathogenic
633803	NM_001378789.1(CERS3):c.731G>A (p.Trp244Ter)	Pathogenic
64621	NM_001378789.1(CERS3):c.43T>C (p.Trp15Arg)	Pathogenic
686196	GRCh37/hg19 15q26.3(chr15:101061066-101081879)x1	Pathogenic
1012384	GRCh37/hg19 15q26.3(chr15:101031022-101031136)x3	Likely pathogenic
1180727	NM_001378789.1(CERS3):c.223C>T (p.Arg75Ter)	Likely pathogenic
1180734	NM_001378789.1(CERS3):c.915C>A (p.Asn305Lys)	Likely pathogenic
1298639	NM_001378789.1(CERS3):c.465+2T>G	Likely pathogenic
3576919	NM_001378789.1(CERS3):c.873del (p.Met292fs)	Likely pathogenic
3576920	NM_001378789.1(CERS3):c.565del (p.Tyr189fs)	Likely pathogenic
3576921	NM_001378789.1(CERS3):c.466-1G>T	Likely pathogenic
3576922	NM_001378789.1(CERS3):c.303_304dup (p.Leu102fs)	Likely pathogenic
4690218	NM_001378789.1(CERS3):c.1006C>T (p.Gln336Ter)	Likely pathogenic
4728363	NM_001378789.1(CERS3):c.174-2A>G	Likely pathogenic
55838	NM_001378789.1(CERS3):c.609+1G>T	Likely pathogenic
804475	NM_001378789.1(CERS3):c.46del (p.Leu16fs)	Likely pathogenic
916165	GRCh37/hg19 15q26.3(chr15:101031022-101031136)x1	Likely pathogenic

SpliceAI

2179 predictions. Top by Δscore:

Variant	Effect	Δscore
15:100402861:ATGCT:A	acceptor_gain	1.0000
15:100402862:TGCT:T	acceptor_gain	1.0000
15:100402864:CT:C	acceptor_gain	1.0000
15:100402866:C:CC	acceptor_gain	1.0000
15:100402867:T:A	acceptor_loss	1.0000
15:100472925:T:TA	donor_gain	1.0000
15:100476179:C:CC	acceptor_gain	1.0000
15:100479423:CTTA:C	donor_loss	1.0000
15:100479424:TTA:T	donor_loss	1.0000
15:100479425:TAC:T	donor_loss	1.0000
15:100479427:C:A	donor_loss	1.0000
15:100484549:CCAAG:C	donor_gain	1.0000
15:100484556:T:TA	donor_gain	1.0000
15:100490811:ACTT:A	donor_loss	1.0000
15:100490812:CT:C	donor_loss	1.0000
15:100490813:TTACT:T	donor_loss	1.0000
15:100490814:TA:T	donor_loss	1.0000
15:100490815:A:AC	donor_gain	1.0000
15:100490816:C:CG	donor_gain	1.0000
15:100490816:CTT:C	donor_gain	1.0000
15:100490816:CTTG:C	donor_gain	1.0000
15:100490927:CAAAT:C	acceptor_gain	1.0000
15:100490942:A:C	acceptor_gain	1.0000
15:100499458:T:A	donor_gain	1.0000
15:100500359:T:TA	donor_gain	1.0000
15:100501847:CATT:C	acceptor_gain	1.0000
15:100402871:C:CT	acceptor_gain	0.9900
15:100402872:A:T	acceptor_gain	0.9900
15:100406676:C:CA	donor_gain	0.9900
15:100438871:T:C	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000064427 (15:100485649 C>T), RS1000100000 (15:100485426 A>G), RS1000109412 (15:100401970 T>C), RS1000125950 (15:100528843 C>T), RS1000151287 (15:100447187 C>G,T), RS1000153963 (15:100482423 C>A,G,T), RS1000191670 (15:100406269 A>G,T), RS1000198982 (15:100443598 C>T), RS1000201482 (15:100405965 G>A), RS1000220570 (15:100524310 A>G,T), RS1000233098 (15:100545286 G>A), RS1000238915 (15:100433477 C>T), RS1000243362 (15:100435182 C>T), RS1000254291 (15:100463992 T>G), RS1000290 (15:100409404 T>A,C)

Disease associations

OMIM: gene MIM:615276 | disease phenotypes: MIM:615023

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive congenital ichthyosis 9	Strong	Autosomal recessive
congenital non-bullous ichthyosiform erythroderma	Supportive	Autosomal recessive

Mondo (5): autosomal recessive congenital ichthyosis 9 (MONDO:0014010), prostate cancer (MONDO:0008315), lamellar ichthyosis (MONDO:0017778), ichthyosis (MONDO:0019269), congenital non-bullous ichthyosiform erythroderma (MONDO:0019306)

Orphanet (4): Congenital ichthyosiform erythroderma (Orphanet:79394), Familial prostate cancer (Orphanet:1331), Lamellar ichthyosis (Orphanet:313), Ichthyosis (Orphanet:79354)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000491	Keratitis
HP:0000656	Ectropion
HP:0000962	Hyperkeratosis
HP:0000966	Hypohidrosis
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001508	Failure to thrive
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0007479	Congenital nonbullous ichthyosiform erythroderma
HP:0008064	Ichthyosis
HP:0012472	Eclabion
HP:0025092	Epidermal acanthosis
HP:0025114	Hypergranulosis
HP:0033252	Palmar hyperlinearity
HP:0040162	Orthokeratosis
HP:0200020	Corneal erosion

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002652_12	Cotinine glucuronidation	3.000000e-08
GCST009530_1	Childhood body mass index	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006508	cotinine glucuronidation measurement
EFO:0004340	body mass index

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007057	Ichthyosis	C16.131.831.512; C16.614.492; C17.800.428.333; C17.800.804.512
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

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 — Ceramide synthase

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Sodium Dodecyl Sulfate	decreases expression	2
Tobacco Smoke Pollution	affects expression	2
bisphenol A	affects cotreatment, decreases methylation	1
butylbenzyl phthalate	increases expression	1
kifunensine	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
fatostatin	increases expression, decreases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Aerosols	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Copper	decreases expression, affects cotreatment	1
Tetrachlorodibenzodioxin	increases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer