ACER3

Summary

ACER3 (alkaline ceramidase 3, HGNC:16066) is a protein-coding gene on chromosome 11q13.5, encoding Alkaline ceramidase 3 (Q9NUN7). Endoplasmic reticulum and Golgi ceramidase that catalyzes the hydrolysis of unsaturated long-chain C18:1-, C20:1- and C20:4-ceramides, dihydroceramides and phytoceramides into sphingoid bases like sphingosine and free fatty acids at alkaline pH.

Enables N-acylsphingosine amidohydrolase activity; calcium ion binding activity; and zinc ion binding activity. Involved in several processes, including myelination; positive regulation of cell population proliferation; and sphingolipid metabolic process. Located in Golgi membrane and endoplasmic reticulum membrane. Biomarker of hepatocellular carcinoma and metabolic dysfunction-associated steatohepatitis.

Source: NCBI Gene 55331 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukodystrophy (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 128 total — 6 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 26
• MANE Select transcript: NM_018367

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16066
Approved symbol	ACER3
Name	alkaline ceramidase 3
Location	11q13.5
Locus type	gene with protein product
Status	Approved
Aliases	FLJ11238, APHC
Ensembl gene	ENSG00000078124
Ensembl biotype	protein_coding
OMIM	617036
Entrez	55331

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 17 nonsense_mediated_decay, 11 retained_intron, 11 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000278544, ENST00000525194, ENST00000525325, ENST00000525861, ENST00000526597, ENST00000527508, ENST00000530182, ENST00000530334, ENST00000530921, ENST00000531352, ENST00000531461, ENST00000532485, ENST00000533873, ENST00000534206, ENST00000679611, ENST00000679754, ENST00000679759, ENST00000679813, ENST00000679866, ENST00000679924, ENST00000680164, ENST00000680351, ENST00000680583, ENST00000680624, ENST00000680842, ENST00000681004, ENST00000681251, ENST00000681257, ENST00000681258, ENST00000681354, ENST00000681375, ENST00000681411, ENST00000681591, ENST00000681732, ENST00000681955, ENST00000880916, ENST00000880917, ENST00000880918, ENST00000923237, ENST00000923238

RefSeq mRNA: 4 — MANE Select: NM_018367 NM_001300953, NM_001300954, NM_001300955, NM_018367

CCDS: CCDS73352, CCDS76454, CCDS8247

Canonical transcript exons

ENST00000532485 — 11 exons

Exon	Start	End
ENSE00001131918	76860918	76861079
ENSE00002153586	77020274	77026797
ENSE00003491913	77016675	77016779
ENSE00003528879	76990539	76990574
ENSE00003555194	76998763	76998821
ENSE00003560804	76976289	76976341
ENSE00003561823	77019731	77019776
ENSE00003610620	77015016	77015117
ENSE00003618406	76958979	76959031
ENSE00003638381	76926557	76926667
ENSE00003639191	76985643	76985724

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 97.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.0753 / max 342.1206, expressed in 1803 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115964	16.0264	1803
115966	0.0278	11
115965	0.0211	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	97.96	gold quality
inferior vagus X ganglion	UBERON:0005363	95.08	gold quality
ileal mucosa	UBERON:0000331	94.11	gold quality
corpus callosum	UBERON:0002336	94.06	gold quality
epithelial cell of pancreas	CL:0000083	93.86	gold quality
substantia nigra pars compacta	UBERON:0001965	93.73	gold quality
substantia nigra pars reticulata	UBERON:0001966	93.73	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.89	gold quality
subthalamic nucleus	UBERON:0001906	92.88	gold quality
buccal mucosa cell	CL:0002336	92.51	gold quality
pons	UBERON:0000988	92.46	gold quality
medulla oblongata	UBERON:0001896	92.26	gold quality
trigeminal ganglion	UBERON:0001675	92.11	gold quality
superior vestibular nucleus	UBERON:0007227	91.80	gold quality
monocyte	CL:0000576	91.78	gold quality
dorsal plus ventral thalamus	UBERON:0001897	91.66	gold quality
ventral tegmental area	UBERON:0002691	91.65	gold quality
pancreatic ductal cell	CL:0002079	91.62	gold quality
visceral pleura	UBERON:0002401	91.49	gold quality
dorsal root ganglion	UBERON:0000044	91.42	gold quality
leukocyte	CL:0000738	90.93	gold quality
placenta	UBERON:0001987	90.14	gold quality
colonic mucosa	UBERON:0000317	89.65	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.59	gold quality
secondary oocyte	CL:0000655	88.68	gold quality
lateral globus pallidus	UBERON:0002476	88.54	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.37	gold quality
esophagus squamous epithelium	UBERON:0006920	88.18	gold quality
parietal lobe	UBERON:0001872	88.10	gold quality
postcentral gyrus	UBERON:0002581	88.09	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-150728	yes	3347.78
E-HCAD-31	yes	2214.27
E-HCAD-23	yes	1499.86
E-ANND-3	yes	7.69
E-MTAB-10596	no	76.49
E-MTAB-6678	no	3.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

269 targeting ACER3, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995

Literature-anchored findings (GeneRIF, showing 8)

• ACER3 catalyzes the hydrolysis of unsaturated long chain ceramides and dihydroceramides and coordinates with ACER2 to regulate cell proliferation and survival (PMID:20068046)
• Homozygosity for the p.E33G mutation in the ACER3 gene results in inactivation of ACER3. (PMID:26792856)
• The ACER3 deficiency resulted in decreased cell growth and colony formation, elevated apoptosis, and lower AKT signaling of leukemia cells. This study indicates that ACER3 contributes to AML pathogenesis, and suggests that alkaline ceramidase inhibition is an option to treat acute myeloid leukemia. (PMID:27470583)
• Our study suggests that Acer3 contributes to hepatocellular carcinoma propagation (PMID:30097213)
• ACER3-related leukoencephalopathy: expanding the clinical and imaging findings spectrum due to novel variants. (PMID:34281620)
• LINC01087 indicates a poor prognosis of glioma patients with preoperative MRI. (PMID:34817752)
• Circular RNA circ_0001955 promotes hepatocellular carcinoma tumorigenesis by up-regulating alkaline ceramidase 3 expression through microRNA-655-3p. (PMID:35034572)
• Alkaline ceramidase catalyzes the hydrolysis of ceramides via a catalytic mechanism shared by Zn2+-dependent amidases. (PMID:36048828)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	acer3	ENSDARG00000093366
mus_musculus	Acer3	ENSMUSG00000030760
rattus_norvegicus	Acer3	ENSRNOG00000036866

Paralogs (2): ACER1 (ENSG00000167769), ACER2 (ENSG00000177076)

Protein

Protein identifiers

Alkaline ceramidase 3 — Q9NUN7 (reviewed: Q9NUN7)

Alternative names: Alkaline dihydroceramidase SB89, Alkaline phytoceramidase

All UniProt accessions (16): Q9NUN7, A0A7P0T836, A0A7P0T842, A0A7P0T8K3, A0A7P0T912, A0A7P0TAD8, A0A7P0TAT0, A0A7P0Z4N4, B7Z2Q2, B7Z2V2, E9PIN9, E9PKR3, E9PL35, E9PLZ9, E9PR08, J3KN85

UniProt curated annotations — full annotation on UniProt →

Function. Endoplasmic reticulum and Golgi ceramidase that catalyzes the hydrolysis of unsaturated long-chain C18:1-, C20:1- and C20:4-ceramides, dihydroceramides and phytoceramides 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. Controls the generation of sphingosine in erythrocytes, and thereby sphingosine-1-phosphate in plasma. Through the regulation of ceramides and sphingosine-1-phosphate homeostasis in the brain may play a role in neurons survival and function. By regulating the levels of pro-inflammatory ceramides in immune cells and tissues, may modulate the inflammatory response.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane.

Tissue specificity. Ubiquitously expressed. Highly expressed in placenta. Expressed in erythrocytes.

Disease relevance. Leukodystrophy, progressive, early childhood-onset (PLDECO) [MIM:617762] A form of leukodystrophy, a disorder of myelin production or maintenance affecting the central nervous system. PELCO features include neurological regression between 6 and 13 months of age, truncal hypotonia, appendicular spasticity, dystonia, optic disk pallor, peripheral neuropathy and neurogenic bladder. Brain imaging shows progressive diffuse abnormal white matter signals, cerebral atrophy, and thin corpus callosum. Sural nerve biopsy shows decreased myelination. PLDECO inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by 5 mM Ca(2+) and inhibited by 5 mM Zn(2+).

Pathway. Lipid metabolism; sphingolipid metabolism.

Similarity. Belongs to the alkaline ceramidase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NUN7-1	1	yes
Q9NUN7-2	2

RefSeq proteins (4): NP_001287882, NP_001287883, NP_001287884, NP_060837* (*=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), 12 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)
• an N-acyl-(4R)-4-hydroxysphinganine + H2O = (4R)-hydroxysphinganine + a fatty acid (RHEA:33555)
• N-(9Z-octadecenoyl)-sphing-4-enine + H2O = sphing-4-enine + (9Z)-octadecenoate (RHEA:41299)
• N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sphing-4-enine + H2O = sphing-4-enine + (5Z,8Z,11Z,14Z)-eicosatetraenoate (RHEA:45348)
• N-(11Z-eicosenoyl)-sphing-4-enine + H2O = (11Z)-eicosenoate + sphing-4-enine (RHEA:45356)
• N-(11Z-eicosenoyl)-sphinganine + H2O = (11Z)-eicosenoate + sphinganine (RHEA:45360)
• N-(11Z-eicosenoyl)-(4R)-hydroxysphinganine + H2O = (11Z)-eicosenoate + (4R)-hydroxysphinganine (RHEA:45364)
• N-(9Z-octadecenoyl)-(4R)-hydroxysphinganine + H2O = (4R)-hydroxysphinganine + (9Z)-octadecenoate (RHEA:45368)
• N-(9Z-octadecenoyl)-sphinganine + H2O = sphinganine + (9Z)-octadecenoate (RHEA:45372)
• N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sphinganine + H2O = sphinganine + (5Z,8Z,11Z,14Z)-eicosatetraenoate (RHEA:45376)
• N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-(4R)-hydroxysphinganine + H2O = (4R)-hydroxysphinganine + (5Z,8Z,11Z,14Z)-eicosatetraenoate (RHEA:45380)

UniProt features (47 total): helix 12, topological domain 8, binding site 8, transmembrane region 7, mutagenesis site 6, splice variant 2, chain 1, sequence variant 1, sequence conflict 1, strand 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6YXH	X-RAY DIFFRACTION	2.6
6G7O	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NUN7-F1	93.23	0.86

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): 19; 20; 22; 24; 33; 81; 217; 221

Mutagenesis-validated functional residues (6):

Position	Phenotype
19	mildly decreased enzyme activity.
22	strongly decreased enzyme activity.
24	strongly decreased enzyme activity.
99	no effect on enzyme activity.
149	decreased enzyme activity.
228	no effect on enzyme 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: 277 (showing top): GOBP_CERAMIDE_CATABOLIC_PROCESS, GCM_PTPRD, GOBP_INFLAMMATORY_RESPONSE, GOBP_POLYOL_METABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_MEMBRANE_LIPID_CATABOLIC_PROCESS, chr11q13, EFC_Q6, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, CDP_01, GOBP_SPHINGOID_METABOLIC_PROCESS, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_ENSHEATHMENT_OF_NEURONS, GROSS_HYPOXIA_VIA_HIF1A_DN

GO Biological Process (10): inflammatory response (GO:0006954), positive regulation of cell population proliferation (GO:0008284), myelination (GO:0042552), regulation of programmed cell death (GO:0043067), sphingosine biosynthetic process (GO:0046512), ceramide catabolic process (GO:0046514), phytosphingosine biosynthetic process (GO:0071602), lipid metabolic process (GO:0006629), sphingolipid metabolic process (GO:0006665), ceramide metabolic process (GO:0006672)

GO Molecular Function (6): calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), N-acylsphingosine amidohydrolase activity (GO:0017040), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides (GO:0016811), metal ion binding (GO:0046872)

GO Cellular Component (5): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794)

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
sphingoid biosynthetic process	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
defense response	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
axon ensheathment	1
programmed cell death	1
regulation of cellular process	1
sphingosine metabolic process	1
diol biosynthetic process	1
ceramide metabolic process	1
sphingolipid catabolic process	1
phytosphingosine metabolic process	1
polyol biosynthetic process	1
primary metabolic process	1
lipid metabolic process	1
sphingolipid metabolic process	1
metal ion binding	1
transition metal ion binding	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
catalytic activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
cation binding	1
Golgi apparatus	1
bounding membrane of organelle	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

712 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACER3	SLC25A3	Q00325	852
ACER3	ASAH2	Q9NR71	817
ACER3	ATP5F1C	P36542	810
ACER3	ATP5F1B	P06576	769
ACER3	ASAH1	Q13510	748
ACER3	SPTLC1	O15269	711
ACER3	SMPD2	O60906	626
ACER3	SPHK1	Q9NYA1	608
ACER3	CERS6	Q6ZMG9	606
ACER3	SPTLC2	O15270	601
ACER3	SPTLC3	Q9NUV7	601
ACER3	CERS2	Q96G23	594
ACER3	SPHK2	Q9NRA0	580
ACER3	CERS3	Q8IU89	553
ACER3	CERK	Q8TCT0	545
ACER3	SMPD4	Q9NXE4	545

IntAct

3 interactions, top by confidence:

A	B	Type	Score
MLH1	ACER3	psi-mi:“MI:0915”(physical association)	0.370
ACER3	CENPF	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): ACER3 (Synthetic Lethality), CACTIN (Affinity Capture-MS), PRPF38A (Affinity Capture-MS), RBM6 (Affinity Capture-MS), CENPF (Affinity Capture-MS), YLPM1 (Affinity Capture-MS), PBRM1 (Affinity Capture-MS), ACER3 (Positive Genetic), ACER3 (Affinity Capture-RNA), ACER3 (Affinity Capture-RNA), ACER3 (Affinity Capture-RNA), ACER3 (Two-hybrid)

ESM2 similar proteins: A1L272, A4FUY9, A5D7C9, A5PN43, A9JSP6, B5DFH9, B9EJG8, D3ZEH5, E2RFJ3, O19133, O70578, P35575, P51811, P97707, Q19KA1, Q28BP2, Q28CV2, Q29RU6, Q49LS5, Q569T7, Q5F383, Q5GH61, Q5TF39, Q5ZI05, Q5ZKY0, Q640L2, Q6GPL4, Q6GQE1, Q6PF45, Q7SYC7, Q80UF9, Q86TG1, Q86X19, Q8BMD6, Q8C8S3, Q8CIF6, Q8CJ61, Q8IZ96, Q8NBJ9, Q8R000

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	63
Likely benign	30
Benign	13

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
2500176	NM_018367.7(ACER3):c.631G>T (p.Gly211Cys)	Pathogenic
2635451	NM_018367.7(ACER3):c.436C>T (p.Gln146Ter)	Pathogenic
3336618	NM_018367.7(ACER3):c.703A>C (p.Ser235Arg)	Pathogenic
548629	NM_018367.7(ACER3):c.607C>T (p.Arg203Ter)	Pathogenic
58916	GRCh38/hg38 11q13.4-13.5(chr11:71928796-77064521)x1	Pathogenic
996745	NM_018367.7(ACER3):c.566G>A (p.Trp189Ter)	Pathogenic
928843	NM_018367.7(ACER3):c.475C>T (p.Arg159Ter)	Likely pathogenic

SpliceAI

2576 predictions. Top by Δscore:

Variant	Effect	Δscore
11:76861075:GTTCT:G	donor_gain	1.0000
11:76861080:G:GG	donor_gain	1.0000
11:76926552:TAAAG:T	acceptor_loss	1.0000
11:76926553:A:AG	acceptor_gain	1.0000
11:76926553:AAAG:A	acceptor_gain	1.0000
11:76926553:AAAGG:A	acceptor_gain	1.0000
11:76926554:AAG:A	acceptor_gain	1.0000
11:76926555:A:AG	acceptor_gain	1.0000
11:76926555:AG:A	acceptor_gain	1.0000
11:76926555:AGG:A	acceptor_gain	1.0000
11:76926556:G:GA	acceptor_loss	1.0000
11:76926556:G:GG	acceptor_gain	1.0000
11:76926556:GG:G	acceptor_gain	1.0000
11:76926556:GGG:G	acceptor_gain	1.0000
11:76926666:AGGTA:A	donor_loss	1.0000
11:76926667:GGT:G	donor_loss	1.0000
11:76926669:T:A	donor_loss	1.0000
11:76976287:A:AG	acceptor_gain	1.0000
11:76976288:G:GG	acceptor_gain	1.0000
11:76976337:TGCAT:T	donor_gain	1.0000
11:76976338:GCAT:G	donor_gain	1.0000
11:76976338:GCATG:G	donor_gain	1.0000
11:76976339:CAT:C	donor_gain	1.0000
11:76976341:TG:T	donor_loss	1.0000
11:76976342:G:A	donor_loss	1.0000
11:76976342:G:GG	donor_gain	1.0000
11:76976343:T:TC	donor_loss	1.0000
11:76976344:AA:A	donor_loss	1.0000
11:76985725:G:GG	donor_gain	1.0000
11:76998275:G:GT	donor_gain	1.0000

AlphaMissense

1745 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:76926568:A:C	S39R	1.000
11:76926570:T:A	S39R	1.000
11:76926570:T:G	S39R	1.000
11:76959002:T:C	F80L	1.000
11:76959004:C:A	F80L	1.000
11:76959004:C:G	F80L	1.000
11:76959005:C:G	H81D	1.000
11:76976290:T:C	L90P	1.000
11:76976296:A:C	D92A	1.000
11:76976296:A:T	D92V	1.000
11:76861034:T:A	W20R	0.999
11:76861034:T:C	W20R	0.999
11:76861036:G:C	W20C	0.999
11:76861036:G:T	W20C	0.999
11:76861037:T:A	C21S	0.999
11:76861037:T:C	C21R	0.999
11:76861038:G:A	C21Y	0.999
11:76861038:G:C	C21S	0.999
11:76861041:A:T	E22V	0.999
11:76861074:A:T	E33V	0.999
11:76861075:G:C	E33D	0.999
11:76861075:G:T	E33D	0.999
11:76926561:T:A	N36K	0.999
11:76926561:T:G	N36K	0.999
11:76926569:G:T	S39I	0.999
11:76926573:C:A	N40K	0.999
11:76926573:C:G	N40K	0.999
11:76958984:G:A	G74R	0.999
11:76958984:G:C	G74R	0.999
11:76958985:G:A	G74E	0.999

dbSNP variants (sampled 300 via entrez): RS1000001432 (11:76891819 A>T), RS1000010130 (11:76912673 G>A), RS1000011843 (11:76863736 A>G), RS1000099929 (11:76921717 T>C), RS1000150771 (11:76872203 A>G), RS1000184871 (11:76997342 A>G), RS1000188086 (11:76961887 A>G), RS1000198788 (11:76917606 A>C,G), RS1000206793 (11:76891258 A>T), RS1000217176 (11:76940262 G>C), RS1000239208 (11:76891405 C>T), RS1000239673 (11:76945128 G>T), RS1000256079 (11:76969164 A>C), RS1000315717 (11:76952036 C>T), RS1000333055 (11:76879028 TG>T)

Disease associations

OMIM: gene MIM:617036 | disease phenotypes: MIM:617762

GenCC curated gene-disease

Disease	Classification	Inheritance
alkaline ceramidase 3 deficiency	Strong	Autosomal recessive
leukodystrophy	Strong	Autosomal recessive

Mondo (3): alkaline ceramidase 3 deficiency (MONDO:0044718), neuromuscular disease (MONDO:0019056), leukodystrophy (MONDO:0019046)

Orphanet (2): Alkaline ceramidase 3 deficiency (Orphanet:502444), Neuromuscular disease (Orphanet:68381)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000179	Thick lower lip vermilion
HP:0000280	Coarse facial features
HP:0000319	Smooth philtrum
HP:0000340	Sloping forehead
HP:0000369	Low-set ears
HP:0000448	Prominent nose
HP:0000543	Optic disc pallor
HP:0000574	Thick eyebrow
HP:0001284	Areflexia
HP:0001332	Dystonia
HP:0002059	Cerebral atrophy
HP:0002079	Hypoplasia of the corpus callosum
HP:0002376	Developmental regression
HP:0002415	Leukodystrophy
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0004322	Short stature
HP:0004482	Relative macrocephaly
HP:0007281	Developmental stagnation
HP:0008936	Axial hypotonia
HP:0009830	Peripheral neuropathy
HP:0010864	Severe intellectual disability
HP:0034353	Appendicular spasticity
HP:0034392	Joint contracture

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST011696_8	Alzheimer’s disease	5.000000e-07

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009468	Neuromuscular Diseases	C10.668

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 — Alkaline ceramidases

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	3
Acetaminophen	increases expression	2
Arsenic	increases abundance, increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
bisphenol A	decreases methylation	1
sodium arsenate	increases abundance, increases expression	1
kojic acid	increases expression	1
trichostatin A	affects expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
sodium arsenite	increases expression, affects cotreatment, increases abundance	1
butyraldehyde	decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Atrazine	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Folic Acid	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methyl Methanesulfonate	increases expression	1
Quercetin	affects expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	PHASE4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	PHASE3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	PHASE3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT01074359	PHASE2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	PHASE2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	PHASE2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	PHASE2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	PHASE2	NOT_YET_RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT00252252	PHASE1	COMPLETED	AutoVPAP Versus VPAP; Assessment of Sleep and Ventilation
NCT01560741	PHASE1	UNKNOWN	Telemedicine and Ventilator Titration in Chronic Respiratory Patients Initiating Non-invasive Ventilation
NCT01621984	PHASE1	COMPLETED	Therapeutic Riding and Neuromuscular Disease
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT03440034	PHASE1	COMPLETED	Study of Pioglitazone in Sporadic Inclusion Body Myositis
NCT05730842	PHASE1	COMPLETED	Absorption, Metabolism, Excretion and Absolute Bioavailability of EDG-5506 in Healthy Volunteers
NCT00889174	Not specified	COMPLETED	The Nosology and Etiology of Leukodystrophies of Unknown Causes
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02843555	Not specified	COMPLETED	Natural History of the Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03639285	Not specified	RECRUITING	Natural History, Diagnosis, and Outcomes for Leukodystrophies
NCT05443906	Not specified	RECRUITING	Home Exercise for Individuals with Neurodegenerative Disease
NCT03272802	PHASE2/PHASE3	UNKNOWN	Treatment Effect of Edaravone in Patients With Amyotrophic Lateral Sclerosis (ALS)