COASY

Summary

COASY (Coenzyme A synthase, HGNC:29932) is a protein-coding gene on chromosome 17q21.2, encoding Bifunctional coenzyme A synthase (Q13057). Bifunctional enzyme that catalyzes the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4’-phosphopantetheine, and the fifth step, the phosphorylation of dephospho-CoA to CoA. It is a selective cancer dependency (DepMap: 66.0% of cell lines).

Coenzyme A (CoA) functions as a carrier of acetyl and acyl groups in cells and thus plays an important role in numerous synthetic and degradative metabolic pathways in all organisms. In eukaryotes, CoA and its derivatives are also involved in membrane trafficking and signal transduction. This gene encodes the bifunctional protein coenzyme A synthase (CoAsy) which carries out the last two steps in the biosynthesis of CoA from pantothenic acid (vitamin B5). The phosphopantetheine adenylyltransferase domain of this bifunctional protein catalyzes the conversion of 4’-phosphopantetheine into dephospho-coenzyme A (dpCoA) while its dephospho-CoA kinase domain completes the final step by phosphorylating dpCoA to form CoA. Mutations in this gene are associated with neurodegeneration with brain iron accumulation (NBIA). Alternative splicing results in multiple isoforms.

Source: NCBI Gene 80347 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegeneration with brain iron accumulation 6 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 450 total — 18 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 52
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 66.0% of screened cell lines
• MANE Select transcript: NM_025233

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29932
Approved symbol	COASY
Name	Coenzyme A synthase
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	DPCK, NBP, PPAT
Ensembl gene	ENSG00000068120
Ensembl biotype	protein_coding
OMIM	609855
Entrez	80347

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000393818, ENST00000421097, ENST00000585811, ENST00000585909, ENST00000586771, ENST00000587157, ENST00000587214, ENST00000587858, ENST00000588353, ENST00000588757, ENST00000590958, ENST00000591583, ENST00000591753, ENST00000591779

RefSeq mRNA: 3 — MANE Select: NM_025233 NM_001042529, NM_001042532, NM_025233

CCDS: CCDS11429, CCDS45685

Canonical transcript exons

ENST00000393818 — 9 exons

Exon	Start	End
ENSE00001516589	42562148	42563322
ENSE00002383561	42564446	42564577
ENSE00002954310	42565906	42566277
ENSE00003525037	42565227	42565311
ENSE00003595827	42563961	42564175
ENSE00003622640	42565471	42565568
ENSE00003641191	42564709	42564898
ENSE00003645992	42565659	42565805
ENSE00003692560	42564983	42565047

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 97.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.2347 / max 344.1798, expressed in 1822 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160959	47.4143	1821
160960	0.6435	351
160962	0.1266	42
160961	0.0502	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	97.19	gold quality
mucosa of transverse colon	UBERON:0004991	97.19	gold quality
lower esophagus mucosa	UBERON:0035834	96.89	gold quality
metanephros cortex	UBERON:0010533	96.63	gold quality
body of pancreas	UBERON:0001150	96.60	gold quality
right adrenal gland cortex	UBERON:0035827	96.53	gold quality
right lobe of liver	UBERON:0001114	96.48	gold quality
right adrenal gland	UBERON:0001233	96.47	gold quality
left adrenal gland	UBERON:0001234	96.37	gold quality
left adrenal gland cortex	UBERON:0035825	96.33	gold quality
adrenal cortex	UBERON:0001235	95.90	gold quality
right lobe of thyroid gland	UBERON:0001119	95.75	gold quality
body of stomach	UBERON:0001161	95.52	gold quality
adrenal gland	UBERON:0002369	95.24	gold quality
left lobe of thyroid gland	UBERON:0001120	95.19	gold quality
esophagus mucosa	UBERON:0002469	95.19	gold quality
granulocyte	CL:0000094	95.17	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.07	gold quality
saliva-secreting gland	UBERON:0001044	94.91	gold quality
skin of leg	UBERON:0001511	94.86	gold quality
pancreas	UBERON:0001264	94.71	gold quality
right uterine tube	UBERON:0001302	94.69	gold quality
minor salivary gland	UBERON:0001830	94.58	gold quality
skin of abdomen	UBERON:0001416	94.54	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.51	gold quality
thyroid gland	UBERON:0002046	94.44	gold quality
transverse colon	UBERON:0001157	94.42	gold quality
tendon of biceps brachii	UBERON:0008188	94.05	gold quality
adenohypophysis	UBERON:0002196	93.99	gold quality
mouth mucosa	UBERON:0003729	93.84	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

11 targeting COASY, 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-589-3P	99.91	69.62	2088
HSA-MIR-6861-3P	99.60	68.46	444
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-548S	98.50	67.17	1213
HSA-MIR-5196-3P	97.57	65.98	979
HSA-MIR-4535	97.27	65.17	469
HSA-MIR-6736-3P	96.98	65.22	1342
HSA-MIR-134-3P	96.83	66.22	1001
HSA-MIR-2861	95.24	65.47	1056
HSA-MIR-6879-3P	93.93	64.00	759

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 66.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 15)

• Identification and characterization of the gene encoding the human phosphopantetheine adenylyltransferase and dephospho-CoA kinase bifunctional enzyme (CoA synthase). (PMID:11994049)
• description of the existence of a novel CoA synthase isoform, which is the product of alternative splicing and possesses a 29aa extension at the N-terminus; termed it CoASy beta (PMID:16460672)
• CoA synthase is involved in signaling events in the cell and forms a functional complex with p85alphaPI3K in vivo. (PMID:19482007)
• EDC4 might contribute to regulation of CoA biosynthesis in addition to its scaffold function in processing bodies (PMID:22982864)
• Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in neurodegeneration with brain iron accumulation (PMID:24360804)
• Mutations in PANK2 and CoASY lead, respectively, to PKAN and CoPAN forms of Neurodegeneration with brain iron accumulation . Mutations in PLA2G6 lead to PLAN. Mutations in C19orf12 lead to MPAN (PMID:25668476)
• The COASY protein contains a mitochondrial localization signal, a regulatory region and a domain for each of the two catalytic kinase domains: adenyl transferase and dephospho CoA (PMID:27021474)
• DNA methylation levels in the COASY and SPINT1 promoter regions were considered to potentially be a convenient and useful biomarker for diagnosis of Alzheimer’s Disease and Amnestic Mild Cognitive Impairment. (PMID:27992572)
• The recruitment of COASY inhibits CBP-mediated TPX2 acetylation, promoting TPX2 degradation for mitotic exit. (PMID:29531224)
• Loss of function variants in COASY are associated with lethal pontocerebellar hypoplasia and arthrogryposis. (PMID:30143804)
• Study identified a novel biomarker, coenzyme A synthase (COASY), whose mRNA expression was consistently elevated in radioresistant human rectal cancers. This observation was validated in independent patient cohorts and further confirmed in colorectal cancer cell lines. COASY protein directly interacted with the PI3K regulatory subunit PI3K-P85alpha, which increased AKT and mTOR phosphorylation, enhancing cell survival. (PMID:31704889)
• CoAsy knockdown in TNBC cell lines resulted in no overt effect on cell proliferation in vitro. (PMID:32828275)
• COASY related pontocerebellar hypoplasia type 12: A common Indian mutation with expansion of the phenotypic spectrum. (PMID:35499143)
• Progressive brain atrophy and severe neurodevelopmental phenotype in siblings with biallelic COASY variants. (PMID:36495139)
• Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases. (PMID:38750253)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	coasy	ENSDARG00000042747
mus_musculus	Coasy	ENSMUSG00000001755
rattus_norvegicus	Coasy	ENSRNOG00000019918
drosophila_melanogaster	Ppat-Dpck	FBGN0035632
caenorhabditis_elegans	Y65B4A.8	WBGENE00022031

Paralogs (1): DCAKD (ENSG00000172992)

Protein

Protein identifiers

Bifunctional coenzyme A synthase — Q13057 (reviewed: Q13057)

Alternative names: NBP, POV-2

All UniProt accessions (8): Q13057, K7EN91, K7EP09, K7EPC2, K7EPT0, K7EQ60, K7ES73, K7ESK6

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional enzyme that catalyzes the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4’-phosphopantetheine, and the fifth step, the phosphorylation of dephospho-CoA to CoA.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm. Cytosol. Mitochondrion matrix.

Tissue specificity. Expressed in all tissues examined including brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung and peripheral blood leukocyte. Lowest expression in peripheral blood leukocytes and highest in kidney and liver. Isoform 2 is expressed mainly in the brain.

Disease relevance. Neurodegeneration with brain iron accumulation 6 (NBIA6) [MIM:615643] A neurodegenerative disorder associated with iron accumulation in the brain, primarily in the basal ganglia. It is characterized by progressive motor and cognitive dysfunction beginning in childhood or young adulthood. Patients show extrapyramidal motor signs, such as spasticity, dystonia, and parkinsonism. The disease is caused by variants affecting the gene represented in this entry. Pontocerebellar hypoplasia 12 (PCH12) [MIM:618266] A form of pontocerebellar hypoplasia, a disorder characterized by structural defects of the pons and cerebellum, evident upon brain imaging. PCH12 is an autosomal recessive form characterized by onset in utero and death in infancy. Brain imaging shows microcephaly, cerebellar hypoplasia, micrognathia, and multiple contractures. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The phosphopantetheine adenylyltransferase domain catalyzes the fourth step of the coenzyme A biosynthetic pathway. The DPCK domain catalyzes the fifth step of the coenzyme A biosynthetic pathway.

Pathway. Cofactor biosynthesis; coenzyme A biosynthesis; CoA from (R)-pantothenate: step 4/5. Cofactor biosynthesis; coenzyme A biosynthesis; CoA from (R)-pantothenate: step 5/5.

Miscellaneous. Major isoform which is active in the cytosol. The physiological significance of this isoform is uncertain.

Similarity. In the central section; belongs to the eukaryotic CoaD family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13057-1	1, CoASy alpha	yes
Q13057-2	2, CoASy beta

RefSeq proteins (3): NP_001035994, NP_001035997, NP_079509* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001977	Depp_CoAkinase	Family
IPR004821	Cyt_trans-like	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF01121, PF01467

Enzyme classification (BRENDA):

• EC 2.7.1.24 — dephospho-CoA kinase (BRENDA: 19 organisms, 31 substrates, 10 inhibitors, 36 Km, 21 kcat entries)
• EC 2.7.7.3 — pantetheine-phosphate adenylyltransferase (BRENDA: 25 organisms, 18 substrates, 81 inhibitors, 22 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.015–0.36	15
3’-DEPHOSPHO-COA	0.0217–0.501	11
DEPHOSPHO-COA	0.003–0.76	7
ATP	0.1157–1	6
3’-DEPHOSPHO-COA	0.0067–0.0147	4
DIPHOSPHATE	0.022–0.272	4
PANTETHEINE 4’-PHOSPHATE	0.015–0.19	4
GTP	0.26	1
DEPHOSPHO-COA	0.017	1
MG-ATP	0.22	1
PHOSPHOPANTETHEINE	0.0047	1

Catalyzed reactions (Rhea), 2 shown:

• 3’-dephospho-CoA + ATP = ADP + CoA + H(+) (RHEA:18245)
• (R)-4’-phosphopantetheine + ATP + H(+) = 3’-dephospho-CoA + diphosphate (RHEA:19801)

UniProt features (18 total): binding site 7, sequence variant 4, modified residue 2, chain 1, domain 1, splice variant 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13057-F1	89.51	0.74

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 (7): 365–372; 389; 393; 396; 423; 445; 514

Post-translational modifications (2): 178, 183

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-196783	Coenzyme A biosynthesis

MSigDB gene sets: 481 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_COENZYME_A_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, KANNAN_TP53_TARGETS_DN, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, BROWNE_HCMV_INFECTION_12HR_UP, USF_C, CAGCTG_AP4_Q5, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (2): coenzyme A biosynthetic process (GO:0015937), biosynthetic process (GO:0009058)

GO Molecular Function (9): dephospho-CoA kinase activity (GO:0004140), pantetheine-phosphate adenylyltransferase activity (GO:0004595), ATP binding (GO:0005524), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial matrix (GO:0005759), extracellular exosome (GO:0070062), sperm head-tail coupling apparatus (GO:0120212), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Vitamin B5 (pantothenate) metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transferase activity, transferring phosphorus-containing groups	2
cellular anatomical structure	2
coenzyme A metabolic process	1
sulfur compound biosynthetic process	1
purine-containing compound biosynthetic process	1
nucleoside phosphate biosynthetic process	1
metabolic process	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
adenylyltransferase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1
organelle outer membrane	1
mitochondrion	1
intracellular organelle lumen	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

3088 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COASY	PPCDC	Q96CD2	986
COASY	PPCS	Q9HAB8	932
COASY	HMGCS2	P54868	899
COASY	HSD17B12	Q53GQ0	865
COASY	HMGCS1	Q01581	851
COASY	SUCLA2	Q9P2R7	824
COASY	PANK2	Q9BZ23	816
COASY	PANK1	Q8TE04	795
COASY	DCAF17	Q5H9S7	768
COASY	SLC27A2	O14975	737
COASY	C19orf12	Q9NSK7	722
COASY	FA2H	Q7L5A8	716
COASY	ACSL4	O60488	715
COASY	SLC27A1	Q6PCB7	708
COASY	WDR45	Q9Y484	708

IntAct

60 interactions, top by confidence:

A	B	Type	Score
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RPS6KB1	COASY	psi-mi:“MI:0915”(physical association)	0.540
COASY	RPS6KB1	psi-mi:“MI:0915”(physical association)	0.540
COASY	RPS6KB1	psi-mi:“MI:0407”(direct interaction)	0.540
APOOL	MTX2	psi-mi:“MI:0914”(association)	0.530
COASY	CFTR	psi-mi:“MI:0915”(physical association)	0.520
CFTR	COASY	psi-mi:“MI:0915”(physical association)	0.520
	COASY	psi-mi:“MI:0407”(direct interaction)	0.440
COASY	MIB1	psi-mi:“MI:0915”(physical association)	0.400
COASY	RPS6KB2	psi-mi:“MI:0915”(physical association)	0.400
EDC4	COASY	psi-mi:“MI:0915”(physical association)	0.400
KRT20	COASY	psi-mi:“MI:0915”(physical association)	0.370
TRADD	HNRNPCL2	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
CISD3	POLRMT	psi-mi:“MI:0914”(association)	0.350
CISD3	TIMM44	psi-mi:“MI:0914”(association)	0.350
G3BP1	AGPS	psi-mi:“MI:0914”(association)	0.350
RPL28	GTPBP10	psi-mi:“MI:0914”(association)	0.350
PRKY	METTL15	psi-mi:“MI:0914”(association)	0.350
CENPM	DNM1L	psi-mi:“MI:0914”(association)	0.350
HNRNPCL2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
CCT8L2	DVL2	psi-mi:“MI:0914”(association)	0.350
LGI1	APAF1	psi-mi:“MI:0914”(association)	0.350
SSX2	GSTA1	psi-mi:“MI:0914”(association)	0.350

BioGRID (125): CNTROB (Two-hybrid), KIAA1958 (Two-hybrid), HEPHL1 (Affinity Capture-MS), CALML3 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), LRRC15 (Affinity Capture-MS), LGALS3 (Affinity Capture-MS), VSIG8 (Affinity Capture-MS), DUSP14 (Affinity Capture-MS), DSG4 (Affinity Capture-MS), HIST1H2AG (Affinity Capture-MS), COASY (Two-hybrid), COASY (Co-fractionation), COASY (Co-fractionation)

ESM2 similar proteins: A0A4X1T4U3, A4IFD0, O00329, O14936, O35904, O61069, O65583, O70589, P07953, P16118, P25114, P49872, P70266, Q13057, Q16875, Q16877, Q24210, Q28901, Q298L5, Q2UM43, Q32M07, Q4R3W4, Q4R8B6, Q4V8A1, Q502L7, Q5B5L3, Q5M7G4, Q5R9C1, Q623S8, Q62915, Q68FP8, Q6DGQ8, Q6DTY7, Q6P618, Q80UN9, Q8IMX7, Q8MIR4, Q91309, Q91348, Q91YL3

Diamond homologs: B9F2L1, C5A3G3, O27918, O28077, O58358, P53332, Q10350, Q13057, Q46A30, Q58436, Q5JHE8, Q6ZLC4, Q8MIR4, Q8PZN4, Q8TGY4, Q8TK70, Q8U1X0, Q8ZY96, Q97BQ0, Q9DBL7, Q9HIY2, Q9UYT0, Q9ZPV8, A6Q4Z6, A7I4S0, B8GJN8, C5A1S7, D3RZA9, E1RHM5, O58466, P27623, Q12YR1, Q2FT79, Q2G2X2, Q5JHT4, Q8RKI6, Q8U1T9, Q9UZ37, Q9ZVI9, C7P607

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	10
Uncertain significance	224
Likely benign	140
Benign	13

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
100662	NM_025233.7(COASY):c.1495C>T (p.Arg499Cys)	Pathogenic
100663	NM_025233.7(COASY):c.175C>T (p.Gln59Ter)	Pathogenic
1373025	NM_025233.7(COASY):c.1567C>T (p.Gln523Ter)	Pathogenic
1418640	NM_025233.7(COASY):c.422dup (p.Tyr141Ter)	Pathogenic
1722462	NM_025233.7(COASY):c.1068_1069del (p.Cys357fs)	Pathogenic
1899292	NM_025233.7(COASY):c.383del (p.Pro128fs)	Pathogenic
2083704	NM_025233.7(COASY):c.1579C>T (p.Gln527Ter)	Pathogenic
2114435	NM_025233.7(COASY):c.946C>T (p.Gln316Ter)	Pathogenic
2267374	NM_025233.7(COASY):c.553_557del (p.Lys185fs)	Pathogenic
2716492	NM_025233.7(COASY):c.423C>A (p.Tyr141Ter)	Pathogenic
2730066	NM_025233.7(COASY):c.545_546del (p.Gly182fs)	Pathogenic
2730393	NM_025233.7(COASY):c.732_733del (p.Thr245fs)	Pathogenic
2918682	NM_025233.7(COASY):c.1401_1404dup (p.Ile469fs)	Pathogenic
3723340	NM_025233.7(COASY):c.183del (p.Phe62fs)	Pathogenic
4704971	NM_025233.7(COASY):c.600dup (p.Asp201Ter)	Pathogenic
620212	NM_025233.7(COASY):c.394C>T (p.Gln132Ter)	Pathogenic
664943	NM_025233.7(COASY):c.876T>A (p.Tyr292Ter)	Pathogenic
832522	NC_000017.11:g.(?42562392)(42565988_?)del	Pathogenic
1690703	NM_025233.7(COASY):c.161_171del (p.Gln54fs)	Likely pathogenic
1698628	NM_025233.7(COASY):c.492del (p.Glu164fs)	Likely pathogenic
2050208	NM_025233.7(COASY):c.1388-2A>G	Likely pathogenic
2690569	NM_025233.7(COASY):c.1303-2A>G	Likely pathogenic
3581965	NM_025233.7(COASY):c.1387+1G>A	Likely pathogenic
3775291	NM_025233.7(COASY):c.586_587del (p.Val196fs)	Likely pathogenic
3779541	NM_025233.7(COASY):c.90_96del (p.Ala30_Arg31insTer)	Likely pathogenic
4074825	NM_025233.7(COASY):c.1130G>T (p.Arg377Leu)	Likely pathogenic
4086116	NM_025233.7(COASY):c.112dup (p.Tyr38fs)	Likely pathogenic
599340	NM_025233.7(COASY):c.641C>T (p.Ala214Val)	Likely pathogenic

SpliceAI

2732 predictions. Top by Δscore:

Variant	Effect	Δscore
17:42563318:GAAGA:G	donor_gain	1.0000
17:42563320:AGA:A	donor_gain	1.0000
17:42563321:GA:G	donor_gain	1.0000
17:42563321:GAG:G	donor_gain	1.0000
17:42563323:G:GG	donor_gain	1.0000
17:42563327:G:GG	donor_gain	1.0000
17:42563946:G:A	acceptor_gain	1.0000
17:42564172:GAAT:G	donor_gain	1.0000
17:42564173:A:T	donor_gain	1.0000
17:42564176:G:GG	donor_gain	1.0000
17:42564188:G:GT	donor_gain	1.0000
17:42564202:G:GT	donor_gain	1.0000
17:42564439:A:AG	acceptor_gain	1.0000
17:42564440:C:G	acceptor_gain	1.0000
17:42564443:CAG:C	acceptor_loss	1.0000
17:42564444:A:AG	acceptor_gain	1.0000
17:42564444:A:T	acceptor_loss	1.0000
17:42564444:AG:A	acceptor_gain	1.0000
17:42564445:G:GT	acceptor_gain	1.0000
17:42564445:GG:G	acceptor_gain	1.0000
17:42564445:GGA:G	acceptor_gain	1.0000
17:42564445:GGAC:G	acceptor_gain	1.0000
17:42564445:GGACC:G	acceptor_gain	1.0000
17:42564573:CATAT:C	donor_gain	1.0000
17:42564574:ATAT:A	donor_gain	1.0000
17:42564575:TAT:T	donor_gain	1.0000
17:42564576:AT:A	donor_gain	1.0000
17:42564578:G:GG	donor_gain	1.0000
17:42564578:GT:G	donor_loss	1.0000
17:42564579:T:A	donor_loss	1.0000

AlphaMissense

3636 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:42562738:T:A	V39D	0.996
17:42565542:T:A	W487R	0.996
17:42565542:T:C	W487R	0.996
17:42563220:T:C	F200L	0.994
17:42563222:T:A	F200L	0.994
17:42563222:T:G	F200L	0.994
17:42563256:A:C	S212R	0.993
17:42563258:T:A	S212R	0.993
17:42563258:T:G	S212R	0.993
17:42564122:A:C	S288R	0.993
17:42564124:C:A	S288R	0.993
17:42564124:C:G	S288R	0.993
17:42565669:G:C	R499P	0.993
17:42565755:A:C	S528R	0.991
17:42565757:C:A	S528R	0.991
17:42565757:C:G	S528R	0.991
17:42564524:A:C	S332R	0.990
17:42564526:C:A	S332R	0.990
17:42564526:C:G	S332R	0.990
17:42565036:T:C	F431L	0.990
17:42565038:T:A	F431L	0.990
17:42565038:T:G	F431L	0.990
17:42564539:C:A	R337S	0.989
17:42562732:T:A	L37H	0.988
17:42564164:C:A	R302S	0.988
17:42563999:C:A	R247S	0.987
17:42564012:T:C	L251P	0.987
17:42562645:T:C	L8P	0.986
17:42562732:T:C	L37P	0.986
17:42563246:G:C	K208N	0.986

dbSNP variants (sampled 300 via entrez): RS1000096293 (17:42564550 G>A,T), RS1000202926 (17:42563654 A>C), RS1000255382 (17:42563936 C>T), RS1000267884 (17:42561480 A>C,G), RS1000543807 (17:42562252 C>A), RS1000695609 (17:42566078 A>G), RS1001208684 (17:42564869 A>G), RS1002869698 (17:42565646 C>T), RS1003238744 (17:42563932 C>A,T), RS1003550138 (17:42566284 T>C), RS1003750155 (17:42560612 C>G), RS1003824340 (17:42563496 C>G), RS1005351725 (17:42561516 C>T), RS1006017247 (17:42560426 T>C), RS1006405638 (17:42565400 G>C)

Disease associations

OMIM: gene MIM:609855 | disease phenotypes: MIM:615643, MIM:234200, MIM:618266, MIM:252920, MIM:616491, MIM:213000, MIM:610217

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration with brain iron accumulation 6	Definitive	Autosomal recessive
pontocerebellar hypoplasia, type 12	Strong	Autosomal recessive

Mondo (7): neurodegeneration with brain iron accumulation 6 (MONDO:0014290), neurodegeneration with brain iron accumulation (MONDO:0018307), pontocerebellar hypoplasia, type 12 (MONDO:0032643), mucopolysaccharidosis type 3B (MONDO:0009656), Charcot-Marie-Tooth disease axonal type 2V (MONDO:0014665), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), neurodegeneration with brain iron accumulation 2B (MONDO:0012444)

Orphanet (9): COASY protein-associated neurodegeneration (Orphanet:397725), Neurodegeneration with brain iron accumulation (Orphanet:385), Pontocerebellar hypoplasia type 12 (Orphanet:611256), Muscular lipidosis (Orphanet:206953), Autosomal dominant Charcot-Marie-Tooth disease type 2V (Orphanet:447964), Sanfilippo syndrome type B (Orphanet:79270), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), Infantile neuroaxonal dystrophy (Orphanet:35069)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000716	Depression
HP:0000722	Compulsive behaviors
HP:0001249	Intellectual disability
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001321	Cerebellar hypoplasia
HP:0001332	Dystonia
HP:0001522	Death in infancy
HP:0001561	Polyhydramnios
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0001838	Rocker bottom foot
HP:0002059	Cerebral atrophy
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002180	Neurodegeneration
HP:0002313	Spastic paraparesis
HP:0002339	Abnormal caudate nucleus morphology
HP:0002365	Hypoplasia of the brainstem
HP:0002376	Developmental regression
HP:0002453	Abnormal globus pallidus morphology
HP:0002454	Eye of the tiger anomaly of globus pallidus

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007923_57	Medication use (drugs used in diabetes)	7.000000e-09
GCST009602_60	Metabolic syndrome	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009924	Drugs used in diabetes use measurement
EFO:0000195	metabolic syndrome

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C562568	Cerebellar Hypoplasia (supp.)
C538421	Neurodegeneration with brain iron accumulation (NBIA) (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105867 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.14	Kd	7170	nM	CHEMBL5653589
5.14	ED50	7275	nM	CHEMBL5653589
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 15 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148103: Binding affinity to human COASY incubated for 45 mins by Kinobead based pull down assay	kd	7.1704	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178848: Inhibition of COASY (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, affects cotreatment, increases expression	3
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	3
Acetaminophen	decreases expression	2
Rotenone	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
glycidyl methacrylate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
tetrahydropalmatine	decreases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
potassium chromate(VI)	increases expression	1
di-n-butylphosphoric acid	affects expression	1
pyrimidifen	increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pyrachlostrobin	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
picoxystrobin	increases expression	1
Arsenic Trioxide	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Indomethacin	increases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Smoke	decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4048631	Binding	Inhibition of human PPAT	Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05492799	PHASE4	ENROLLING_BY_INVITATION	Safety, Tolerability and Efficacy of ICV AX 250 Treatment in MPS IIIB -OLE
NCT07579910	PHASE3	NOT_YET_RECRUITING	Intracerebroventricular Tralesinidase Alfa in Children With Mucopolysaccharidosis Type IIIB
NCT03784287	PHASE2	UNKNOWN	A Treatment Extension Study of Mucopolysaccharidosis Type IIIB
NCT02587858	Not specified	UNKNOWN	NBIAready: Online Collection of Natural History Patient-reported Outcome Measures
NCT05522374	Not specified	RECRUITING	TIRCON International NBIA Registry
NCT05615571	Not specified	COMPLETED	Testing of NBIA Genes: Analysis of Genetic Heterogeneity and Validation of Mitochondrial Markers for Assessing Causality of Sequence Variants.
NCT05696912	Not specified	UNKNOWN	Functional Tests to Resolve Unsolved Rare Diseases. Rares.
NCT06596746	Not specified	RECRUITING	Neurodegenerative Diseases Progression Markers (MARKERS-NDD)
NCT02618512	PHASE1/PHASE2	TERMINATED	A Open Label Study in Previously Studied, SBC-103 Treatment Naïve MPS IIIB Subjects to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics/Efficacy of SBC-103 Administered Intravenously
NCT02754076	PHASE1/PHASE2	COMPLETED	A Treatment Study of Mucopolysaccharidosis Type IIIB
NCT03300453	PHASE1/PHASE2	COMPLETED	Intracerebral Gene Therapy in Children With Sanfilippo Type B Syndrome
NCT01509768	Not specified	COMPLETED	Natural History Study of Patients With Mucopolysaccharidosis Type IIIB (MPS IIIB, Sanfilippo Syndrome Type B)
NCT01873911	Not specified	COMPLETED	Neurobehavioral Phenotypes in MPS III
NCT02037880	Not specified	COMPLETED	Natural History Studies of Mucopolysaccharidosis III
NCT02090179	Not specified	COMPLETED	Evaluation of Blood Brain Barrier Integrity and Structural Abnormalities in MPS IIIB Patients Using Multimodal Magnetic Resonance Imaging
NCT02293382	Not specified	COMPLETED	A Retrospective Chart Review of Deceased Patients With Mucopolysaccharidosis Type IIIB
NCT02293408	Not specified	TERMINATED	Natural History Study to Characterise the Course of Disease Progression in Participants With Mucopolysaccharidosis Type IIIB
NCT02493998	Not specified	COMPLETED	A Study of Mucopolysaccharidosis Type IIIB (MPS IIIB)
NCT03227042	Not specified	UNKNOWN	A Prospective Natural History Study of Mucopolysaccharidosis Type IIIB (MPS IIIB)
NCT05440994	Not specified	UNKNOWN	Phenotypic Description of Patients With Atypical Clinical Forms of PLA2G6 Mutations