ACER2

Summary

ACER2 (alkaline ceramidase 2, HGNC:23675) is a protein-coding gene on chromosome 9p22.1, encoding Alkaline ceramidase 2 (Q5QJU3). Golgi ceramidase that catalyzes the hydrolysis of ceramides into sphingoid bases like sphingosine and free fatty acids at alkaline pH.

The sphingolipid metabolite sphingosine-1-phosphate promotes cell proliferation and survival, whereas its precursor, sphingosine, has the opposite effect. The ceramidase ACER2 hydrolyzes very long chain ceramides to generate sphingosine (Xu et al., 2006 [PubMed 16940153]).

Source: NCBI Gene 340485 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 88 total — 22 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001010887

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23675
Approved symbol	ACER2
Name	alkaline ceramidase 2
Location	9p22.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ41587, ALKCDase2
Ensembl gene	ENSG00000177076
Ensembl biotype	protein_coding
OMIM	613492
Entrez	340485

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000340967

RefSeq mRNA: 1 — MANE Select: NM_001010887 NM_001010887

CCDS: CCDS34992

Canonical transcript exons

ENST00000340967 — 6 exons

Exon	Start	End
ENSE00001239297	19446281	19446418
ENSE00001239305	19434947	19435084
ENSE00001239315	19424700	19424841
ENSE00001379314	19450450	19452505
ENSE00001953110	19409009	19409192
ENSE00003493442	19423862	19423976

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 82.59.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9560 / max 433.9727, expressed in 888 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96255	2.7207	831
96254	0.2353	86

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
urinary bladder	UBERON:0001255	82.59	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.55	gold quality
placenta	UBERON:0001987	79.38	gold quality
subcutaneous adipose tissue	UBERON:0002190	78.14	gold quality
adipose tissue	UBERON:0001013	77.59	gold quality
stomach	UBERON:0000945	77.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.18	gold quality
body of stomach	UBERON:0001161	77.12	gold quality
omental fat pad	UBERON:0010414	76.77	gold quality
duodenum	UBERON:0002114	73.81	gold quality
body of pancreas	UBERON:0001150	73.34	gold quality
islet of Langerhans	UBERON:0000006	73.32	gold quality
pancreas	UBERON:0001264	73.29	gold quality
stromal cell of endometrium	CL:0002255	72.94	gold quality
rectum	UBERON:0001052	72.88	gold quality
thoracic mammary gland	UBERON:0005200	72.62	gold quality
mucosa of stomach	UBERON:0001199	71.60	gold quality
fundus of stomach	UBERON:0001160	70.47	gold quality
cortical plate	UBERON:0005343	69.86	gold quality
right atrium auricular region	UBERON:0006631	69.27	gold quality
zone of skin	UBERON:0000014	68.60	gold quality
adrenal tissue	UBERON:0018303	68.45	gold quality
skin of leg	UBERON:0001511	68.43	gold quality
skin of abdomen	UBERON:0001416	68.40	gold quality
heart	UBERON:0000948	68.36	gold quality
heart left ventricle	UBERON:0002084	68.30	gold quality
calcaneal tendon	UBERON:0003701	68.08	gold quality
colonic epithelium	UBERON:0000397	67.85	gold quality
tonsil	UBERON:0002372	67.59	gold quality
superior frontal gyrus	UBERON:0002661	67.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

107 targeting ACER2, 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-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6077	99.99	68.04	2299
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-302C-5P	99.97	72.56	3642
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-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-12133	99.92	71.82	2006

Literature-anchored findings (GeneRIF, showing 10)

• ACER2/sphingosine pathway plays an important role in regulating beta1 maturation and cell adhesion mediated by beta1 integrins (PMID:18945876)
• ACER2 has broad substrate specificity and requires Ca(2+) for its activity; ACER2 has the cytosolic C terminus and luminal N terminus, which are essential for its activity, correct cellular localization, and regulation for protein glycosylation (PMID:20089856)
• Results suggest that up-regulation of the ACER2/DHS pathway mediates the cytotoxicity of 4-HPR in tumor cells and that up-regulating or activating ACER2 may improve the anti-cancer activity of 4-HRR and other DHC-inducing agents. (PMID:20628055)
• c-Src-mediated signal positively regulates ACER activity in a Ca2+-independent manner. (PMID:24708996)
• Results suggest that the ACER2/sphingosine pathway mediates programmed cell death in response to DNA damage through ROS production. (PMID:26943039)
• Consistently, forced expression of p53 significantly stimulated ACER2 transcription. Notably, p53-mediated autophagy and apoptosis were markedly enhanced by ACER2. Depletion of the essential autophagy gene ATG5 revealed that ACER2-induced autophagy facilitates its effect on apoptosis. (PMID:28294157)
• These results suggest that p53 mediates DDR and exerts its tumor suppressive role in part by regulating the expression of ACER2, which in turn regulates the bioactive sphingolipid lipids. (PMID:29229990)
• TIMELESS regulates sphingolipid metabolism and tumor cell growth through Sp1/ACER2/S1P axis in ER-positive breast cancer. (PMID:33093451)
• miR-196a-5p Correlates with Chronic Atrophic Gastritis Progression to Gastric Cancer and Induces Malignant Biological Behaviors of Gastric Cancer Cells by Targeting ACER2. (PMID:36513872)
• Targeting YTHDF2 inhibits tumorigenesis of diffuse large B-cell lymphoma through ACER2-mediated ceramide catabolism. (PMID:37865189)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	acer2	ENSDARG00000077782
mus_musculus	Acer2	ENSMUSG00000038007
rattus_norvegicus	Acer2	ENSRNOG00000007637
drosophila_melanogaster	bwa	FBGN0045064
caenorhabditis_elegans		WBGENE00020947

Paralogs (2): ACER3 (ENSG00000078124), ACER1 (ENSG00000167769)

Protein

Protein identifiers

Alkaline ceramidase 2 — Q5QJU3 (reviewed: Q5QJU3)

Alternative names: Acylsphingosine deacylase 3-like, N-acylsphingosine amidohydrolase 3-like

All UniProt accessions (1): Q5QJU3

UniProt curated annotations — full annotation on UniProt →

Function. Golgi ceramidase that catalyzes the hydrolysis of ceramides into sphingoid bases like sphingosine and free fatty acids at alkaline pH. Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation. Has a better catalytic efficiency towards unsaturated long-chain ceramides, including C18:1-, C20:1- and C24:1-ceramides. Saturated long-chain ceramides and unsaturated very long-chain ceramides are also good substrates, whereas saturated very long-chain ceramides and short-chain ceramides are poor substrates. Also hydrolyzes dihydroceramides to produce dihydrosphingosine. It is the ceramidase that controls the levels of circulating sphingosine-1-phosphate and dihydrosphingosine-1-phosphate in plasma through their production by hematopoietic cells. Regulates cell proliferation, autophagy and apoptosis by the production of sphingosine and sphingosine-1-phosphate. As part of a p53/TP53-dependent pathway, promotes for instance autophagy and apoptosis in response to DNA damage. Through the production of sphingosine, may also regulate the function of the Golgi complex and regulate the glycosylation of proteins.

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Highly expressed in placenta.

Activity regulation. Specifically activated by lumenal, but not cytosolic Ca(2+). Inhibited by Zn(2+) or Cu(2+). Mg(2+) or Mn(2+) have no effect on ceramidase activity. Inhibited by De-MAPP.

Induction. Up-regulated upon serum deprivation. Up-regulated by N-(4-hydroxyphenyl)retinamode/4-HPR. Up-regulated upon DNA damage, in a p53/TP53-dependent manner, resulting in increased levels of sphingosine and sphingosine-1-phosphate (at protein level).

Pathway. Lipid metabolism; sphingolipid metabolism.

Similarity. Belongs to the alkaline ceramidase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5QJU3-1	1	yes
Q5QJU3-2	2
Q5QJU3-3	3

RefSeq proteins (1): NP_001010887* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008901	ACER	Family

Pfam: PF05875

Enzyme classification (BRENDA):

• EC 3.5.1.23 — ceramidase (BRENDA: 26 organisms, 303 substrates, 355 inhibitors, 64 Km, 14 kcat entries)

Substrate kinetics (BRENDA)

43 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-LAUROYLSPHINGOSINE	0.149–0.4132	5
D-ERYTHRO-C12-4-NITROBENZO-2-OXA-1,3-DIAZOLE-CER	0.0393–0.0601	3
N-[12-[(7-NITRO-2-1,3-BENZOXADIAZOL-4-YL)AMINE]D	0.0155–0.066	3
(2R,3Z)-2-([(2E)-1-HYDROXY-12-[(7-NITRO-2,1,3-BE	0.087–0.19	2
N-[(2S,3R,4E)-1,3-DIHYDROXY-14-[(7-NITRO-2,1,3-B	0.193–0.204	2
N-[(2S,3R,4E)-1,3-DIHYDROXYNONADEC-4-EN-2-YL]-12	0.085–0.11	2
N-[(2S,3R,4E)-13-[[9-(ETHYLAMINO)-5-OXO-5H-BENZO	0.036–0.082	2
N-[(2S,3R,4E)-7-[[9-(DIETHYLAMINO)-5-OXO-5H-BENZ	0.1418–0.1818	2
(13E)-N-[(2S,3R,4E)-1,3-DIHYDROXY-7-[(2-OXO-2H-1	0.033	1
(15E)-N-[(2S,3R,4E)-1,3-DIHYDROXY-7-[(2-OXO-2H-1	0.04	1
(2R)-N-[(2S,3R,4E)-1,3-DIHYDROXY-7-[(2-OXO-2H-1-	0.042	1
(2S)-N-[(2S,3R,4E)-1,3-DIHYDROXY-7-[(2-OXO-2H-1-	0.021	1
(4E,2S,3R)-2-N-(10-PYRENEDECANOYL)-1,3,17-TRIHYD	0.0005	1
(9E)-N-[(2S,3R,4E)-1,3-DIHYDROXY-7-[(2-OXO-2H-1-	0.139	1
2,4-DIDEOXY-2-(HEXADECANOYLAMINO)-5-O-(2-OXO-2H-	0.016	1

Catalyzed reactions (Rhea), 11 shown:

• an N-acylsphing-4-enine + H2O = sphing-4-enine + a fatty acid (RHEA:20856)
• an N-acylsphinganine + H2O = sphinganine + a fatty acid (RHEA:33551)
• N-hexadecanoylsphing-4-enine + H2O = sphing-4-enine + hexadecanoate (RHEA:38891)
• N-(15Z-tetracosenoyl)-sphing-4-enine + H2O = (15Z)-tetracosenoate + sphing-4-enine (RHEA:41267)
• N-eicosanoyl-sphing-4-enine + H2O = eicosanoate + sphing-4-enine (RHEA:41275)
• N-octadecanoylsphing-4-enine + H2O = sphing-4-enine + octadecanoate (RHEA:41279)
• N-tetracosanoyl-sphing-4-enine + H2O = tetracosanoate + sphing-4-enine (RHEA:41283)
• N-tetradecanoylsphing-4-enine + H2O = sphing-4-enine + tetradecanoate (RHEA:41287)
• N-dodecanoylsphing-4-enine + H2O = dodecanoate + sphing-4-enine (RHEA:41291)
• N-(hexanoyl)sphing-4-enine + H2O = hexanoate + sphing-4-enine (RHEA:41295)
• N-(9Z-octadecenoyl)-sphing-4-enine + H2O = sphing-4-enine + (9Z)-octadecenoate (RHEA:41299)

UniProt features (32 total): topological domain 8, binding site 8, transmembrane region 7, splice variant 3, chain 1, region of interest 1, glycosylation site 1, sequence variant 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5QJU3-F1	93.23	0.85

Functional residue map

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

Ligand- & substrate-binding residues (8): 18; 19; 21; 23; 32; 82; 211; 215

Glycosylation sites (1): 23

Mutagenesis-validated functional residues (1):

Position	Phenotype
1–16	loss of localization to the golgi. no effect on the ceramidase activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9845614	Sphingolipid catabolism
R-HSA-1430728	Metabolism
R-HSA-428157	Sphingolipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 141 (showing top): GOBP_CERAMIDE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_AUTOPHAGY, ACTACCT_MIR196A_MIR196B, GOBP_POLYOL_METABOLIC_PROCESS, GOBP_MEMBRANE_LIPID_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_SUBSTRATE_ADHESION, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_GLYCOPROTEIN_METABOLIC_PROCESS, GOBP_SPHINGOID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_MATRIX_ADHESION, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS

GO Biological Process (17): negative regulation of cell-matrix adhesion (GO:0001953), DNA damage response (GO:0006974), positive regulation of cell population proliferation (GO:0008284), regulation of autophagy (GO:0010506), regulation of glycoprotein biosynthetic process (GO:0010559), sphingolipid catabolic process (GO:0030149), DNA damage response, signal transduction by p53 class mediator (GO:0030330), response to retinoic acid (GO:0032526), negative regulation of cell adhesion mediated by integrin (GO:0033629), regulation of apoptotic process (GO:0042981), sphingosine biosynthetic process (GO:0046512), ceramide catabolic process (GO:0046514), cellular response to xenobiotic stimulus (GO:0071466), lipid metabolic process (GO:0006629), sphingolipid metabolic process (GO:0006665), ceramide metabolic process (GO:0006672), obsolete regulation of protein glycosylation (GO:0060049)

GO Molecular Function (4): N-acylsphingosine amidohydrolase activity (GO:0017040), metal ion binding (GO:0046872), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides (GO:0016811)

GO Cellular Component (3): Golgi membrane (GO:0000139), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Sphingolipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sphingolipid metabolic process	2
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
negative regulation of cell-substrate adhesion	1
cellular response to stress	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
autophagy	1
regulation of catabolic process	1
glycoprotein biosynthetic process	1
regulation of macromolecule biosynthetic process	1
regulation of glycoprotein metabolic process	1
lipid catabolic process	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
response to lipid	1
response to oxygen-containing compound	1
negative regulation of cell adhesion	1
cell adhesion mediated by integrin	1
regulation of cell adhesion mediated by integrin	1
apoptotic process	1
regulation of programmed cell death	1
sphingosine metabolic process	1
diol biosynthetic process	1
sphingoid biosynthetic process	1
ceramide metabolic process	1
sphingolipid catabolic process	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
primary metabolic process	1
lipid metabolic process	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
cation binding	1
catalytic activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
Golgi apparatus	1
bounding membrane of organelle	1
cytoplasm	1
endomembrane system	1

Protein interactions and networks

STRING

648 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACER2	ASAH2	Q9NR71	871
ACER2	ASAH1	Q13510	789
ACER2	SPTLC1	O15269	746
ACER2	S1PR1	P21453	717
ACER2	SPTLC2	O15270	690
ACER2	SPTLC3	Q9NUV7	688
ACER2	SMPD2	O60906	674
ACER2	SPHK2	Q9NRA0	670
ACER2	CERK	Q8TCT0	665
ACER2	CERS6	Q6ZMG9	647
ACER2	LAMP1	P11279	640
ACER2	CERS4	Q9HA82	635
ACER2	SPHK1	Q9NYA1	635
ACER2	CERS2	Q96G23	630
ACER2	SMPD1	P17405	603

IntAct

1 interactions, top by confidence:

BioGRID (2): ACER2 (Two-hybrid), ACER2 (Affinity Capture-RNA)

ESM2 similar proteins: A4IFN5, A6NDV4, B1AWJ5, B1AZA5, B2LYG4, P59266, Q05B45, Q0VCJ8, Q3KRC4, Q3UMZ3, Q5EA70, Q5H8A4, Q5QJU3, Q5RBJ7, Q5U3C3, Q5VTY9, Q5ZMH6, Q6PHN7, Q6TCH4, Q6W5G4, Q6ZVK1, Q7Z7J7, Q865K8, Q86WK9, Q8BHH9, Q8BMT9, Q8BWB6, Q8C1E7, Q8K3J9, Q8N6M3, Q8NBT3, Q8NEB5, Q8NFT2, Q8VCW4, Q8VCY8, Q8VD53, Q8VDI9, Q96GM1, Q9BSA9, Q9BXJ8

Diamond homologs: P38298, Q02896, Q568I2, Q5QJU3, Q8VD53, Q9D099, Q9NUN7, Q9VIP7, Q8R4X1, Q8TDN7, O45145, Q60WT2, Q6TMJ1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	1
Uncertain significance	50
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
148673	GRCh38/hg38 9p24.1-13.2(chr9:7162304-37038771)x3	Pathogenic
150242	GRCh38/hg38 9p24.3-13.1(chr9:204104-38768294)x3	Pathogenic
1527495	GRCh37/hg19 9p24.3-13.3(chr9:676264-33743670)	Pathogenic
153184	GRCh38/hg38 9p24.3-21.1(chr9:203861-31423873)x4	Pathogenic
160921	GRCh38/hg38 9p24.3-13.1(chr9:204193-38815478)x3	Pathogenic
1704647	GRCh37/hg19 9p24.3-13.3(chr9:203861-35903398)x3	Pathogenic
253592	GRCh37/hg19 9p24.3-11.2(chr9:213161-47212321)x4	Pathogenic
253667	GRCh37/hg19 9p24.3-13.1(chr9:213161-39092820)x3	Pathogenic
393860	GRCh37/hg19 9p24.3-q21.11(chr9:13997-70919878)x4	Pathogenic
4075951	GRCh37/hg19 9p24.3-q21.11(chr9:203862-69977404)x3	Pathogenic
442183	GRCh37/hg19 9p24.1-21.1(chr9:5900425-30008330)x3	Pathogenic
442255	GRCh37/hg19 9p22.2-21.1(chr9:17684434-30889762)x3	Pathogenic
563681	GRCh37/hg19 9p24.3-21.3(chr9:203861-20653468)x3	Pathogenic
563682	GRCh37/hg19 9p24.3-21.2(chr9:203861-26397133)x3	Pathogenic
563683	GRCh37/hg19 9p24.3-13.1(chr9:203861-38787480)x3	Pathogenic
563687	GRCh37/hg19 9p24.3-q21.12(chr9:203861-72717793)x3	Pathogenic
59836	GRCh38/hg38 9p24.3-21.3(chr9:204193-22086858)x3	Pathogenic
59876	GRCh38/hg38 9p24.3-13.1(chr9:220253-38815419)x3	Pathogenic
59878	GRCh38/hg38 9p23-21.1(chr9:9543538-30266463)x3	Pathogenic
625636	GRCh37/hg19 9p24.3-13.1(chr9:214309-39156958)	Pathogenic
685107	GRCh37/hg19 9p24.3-q13(chr9:203861-67986965)x3	Pathogenic
687476	GRCh37/hg19 9p24.3-13.1(chr9:203861-38472979)x3	Pathogenic
1707628	GRCh37/hg19 9p24.3-13.1(chr9:48827-39154913)x3	Likely pathogenic

SpliceAI

1332 predictions. Top by Δscore:

Variant	Effect	Δscore
9:19423973:GTGG:G	donor_gain	1.0000
9:19423975:GG:G	donor_gain	1.0000
9:19423976:GG:G	donor_gain	1.0000
9:19423977:G:GG	donor_gain	1.0000
9:19423977:GTA:G	donor_loss	1.0000
9:19423978:T:TC	donor_loss	1.0000
9:19434937:AT:A	acceptor_gain	1.0000
9:19434937:ATG:A	acceptor_gain	1.0000
9:19434938:T:TA	acceptor_gain	1.0000
9:19409192:GGTGC:G	donor_loss	0.9900
9:19409193:G:A	donor_loss	0.9900
9:19409193:G:GG	donor_gain	0.9900
9:19409194:T:A	donor_loss	0.9900
9:19409213:G:T	donor_gain	0.9900
9:19409854:A:T	donor_gain	0.9900
9:19423848:T:G	acceptor_gain	0.9900
9:19423858:GCAG:G	acceptor_loss	0.9900
9:19423859:CAG:C	acceptor_loss	0.9900
9:19423860:A:AG	acceptor_gain	0.9900
9:19423860:A:AT	acceptor_loss	0.9900
9:19423861:G:GG	acceptor_gain	0.9900
9:19423861:GATC:G	acceptor_gain	0.9900
9:19423861:GATCA:G	acceptor_gain	0.9900
9:19424837:GACCG:G	donor_gain	0.9900
9:19424839:CCGGT:C	donor_loss	0.9900
9:19424842:G:GG	donor_gain	0.9900
9:19424842:GT:G	donor_loss	0.9900
9:19424843:T:G	donor_loss	0.9900
9:19424844:AA:A	donor_loss	0.9900
9:19434938:T:G	acceptor_gain	0.9900

AlphaMissense

1801 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:19423865:A:C	S38R	0.994
9:19423867:C:A	S38R	0.994
9:19423867:C:G	S38R	0.994
9:19424771:T:A	W99R	0.993
9:19424771:T:C	W99R	0.993
9:19450547:T:C	F247L	0.993
9:19450549:C:A	F247L	0.993
9:19450549:C:G	F247L	0.993
9:19424717:T:C	F81L	0.987
9:19424719:C:A	F81L	0.987
9:19424719:C:G	F81L	0.987
9:19424766:T:A	V97D	0.987
9:19424732:A:C	S86R	0.985
9:19424734:T:A	S86R	0.985
9:19424734:T:G	S86R	0.985
9:19446330:T:A	W185R	0.985
9:19446330:T:C	W185R	0.985
9:19409180:G:C	E32D	0.983
9:19409180:G:T	E32D	0.983
9:19423866:G:T	S38I	0.981
9:19450581:T:A	V258D	0.981
9:19409181:T:C	F33L	0.980
9:19409183:C:A	F33L	0.980
9:19409183:C:G	F33L	0.980
9:19446327:T:A	W184R	0.980
9:19446327:T:C	W184R	0.980
9:19450548:T:C	F247S	0.980
9:19409176:C:A	A31D	0.979
9:19424723:G:C	A83P	0.978
9:19450497:C:A	A230D	0.978

dbSNP variants (sampled 300 via entrez): RS1000032694 (9:19418908 C>T), RS1000040527 (9:19430500 C>G,T), RS1000059743 (9:19424616 G>A), RS1000063179 (9:19423053 T>A,G), RS1000094488 (9:19437205 G>A,C), RS1000133041 (9:19424332 T>G), RS1000156310 (9:19422586 A>G), RS1000246860 (9:19411963 G>A), RS1000255438 (9:19428375 C>G,T), RS1000307692 (9:19428233 T>C,G), RS1000342527 (9:19442314 A>C,G), RS1000361485 (9:19419139 C>T), RS1000414903 (9:19434707 A>T), RS1000438450 (9:19414544 A>T), RS1000470697 (9:19439623 A>G,T)

Disease associations

OMIM: gene MIM:613492 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (1): Syndromic anorectal malformation (Orphanet:117573)

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2331067 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Alkaline ceramidases

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
6.00	IC50	1000	nM	CHEMBL429926

PubChem BioAssay actives

1 with measured affinity, of 1 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
N-[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]tetradecanamide	734964: Inhibition of alkaline ceramidase 2 in human HL-60 cells using 3H]C16-ceramide as substrate after 1 hr by liquid scintillation counting analysis	ic50	1.0000	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases methylation	2
Acetaminophen	increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
tebuconazole	decreases expression	1
nutlin 3	increases expression, affects cotreatment	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Methotrexate	increases expression	1
N-Nitrosopyrrolidine	increases expression	1
Oxygen	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Urethane	increases expression	1
Aflatoxin B1	increases expression	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1
Sirolimus	decreases expression, decreases reaction	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2339238	Binding	Inhibition of alkaline ceramidase 2 in human HL-60 cells using 3H]C16-ceramide as substrate after 1 hr by liquid scintillation counting analysis	Effective inhibition of acid and neutral ceramidases by novel B-13 and LCL-464 analogues. — Bioorg Med Chem

Clinical trials (associated diseases)

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