ADAMTS12

Summary

ADAMTS12 (ADAM metallopeptidase with thrombospondin type 1 motif 12, HGNC:14605) is a protein-coding gene on chromosome 5p13.3-p13.2, encoding A disintegrin and metalloproteinase with thrombospondin motifs 12 (P58397). Metalloprotease that may play a role in the degradation of COMP.

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS-1) motif. Individual members of this family differ in the number of C-terminal TS-1 motifs, and some have unique C-terminal domains. The enzyme encoded by this gene contains eight TS-1 motifs. It may play roles in pulmonary cells during fetal development or in tumor processes through its proteolytic activity or as a molecule potentially involved in regulation of cell adhesion.

Source: NCBI Gene 81792 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 335 total — 11 pathogenic, 3 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_030955

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14605
Approved symbol	ADAMTS12
Name	ADAM metallopeptidase with thrombospondin type 1 motif 12
Location	5p13.3-p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000151388
Ensembl biotype	protein_coding
OMIM	606184
Entrez	81792

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000352040, ENST00000504582, ENST00000504830, ENST00000506952, ENST00000509762, ENST00000515401

RefSeq mRNA: 3 — MANE Select: NM_030955 NM_001324511, NM_001324512, NM_030955

CCDS: CCDS34140, CCDS87292, CCDS87293

Canonical transcript exons

ENST00000504830 — 24 exons

Exon	Start	End
ENSE00001082104	33534833	33534992
ENSE00001082109	33881119	33881480
ENSE00001082110	33561027	33561179
ENSE00001082113	33549207	33549383
ENSE00001082115	33576054	33577160
ENSE00001200019	33546059	33546202
ENSE00001397483	33891730	33891990
ENSE00002021979	33523535	33527366
ENSE00003482111	33648822	33648966
ENSE00003486037	33637577	33637746
ENSE00003488600	33614238	33614376
ENSE00003530793	33649554	33649697
ENSE00003531084	33595934	33596060
ENSE00003531234	33624231	33624351
ENSE00003534380	33630780	33630913
ENSE00003549651	33615828	33616072
ENSE00003554124	33588599	33588809
ENSE00003560726	33643378	33643470
ENSE00003599871	33683859	33684055
ENSE00003611060	33658184	33658333
ENSE00003621853	33751404	33751548
ENSE00003625310	33683018	33683101
ENSE00003645798	33641810	33641955
ENSE00003679391	33661916	33662040

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 89.33.

FANTOM5 (CAGE): breadth broad, TPM avg 11.9914 / max 405.7733, expressed in 901 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61222	7.8107	810
61223	1.3764	582
61224	1.2012	633
61225	1.0090	572
61226	0.5942	410

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	89.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.73	gold quality
stromal cell of endometrium	CL:0002255	83.46	gold quality
visceral pleura	UBERON:0002401	82.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.78	gold quality
islet of Langerhans	UBERON:0000006	81.28	gold quality
adipose tissue	UBERON:0001013	80.65	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.10	gold quality
connective tissue	UBERON:0002384	79.91	gold quality
sural nerve	UBERON:0015488	79.17	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.13	gold quality
pleura	UBERON:0000977	79.07	gold quality
omental fat pad	UBERON:0010414	78.81	gold quality
peritoneum	UBERON:0002358	78.77	gold quality
parietal pleura	UBERON:0002400	77.00	gold quality
skin of hip	UBERON:0001554	75.50	gold quality
left adrenal gland cortex	UBERON:0035825	75.02	gold quality
endometrium	UBERON:0001295	74.96	gold quality
right adrenal gland cortex	UBERON:0035827	74.83	gold quality
mammary duct	UBERON:0001765	74.70	silver quality
mammary gland	UBERON:0001911	74.69	gold quality
thoracic mammary gland	UBERON:0005200	74.65	gold quality
smooth muscle tissue	UBERON:0001135	74.47	gold quality
adrenal cortex	UBERON:0001235	74.42	gold quality
gall bladder	UBERON:0002110	74.07	gold quality
adrenal gland	UBERON:0002369	73.58	gold quality
buccal mucosa cell	CL:0002336	73.53	silver quality
sperm	CL:0000019	73.45	gold quality
right adrenal gland	UBERON:0001233	73.32	gold quality
right lung	UBERON:0002167	73.27	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-83139	yes	6.91
E-ENAD-27	yes	6.44
E-ANND-3	yes	5.81

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 22)

• ADAMTS-12 is a new COMP-interacting and -degrading enzyme and thus may play an important role in the COMP degradation in the initiation and progression of arthritis (PMID:16611630)
• data suggest that ADAMTS12 confers tumour-protective functions upon cells that produce this proteolytic enzyme (PMID:17895370)
• ADAMTS-7 and ADAMTS-12 are newly identified enzymes responsible for cartilage oligomeric matrix protein degradation in arthritis. (PMID:19098927)
• Results demonstrate that ADAMTS-12, a downstream molecule of PTHrP signaling, is a novel regulator of chondrogenesis. (PMID:19151918)
• ADAMTS-12 is a novel anti-tumor protease that can reduce the proliferative properties of tumor cells. (PMID:19638407)
• This study identifies a novel biological role for ADAMTS-12, and highlights the importance and complexity of its non-proteolytic domain(s) pertaining to its function. (PMID:21494557)
• expression of ADAMTS12 in colorectal cancer stroma plays an important role in inhibiting tumor development (PMID:21559743)
• statistically significant increase in mRNA expression of ADAMTS-7 and ADAMTS-12 was observed in the endplate cells in degenerative discs compared with nondegenerative discs (PMID:22247065)
• The data supported the hypothesis that genetic variations in ADAMTS12 influence the risk of schizophrenia. (PMID:22322903)
• Our results suggest that ADAMTS12 may be a susceptibility gene for RA development. (PMID:22505177)
• ADAMTS-12 is implicated in the inflammatory response by modulating normal neutrophil apoptosis. (PMID:23019333)
• ADAMTS-12 is a multifaced metalloproteinase in arthritis and inflammation [review] (PMID:24876675)
• Decreased levels of ADAMTS-12 were found to be associated with intrahepatic cholestasis of pregnancy. (PMID:26363034)
• ADAMTS12 expression is significantly upregulated in human masticatory mucosa during wound healing (PMID:28005267)
• ADAMTS 1, 4, 12, and 13 levels in the maternal and cord blood were lower in the preeclampsia group than in the control group. ADAMTS 1, 4, and 12 levels in placental tissues were higher in the preeclampsia group. (PMID:29135310)
• ADAMTS12 acts as a tumor microenvironment related cancer promoter in gastric cancer. (PMID:34040054)
• Promoter Methylation of PRKCB, ADAMTS12, and NAALAD2 Is Specific to Prostate Cancer and Predicts Biochemical Disease Recurrence. (PMID:34198725)
• ADAMTS12 promotes migration and epithelial-mesenchymal transition and predicts poor prognosis for pancreatic cancer. (PMID:35508435)
• MicroRNA-186 suppresses cell proliferation and metastasis in bladder cancer. (PMID:37092087)
• ADAMTS12 promotes oxaliplatin chemoresistance and angiogenesis in gastric cancer through VEGF upregulation. (PMID:37619822)
• ADAMTS12 is a stromal modulator in chronic liver disease. (PMID:37819632)
• ADAMTS12 promotes fibrosis by restructuring extracellular matrix to enable activation of injury-responsive fibroblasts. (PMID:39286973)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adamts12	ENSDARG00000067549
mus_musculus	Adamts12	ENSMUSG00000047497
rattus_norvegicus	Adamts12	ENSRNOG00000018865

Paralogs (25): ADAMTS6 (ENSG00000049192), ADAMTS2 (ENSG00000087116), PAPLN (ENSG00000100767), ADAMTS8 (ENSG00000134917), ADAMTS7 (ENSG00000136378), ADAMTS14 (ENSG00000138316), ADAMTS17 (ENSG00000140470), ADAMTS18 (ENSG00000140873), ADAMTS10 (ENSG00000142303), ADAMTSL4 (ENSG00000143382), ADAMTS16 (ENSG00000145536), ADAMTS19 (ENSG00000145808), ADAMTS1 (ENSG00000154734), ADAMTS5 (ENSG00000154736), ADAMTS3 (ENSG00000156140), ADAMTSL3 (ENSG00000156218), ADAMTS4 (ENSG00000158859), ADAMTS13 (ENSG00000160323), ADAMTS9 (ENSG00000163638), ADAMTS15 (ENSG00000166106), ADAMTS20 (ENSG00000173157), ADAMTSL1 (ENSG00000178031), ADAMTSL5 (ENSG00000185761), THSD4 (ENSG00000187720), ADAMTSL2 (ENSG00000197859)

Protein

Protein identifiers

A disintegrin and metalloproteinase with thrombospondin motifs 12 — P58397 (reviewed: P58397)

All UniProt accessions (2): D6REX0, P58397

UniProt curated annotations — full annotation on UniProt →

Function. Metalloprotease that may play a role in the degradation of COMP. Also cleaves alpha-2 macroglobulin and aggregan. Has anti-tumorigenic properties.

Subunit / interactions. Interacts with COMP.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in skeletal muscle and fat.

Post-translational modifications. The precursor is cleaved by a furin endopeptidase. Subjected to an intracellular maturation process yielding a 120 kDa N-terminal fragment containing the metalloproteinase, disintegrin, one TSP type-1 and the Cys-rich domains and a 83 kDa C-terminal fragment containing the spacer 2 and four TSP type-1 domains. Glycosylated. Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Can also be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs, and N-glycosylated. These other glycosylations can also facilitate secretion.

Activity regulation. Inhibited by alpha-2 macroglobulin.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The spacer domain and the TSP type-1 domains are important for a tight interaction with the extracellular matrix. The C-terminal four TSP1-like repeats are necessary and sufficient for binding COMP. The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.

Induction. By IFN-alpha and by IL1B/interleukin-1 beta. Up-regulated in articular cartilage and synovium from arthritis patients. Up-regulared in chondrocytes.

Isoforms (3)

UniProt ID	Names	Canonical?
P58397-1	1	yes
P58397-2	2
P58397-3	3

RefSeq proteins (3): NP_001311440, NP_001311441, NP_112217* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR001590	Peptidase_M12B	Domain
IPR002870	Peptidase_M12B_N	Domain
IPR010294	ADAMTS_spacer1	Domain
IPR010909	PLAC	Domain
IPR013273	ADAMTS/ADAMTS-like	Family
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR041645	ADAMTS_CR_2	Domain
IPR045371	ADAMTS_CR_3	Domain
IPR050439	ADAMTS_ADAMTS-like	Family

Pfam: PF00090, PF01421, PF01562, PF05986, PF17771, PF19030, PF19236

UniProt features (66 total): glycosylation site 14, domain 11, disulfide bond 11, compositionally biased region 7, region of interest 5, sequence variant 5, binding site 4, splice variant 3, signal peptide 1, propeptide 1, short sequence motif 1, chain 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P58397-F1	64.56	0.07

Functional residue map

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

Catalytic / active sites (1): 393

Ligand- & substrate-binding residues (4): 208 (in inhibited form); 392; 396; 402

Disulfide bonds (11): 322–376, 351–358, 370–451, 409–435, 478–501, 489–507, 496–526, 520–531, 554–591, 558–596, 569–581

Glycosylation sites (14): 105, 125, 215, 485, 685, 790, 952, 1105, 1276, 1301, 1321, 1372, 1379, 1504

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-5083635	Defective B3GALTL causes PpS
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins
R-HSA-1643685	Disease
R-HSA-3781865	Diseases of glycosylation
R-HSA-3906995	Diseases associated with O-glycosylation of proteins
R-HSA-392499	Metabolism of proteins
R-HSA-5173105	O-linked glycosylation
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 137 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_RESPONSE_TO_PEPTIDE, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, MEF2_02, GGGTGGRR_PAX4_03

GO Biological Process (20): chondrocyte differentiation (GO:0002062), proteolysis (GO:0006508), cell-matrix adhesion (GO:0007160), cell migration (GO:0016477), proteoglycan catabolic process (GO:0030167), extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), negative regulation of chondrocyte differentiation (GO:0032331), ossification involved in bone maturation (GO:0043931), regulation of inflammatory response (GO:0050727), obsolete proteolysis involved in protein catabolic process (GO:0051603), cellular response to interleukin-1 (GO:0071347), cellular response to tumor necrosis factor (GO:0071356), cellular response to BMP stimulus (GO:0071773), regulation of endothelial tube morphogenesis (GO:1901509), negative regulation of hepatocyte growth factor receptor signaling pathway (GO:1902203), negative regulation of cellular response to vascular endothelial growth factor stimulus (GO:1902548), negative regulation of cellular response to hepatocyte growth factor stimulus (GO:2001113), ossification (GO:0001503), proteoglycan metabolic process (GO:0006029)

GO Molecular Function (6): metalloendopeptidase activity (GO:0004222), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (2): extracellular matrix (GO:0031012), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Diseases associated with O-glycosylation of proteins	1
O-linked glycosylation	1
Diseases of metabolism	1
Diseases of glycosylation	1
Post-translational protein modification	1
Disease	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to cytokine stimulus	2
negative regulation of cellular response to growth factor stimulus	2
cell differentiation	1
cartilage development	1
protein metabolic process	1
cell-substrate adhesion	1
cell motility	1
proteoglycan metabolic process	1
glycoprotein catabolic process	1
extracellular structure organization	1
external encapsulating structure organization	1
extracellular matrix organization	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
negative regulation of cell differentiation	1
negative regulation of cartilage development	1
ossification	1
bone maturation	1
inflammatory response	1
regulation of defense response	1
regulation of response to external stimulus	1
response to interleukin-1	1
response to tumor necrosis factor	1
cellular response to growth factor stimulus	1
response to BMP	1
endothelial tube morphogenesis	1
regulation of morphogenesis of an epithelium	1
negative regulation of signal transduction	1
hepatocyte growth factor receptor signaling pathway	1
regulation of hepatocyte growth factor receptor signaling pathway	1
cellular response to vascular endothelial growth factor stimulus	1
regulation of cellular response to vascular endothelial growth factor stimulus	1
cellular response to hepatocyte growth factor stimulus	1
regulation of cellular response to hepatocyte growth factor stimulus	1
multicellular organismal process	1
glycoprotein metabolic process	1
endopeptidase activity	1
metallopeptidase activity	1
cation binding	1
binding	1

Protein interactions and networks

STRING

1064 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAMTS12	COMP	P49747	786
ADAMTS12	FURIN	P09958	707
ADAMTS12	SCARB2	Q14108	694
ADAMTS12	CD36	P16671	690
ADAMTS12	SCARB1	Q8WTV0	652
ADAMTS12	FBLN2	P98095	565
ADAMTS12	SULF1	Q8IWU6	522
ADAMTS12	ADAMTS7	Q9UKP4	495
ADAMTS12	EGF	P01133	478
ADAMTS12	TMC5	Q6UXY8	472
ADAMTS12	ACAN	P16112	448
ADAMTS12	COL3A1	P02461	429
ADAMTS12	CD47	Q08722	423
ADAMTS12	PALM3	A6NDB9	419
ADAMTS12	POU6F2	P78424	386

IntAct

43 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
ADAMTS12	COMP	psi-mi:“MI:0915”(physical association)	0.680
COMP	ADAMTS12	psi-mi:“MI:0570”(protein cleavage)	0.680
ADAMTS12	COMP	psi-mi:“MI:0570”(protein cleavage)	0.680
MYL6	ADAMTS12	psi-mi:“MI:0915”(physical association)	0.670
ADAMTS12	MYL6	psi-mi:“MI:0915”(physical association)	0.670
ADAMTS12	Comp	psi-mi:“MI:0915”(physical association)	0.590
Comp	ADAMTS12	psi-mi:“MI:0915”(physical association)	0.590
Comp	ADAMTS12	psi-mi:“MI:0407”(direct interaction)	0.590
ADAMTS12	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
HEL-S-72	ADAMTS12	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	ADAMTS12	psi-mi:“MI:0915”(physical association)	0.560
ADAMTS12	HEL-S-72	psi-mi:“MI:0915”(physical association)	0.560
DNAJC30	NDUFS4	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
DNAJC3	DEDD	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
GPIHBP1	ADAM10	psi-mi:“MI:0914”(association)	0.530
EDN3	MGRN1	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
PSG8	MGRN1	psi-mi:“MI:0914”(association)	0.530
WNT4	TOMM40	psi-mi:“MI:0914”(association)	0.530
A2M	ADAMTS12	psi-mi:“MI:0570”(protein cleavage)	0.440
		psi-mi:“MI:0914”(association)	0.350
ADAMTS12	FKBP9	psi-mi:“MI:0914”(association)	0.350

BioGRID (67): ADAMTS12 (Two-hybrid), ADAMTS12 (Two-hybrid), ADAMTS12 (Two-hybrid), UBR1 (Affinity Capture-MS), FKBP9 (Affinity Capture-MS), SP3 (Affinity Capture-MS), PPM1A (Affinity Capture-MS), SNRK (Affinity Capture-MS), USF2 (Affinity Capture-MS), USF1 (Affinity Capture-MS), SNRK (Affinity Capture-MS), USF1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), PPM1A (Affinity Capture-MS), FKBP9 (Affinity Capture-MS)

ESM2 similar proteins: F8VQ03, O15072, O15204, O35227, O77780, P58397, P59509, P59510, P70505, P97776, P97857, Q1EHB3, Q28475, Q28478, Q28483, Q28660, Q3TTE0, Q5BK84, Q60411, Q60472, Q60718, Q60813, Q63180, Q63202, Q68SA9, Q811B3, Q811Q4, Q8C9W3, Q8K410, Q8N2E2, Q8R534, Q8TC27, Q8TE59, Q99965, Q9H2U9, Q9JI76, Q9JLN6, Q9R0X2, Q9R157, Q9R158

Diamond homologs: A2VEC9, A6QNY1, B3EWZ3, B3EWZ8, C0HL12, C5IAW9, D3YXG0, D3ZTD8, F1LW30, O08721, O08722, O08747, O14514, O15072, O55225, O60241, O60242, O75173, O88783, O95185, O95450, P04275, P07358, P07996, P27918, P35441, P35442, P35448, P55314, P57110, P58397, P58459, P59384, P79331, P80012, P97857, P98088, P98092, P98160, P98164

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	3
Uncertain significance	229
Likely benign	15
Benign	7

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1012370	GRCh37/hg19 5p13.3-12(chr5:29081195-45294031)x3	Pathogenic
146130	GRCh38/hg38 5p15.33-11(chr5:49978-46114984)x3	Pathogenic
1527153	GRCh37/hg19 5p14.1-11(chr5:26382110-46389339)	Pathogenic
1808669	GRCh37/hg19 5p13.3-11(chr5:29348753-46389339)x3	Pathogenic
253537	GRCh37/hg19 5p15.33-13.2(chr5:22149-34041255)x3	Pathogenic
253597	GRCh37/hg19 5p15.2-12(chr5:13461664-46098927)x3	Pathogenic
2685139	GRCh37/hg19 5p15.33-13.2(chr5:113577-35613146)x1	Pathogenic
394369	GRCh37/hg19 5p15.33-13.2(chr5:22149-34041196)x1	Pathogenic
563027	GRCh37/hg19 5p15.33-13.2(chr5:113576-35739404)x3	Pathogenic
563053	GRCh37/hg19 5p14.1-12(chr5:27227243-45685844)x3	Pathogenic
59606	GRCh38/hg38 5p13.3-13.2(chr5:30149035-35213678)x1	Pathogenic
146364	GRCh38/hg38 5p13.3-13.2(chr5:30961310-36143306)x1	Likely pathogenic
2683745	GRCh38/hg38 5p13.3-12(chr5:29299893-45899898)x3	Likely pathogenic
442809	GRCh37/hg19 5p14.2-11(chr5:24281195-46389339)x3	Likely pathogenic

SpliceAI

6077 predictions. Top by Δscore:

Variant	Effect	Δscore
5:33527278:AGC:A	donor_gain	1.0000
5:33534991:CA:C	acceptor_gain	1.0000
5:33534993:C:CC	acceptor_gain	1.0000
5:33549203:CTA:C	donor_loss	1.0000
5:33549204:TACC:T	donor_loss	1.0000
5:33549206:CCTGG:C	donor_gain	1.0000
5:33549379:GAGCA:G	acceptor_gain	1.0000
5:33549380:AGCA:A	acceptor_gain	1.0000
5:33549381:GCA:G	acceptor_gain	1.0000
5:33549381:GCAC:G	acceptor_loss	1.0000
5:33549382:CA:C	acceptor_gain	1.0000
5:33549382:CACTG:C	acceptor_gain	1.0000
5:33549383:ACT:A	acceptor_loss	1.0000
5:33549384:C:A	acceptor_loss	1.0000
5:33549384:C:CC	acceptor_gain	1.0000
5:33549386:G:C	acceptor_gain	1.0000
5:33549388:A:AC	acceptor_gain	1.0000
5:33549388:A:C	acceptor_gain	1.0000
5:33614372:AGAAG:A	acceptor_gain	1.0000
5:33614373:GAAG:G	acceptor_gain	1.0000
5:33614374:AAG:A	acceptor_gain	1.0000
5:33614375:AG:A	acceptor_gain	1.0000
5:33614377:C:CC	acceptor_gain	1.0000
5:33615887:T:A	donor_gain	1.0000
5:33616069:TAAC:T	acceptor_gain	1.0000
5:33616073:C:CA	acceptor_loss	1.0000
5:33616074:T:G	acceptor_loss	1.0000
5:33624239:T:TA	donor_gain	1.0000
5:33624264:CAGT:C	donor_gain	1.0000
5:33637571:CCTTA:C	donor_loss	1.0000

AlphaMissense

10562 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:33641951:C:G	C526S	1.000
5:33641952:A:T	C526S	1.000
5:33588605:C:A	W953C	0.999
5:33588605:C:G	W953C	0.999
5:33614375:A:G	L797P	0.999
5:33641936:C:G	C531S	0.999
5:33641937:A:T	C531S	0.999
5:33641952:A:G	C526R	0.999
5:33643391:C:G	C520S	0.999
5:33643392:A:T	C520S	0.999
5:33643448:C:G	C501S	0.999
5:33643449:A:T	C501S	0.999
5:33648867:G:C	C478W	0.999
5:33648868:C:G	C478S	0.999
5:33648869:A:T	C478S	0.999
5:33658322:C:G	C351S	0.999
5:33658323:A:T	C351S	0.999
5:33661984:C:A	W324C	0.999
5:33661984:C:G	W324C	0.999
5:33588620:C:A	W948C	0.998
5:33588620:C:G	W948C	0.998
5:33588806:C:A	W886C	0.998
5:33588806:C:G	W886C	0.998
5:33614337:A:C	Y810D	0.998
5:33615868:A:G	L783P	0.998
5:33615954:A:C	N754K	0.998
5:33615954:A:T	N754K	0.998
5:33615999:G:C	N739K	0.998
5:33615999:G:T	N739K	0.998
5:33624272:C:G	C701S	0.998

dbSNP variants (sampled 300 via entrez): RS1000012145 (5:33544543 T>C), RS1000022271 (5:33629161 A>C), RS1000041840 (5:33829355 T>A,C,G), RS1000063725 (5:33637892 A>G), RS1000063814 (5:33585804 G>A), RS1000067423 (5:33589063 G>A), RS1000068770 (5:33885984 G>A), RS1000073055 (5:33829099 C>A,G,T), RS1000097474 (5:33630146 T>A), RS1000110771 (5:33538275 C>T), RS1000111837 (5:33844149 G>A), RS1000115311 (5:33800696 A>C,G), RS1000121639 (5:33579380 C>G,T), RS1000130731 (5:33887530 T>G), RS1000133436 (5:33674917 A>G)

Disease associations

OMIM: gene MIM:606184 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000661_9	Mortality in heart failure	2.000000e-06
GCST001689_2	Stroke (pediatric)	3.000000e-06
GCST006988_195	Blond vs. brown/black hair color	1.000000e-77
GCST007102_12	Seasonality and depression	2.000000e-06
GCST008053_109	Height	1.000000e-10
GCST008053_183	Height	2.000000e-07
GCST008821_10	Neurofibrillary tangles	6.000000e-06
GCST009391_1612	Metabolite levels	8.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004352	mortality
EFO:0003924	hair color
EFO:0006876	seasonality measurement
EFO:0006797	neurofibrillary tangles measurement
EFO:0010377	phosphatidylcholine 34:3 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066065 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M12: Astacin/Adamalysin

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
7.52	IC50	30	nM	CHEMBL5575976

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, decreases expression, affects cotreatment, increases abundance, increases expression (+1 more)	4
Valproic Acid	affects cotreatment, increases expression	4
mercuric bromide	increases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Smoke	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
bisphenol A	increases methylation	1
beta-lapachone	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Amphotericin B	increases expression	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Clozapine	decreases expression, affects cotreatment	1
Cuprizone	affects cotreatment, decreases expression	1
Doxorubicin	increases expression	1
Estradiol	affects cotreatment, increases expression	1
Lead	affects methylation	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
CHEMBL5723910	Binding	Biochemical enzymatic FRET assay (hADAMTS12) ( FRET substrate, HiLyteFluor-488 DELSSMVLELRGLRT-K(QXL520)-E-NH2 (custom synthesis by Anaspec) was used.)	Data for DCP probe BAY-9835

Clinical trials (associated diseases)

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