ADAMTS9

Summary

ADAMTS9 (ADAM metallopeptidase with thrombospondin type 1 motif 9, HGNC:13202) is a protein-coding gene on chromosome 3p14.1, encoding A disintegrin and metalloproteinase with thrombospondin motifs 9 (Q9P2N4). Cleaves the large aggregating proteoglycans, aggrecan (at the ‘1838-Glu-|-Ala-1839’ site) and versican (at the ‘1428-Glu-|-Ala-1429’ site).

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) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. Members of the ADAMTS family have been implicated in the cleavage of proteoglycans, the control of organ shape during development, and the inhibition of angiogenesis. This gene is localized to chromosome 3p14.3-p14.2, an area known to be lost in hereditary renal tumors. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing.

Source: NCBI Gene 56999 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephropathy-associated ciliopathy (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 75
• Clinical variants (ClinVar): 560 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 1
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_182920

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13202
Approved symbol	ADAMTS9
Name	ADAM metallopeptidase with thrombospondin type 1 motif 9
Location	3p14.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1312
Ensembl gene	ENSG00000163638
Ensembl biotype	protein_coding
OMIM	605421
Entrez	56999

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 retained_intron, 4 protein_coding, 1 nonsense_mediated_decay

ENST00000295903, ENST00000459780, ENST00000467119, ENST00000467257, ENST00000475557, ENST00000477180, ENST00000481060, ENST00000482490, ENST00000494004, ENST00000498707

RefSeq mRNA: 2 — MANE Select: NM_182920 NM_001318781, NM_182920

CCDS: CCDS2903, CCDS82801

Canonical transcript exons

ENST00000498707 — 40 exons

Exon	Start	End
ENSE00001205908	64550892	64551062
ENSE00001339979	64533166	64533270
ENSE00001339983	64539203	64539294
ENSE00001339985	64541095	64541228
ENSE00001339988	64541320	64541414
ENSE00001339989	64541526	64541620
ENSE00001339992	64541838	64541970
ENSE00001339995	64546758	64546952
ENSE00001823331	64515654	64517121
ENSE00001849629	64687543	64688000
ENSE00003487562	64655576	64655691
ENSE00003501857	64654572	64654612
ENSE00003505322	64601944	64602213
ENSE00003510397	64686568	64686968
ENSE00003530643	64633472	64633608
ENSE00003534279	64622198	64622327
ENSE00003542560	64681201	64681363
ENSE00003558417	64658502	64658791
ENSE00003560611	64633698	64633879
ENSE00003561061	64622420	64622586
ENSE00003561749	64615321	64615485
ENSE00003564975	64651017	64651163
ENSE00003568127	64604227	64604331
ENSE00003585800	64596830	64596991
ENSE00003588794	64641848	64641993
ENSE00003594785	64649637	64649778
ENSE00003595049	64603922	64604089
ENSE00003595161	64594258	64594434
ENSE00003597236	64631808	64631925
ENSE00003610692	64655792	64655875
ENSE00003629206	64647940	64648044
ENSE00003631355	64631455	64631550
ENSE00003635149	64568368	64568535
ENSE00003672745	64654353	64654458
ENSE00003676568	64613345	64613509
ENSE00003683330	64606960	64607079
ENSE00003685581	64615960	64616170
ENSE00003689376	64561578	64561751
ENSE00003691770	64621114	64621240
ENSE00003716272	64522166	64522260

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 95.80.

FANTOM5 (CAGE): breadth broad, TPM avg 7.6634 / max 690.2600, expressed in 822 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42876	6.3963	766
42874	0.6346	329
42875	0.3970	229
42873	0.1518	64
42872	0.0838	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
omental fat pad	UBERON:0010414	95.80	gold quality
peritoneum	UBERON:0002358	95.74	gold quality
sural nerve	UBERON:0015488	95.51	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.78	gold quality
tibial nerve	UBERON:0001323	93.70	gold quality
endometrium	UBERON:0001295	91.31	gold quality
metanephros cortex	UBERON:0010533	91.16	gold quality
adrenal tissue	UBERON:0018303	90.64	gold quality
parietal pleura	UBERON:0002400	90.32	gold quality
body of uterus	UBERON:0009853	90.30	gold quality
heart right ventricle	UBERON:0002080	90.01	gold quality
pericardium	UBERON:0002407	89.73	gold quality
upper lobe of left lung	UBERON:0008952	89.65	gold quality
left uterine tube	UBERON:0001303	89.63	gold quality
left coronary artery	UBERON:0001626	89.31	gold quality
ascending aorta	UBERON:0001496	88.82	gold quality
upper lobe of lung	UBERON:0008948	88.81	gold quality
thoracic aorta	UBERON:0001515	88.75	gold quality
tibia	UBERON:0000979	88.74	gold quality
lower esophagus mucosa	UBERON:0035834	88.71	gold quality
pleura	UBERON:0000977	88.64	gold quality
colonic epithelium	UBERON:0000397	88.54	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.45	gold quality
lower esophagus	UBERON:0013473	88.42	gold quality
endocervix	UBERON:0000458	88.25	gold quality
coronary artery	UBERON:0001621	88.09	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.95	gold quality
adipose tissue	UBERON:0001013	87.83	gold quality
heart left ventricle	UBERON:0002084	87.45	gold quality
uterus	UBERON:0000995	87.27	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	4980.81
E-MTAB-10855	yes	944.25
E-MTAB-8142	yes	130.99
E-CURD-119	yes	27.61
E-HCAD-10	yes	26.83
E-HCAD-35	yes	19.04
E-CURD-112	yes	12.60
E-GEOD-130148	yes	4.54
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

150 targeting ADAMTS9, 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-8485	100.00	77.57	4731
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487

Literature-anchored findings (GeneRIF, showing 40)

• ancillary domains of ADAMTS-9 are required both for specific extracellular localization and for its versicanase and aggrecanase activities (PMID:12514189)
• negative effect of TGFbeta1 on ADAMTS-1, -5, -9, and -15 coupled with increases in their inhibitor, TIMP-3 may aid the accumulation of versican in the stromal compartment of the prostate in BPH and prostate cancer (PMID:15599946)
• TSR-1 domain-bearing truncated ADAMTS-9 demonstrates positive GAG-binding ability & displayed low aggrecanase activity. (PMID:16507336)
• pro-ADAMTS9 is processed at the cell surface by furin (PMID:16537537)
• this study identifies and provides functional evidence for a critical region associated with tumor suppression on 3p14.2 and provides the first evidence that ADAMTS9, mapping to this region, may contribute to esophageal cancer development (PMID:16799631)
• ADAMTS9 expression was downregulated or lost in 17 of 23 (73.9%) lymph node metastatic nasopharyngeal carcinoma (NPC) specimens. After transfection of the ADAMTS9 gene into 7 NPC cell lines, a dramatic reduction of colony forming ability was observed. (PMID:18449890)
• Study show that polymorphisms in ADAMTS9 were associated with type 2 diabetes risk in the studied population. (PMID:18694974)
• These findings may provide a better understanding of the NFATc1 regulation of ADAMTS9 expression induced by inflammatory cytokines such as IL-1 beta. (PMID:19052845)
• These data identify for the first time the cellular chaperones associated with secretion of an ADAMTS protease and suggest a role for gp96 in modulating pro-ADAMTS9 processing. (PMID:19875450)
• present study is novel in evaluating the prevalence of ADAMTS9 methylation based on a large number of tumor samples and showing that epigenetic regulation of ADAMTS9 was associated with carcinogenesis (PMID:19963134)
• These data identify ADAMTS9 as a novel, constitutive, endogenous angiogenesis inhibitor that operates cell-autonomously in endothelial cells. (PMID:20093484)
• Results indicate that ADAMTS9 contributes an important function in the tumor microenvironment that acts to inhibit angiogenesis and tumor growth in both esophageal cancer and nasophageal cancer. (PMID:20551050)
• four of the six aggrecanases are expressed in immortalized chondrocyte cell-lines and can be upregulated in response to inflammatory cytokines (PMID:20568084)
• ADAMTS9 and GON-1 in the ER that promotes protein transport from the ER to the Golgi. This function is GON-domain dependent but protease activity independent. (PMID:22419820)
• Data show that the expression of ADAMTS4, 9, 16 and was up-regulated during chondrogenesis, ADAMTS1 and 5 were down-regulated. (PMID:22562232)
• ADAMTS9 acts as a functional tumor suppressor in gastric cancer through inhibiting oncogenic AKT/mTOR signaling pathway (PMID:22907434)
• The present study reveals ADAMT-9 expression by mast cells(MCs) and that MC activation regulates the expression of the protease, thus implicating the ADAMT-9 of protease in MC function. (PMID:23154421)
• PPARG2 and ADAMTS9 variants are both associated with type 2 diabetes mellitus and with insulin resistance, whereas only ADAMTS9 may be related to beta cell function. (PMID:23161442)
• The pathways MAPK and NF-kappaB were responsible pathways for the induction of ADAMTS9 gene. (PMID:23175174)
• LncRNA ADAMTS9-AS2 is regulated by DNMT1 and inhibits migration of glioma cells. (PMID:24833086)
• NF-kappaBp65 bound to elements located at -1177 and -1335 in the ADAMTS9 promoter region, in contrast to the untreated samples. The results of the present study suggested that NF-kappaB may be involved in IL-1beta-induced activation of ADAMTS9 in human chondrocytes (PMID:25760020)
• A deletion at ADAMTS9-MAGI1 locus is associated with psoriatic arthritis risk. (PMID:25990289)
• study identified a suggestive genome-wide significant association of ADAMTS9 with asthma in Spanish subjects (PMID:26620591)
• ADAMTS9 gene cytosine-adenine repeat polymorphism may be used to determine the prognosis for knee osteoarthritis radiologic progression. (PMID:27230574)
• we identified the top 10 highly differentiated SNPs in Brazilian Amerindian ancestry compared to Asian, European, and African Genomes.SNPs within or proximal to CIITA (rs6498115), SMC6 (rs1834619), and KLHL29 (rs2288697) were most differentiated in the Amerindian-specific branch. SNPs in ADAMTS9 (rs7631391), DOCK2 (rs77594147), SLC28A1 (rs28649017), ARHGAP5 (rs7151991), and CIITA (rs45601437) in the Asian comparison. (PMID:28100790)
• Our data showed that four SNPs (rs73832338, rs9985304, rs4317088, and rs9831846) in the ADAMTS9 gene were significantly associated with cognitive aging among the subjects. Additionally, we found that interactions between the ADAMTS9 rs9985304 and ADAMTS9 rs76346246 SNPs influenced cognitive aging. (PMID:28225792)
• By inhibiting ADAMTS-9, miR-338-5p suppressed the proliferation and metastasis of rheumatoid arthritis synovial fibroblasts. (PMID:28850027)
• expression by synovial cells induced by hemoglobin at low doses, suggesting a possible role for hemoglobin in cartilage damage after intra-articular hemorrhage (PMID:29137610)
• Exogenous expression of ADAMTS9 in colorectal cancer cell lines inhibited cell proliferation and migration through the regulation of cell cycle and apoptosis. (PMID:29186710)
• ADAMTS9 expression and methylation was analysed in breast cancer cell lines and tissue samples. (PMID:29193730)
• Low ADAMTS9 expression is associated with non-alcoholic fatty liver disease. (PMID:29575055)
• ADAMTS9, a secreted metalloprotease, is required for myometrial activation during late gestation and for parturition. Through knockdown of ADAMTS9 in uterine SMC, and manipulation of pericellular versican via knockdown or proteolysis, regulated pericellular matrix dynamics is essential for focal adhesion maintenance. (PMID:29642006)
• This study identified ADAMTS9, FKBP5, and PFKBF3 were identified as valuable methylation-based biomarkers for osteoarthritis. (PMID:30317616)
• Data indicate that miR-32 accelerates progression in HCC by targeting ADAMTS9, and the abnormal expression of miR-32 is correlated with prognosis. (PMID:30393368)
• The results of the present study indicated that ADAMTS-1 and ADAMTS-9 as well as PRs are downregulated in the human CCs (cumulus cells) in PCOS polycystic ovary syndrome) patients, which could be associated with impaired oocyte maturation and may result in a lower oocyte recovery and oocyte maturity rates, as well as lower fertilization rate.. (PMID:30446843)
• findings suggest that the identified mutations in ADAMTS9 cause nephronophthisis-related ciliopathies and that ADAMTS9 is required for the formation and function of primary cilia (PMID:30609407)
• ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations. (PMID:30626608)
• CRISPR-Cas9 inactivation of ADAMTS9 impaired ciliogenesis in RPE-1 cells, which was restored by catalytically active ADAMTS9 or ADAMTS20 acting in trans, but not by their proteolytically inactive mutants. (PMID:30814516)
• The ADAMTS9-AS2 is lowly expressed in BC tissues and drug-resistant BC cells. Low expression of ADAMTS9-AS2 inhibits PTEN expression and enhances tamoxifen resistance through targeting microRNA-130a-5p. (PMID:30840279)
• decreased ADAM metallopeptidase with thrombospondin type 1 motif 9(ADAMTS-9 protein) may have a role in the pathogenesis of endometrial polyps (PMID:31010360)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adamts9	ENSDARG00000077778
mus_musculus	Adamts9	ENSMUSG00000030022
rattus_norvegicus	Adamts9	ENSRNOG00000023257

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), ADAMTS12 (ENSG00000151388), ADAMTS1 (ENSG00000154734), ADAMTS5 (ENSG00000154736), ADAMTS3 (ENSG00000156140), ADAMTSL3 (ENSG00000156218), ADAMTS4 (ENSG00000158859), ADAMTS13 (ENSG00000160323), ADAMTS15 (ENSG00000166106), ADAMTS20 (ENSG00000173157), ADAMTSL1 (ENSG00000178031), ADAMTSL5 (ENSG00000185761), THSD4 (ENSG00000187720), ADAMTSL2 (ENSG00000197859)

Protein

Protein identifiers

A disintegrin and metalloproteinase with thrombospondin motifs 9 — Q9P2N4 (reviewed: Q9P2N4)

All UniProt accessions (4): A0A087WTS1, C9JWI2, Q9P2N4, H0Y859

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves the large aggregating proteoglycans, aggrecan (at the ‘1838-Glu-|-Ala-1839’ site) and versican (at the ‘1428-Glu-|-Ala-1429’ site). Has a protease-independent function in promoting the transport from the endoplasmic reticulum to the Golgi apparatus of a variety of secretory cargos.

Subcellular location. Secreted. Extracellular space. Extracellular matrix. Endoplasmic reticulum.

Tissue specificity. Highly expressed in all fetal tissues. Expressed in a number of adult tissues with highest expression in heart, placenta and skeletal muscle.

Post-translational modifications. The precursor is cleaved by a furin endopeptidase. N-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.

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 ancillary domains, including the TSRs domain, are required for specific extracellular localization and for its versicanase and aggrecanase activities. 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. The GON domain mediates protease-independent function in ER to Golgi transport.

Miscellaneous. May result from the retention of an intron in the cDNA leading to a prematurate stop codon.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9P2N4-3	1, ADAMTS-9B	yes
Q9P2N4-1	2, Long
Q9P2N4-2	3, Short
Q9P2N4-4	4

RefSeq proteins (2): NP_001305710, NP_891550* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR001590	Peptidase_M12B	Domain
IPR002870	Peptidase_M12B_N	Domain
IPR010294	ADAMTS_spacer1	Domain
IPR012314	Pept_M12B_GON-ADAMTSs	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, PF08685, PF17771, PF19030, PF19236

UniProt features (84 total): disulfide bond 20, domain 18, glycosylation site 9, sequence variant 8, splice variant 5, binding site 4, mutagenesis site 4, sequence conflict 4, region of interest 3, compositionally biased region 3, signal peptide 1, propeptide 1, chain 1, short sequence motif 1, active site 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2N4-F1	69.47	0.09

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 (2): 435; 287–288 (cleavage)

Ligand- & substrate-binding residues (4): 223 (in inhibited form); 434; 438; 444

Disulfide bonds (20): 368–418, 394–400, 412–494, 450–478, 521–543, 532–553, 538–572, 566–577, 600–637, 604–642, 615–627, 890–931, 894–935, 904–918, 1250–1290, 1254–1295, 1265–1278, 1624–1670, 1628–1675, 1639–1659

Glycosylation sites (9): 112, 135, 271, 749, 840, 1213, 1267, 1788, 1806

Mutagenesis-validated functional residues (4):

Position	Phenotype
33	no effect on mature form production.
74	no effect on mature form production.
280	no effect on mature form production.
287	no mature form produced.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-5083635	Defective B3GALTL causes PpS
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins
R-HSA-1474244	Extracellular matrix organization
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: 238 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GSE45365_NK_CELL_VS_CD11B_DC_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, AGGAAGC_MIR5163P, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOMF_METALLOPEPTIDASE_ACTIVITY, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, ATACCTC_MIR202, AAGCCAT_MIR135A_MIR135B, GOCC_CELL_SURFACE, GOBP_ARTERY_DEVELOPMENT, GOBP_VESICLE_MEDIATED_TRANSPORT, GGGTGGRR_PAX4_03, GOBP_PIGMENTATION

GO Biological Process (17): lens development in camera-type eye (GO:0002088), heart valve morphogenesis (GO:0003179), ventricular cardiac muscle tissue development (GO:0003229), proteolysis (GO:0006508), response to bacterium (GO:0009617), negative regulation of endothelial cell migration (GO:0010596), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), extracellular matrix organization (GO:0030198), melanocyte differentiation (GO:0030318), aorta morphogenesis (GO:0035909), positive regulation of melanocyte differentiation (GO:0045636), camera-type eye morphogenesis (GO:0048593), cornea development in camera-type eye (GO:0061303), endothelial cell-matrix adhesion (GO:0090673), negative regulation of sprouting angiogenesis (GO:1903671), regulation of developmental pigmentation (GO:0048070)

GO Molecular Function (7): metalloendopeptidase activity (GO:0004222), metallopeptidase activity (GO:0008237), zinc ion binding (GO:0008270), endopeptidase activity (GO:0004175), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), cell surface (GO:0009986), extracellular matrix (GO:0031012), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Extracellular matrix organization	1
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
camera-type eye development	3
anatomical structure development	2
transport	2
peptidase activity	2
cellular anatomical structure	2
heart valve development	1
anatomical structure morphogenesis	1
cardiac muscle tissue development	1
protein metabolic process	1
response to other organism	1
regulation of endothelial cell migration	1
negative regulation of cell migration	1
endothelial cell migration	1
intracellular protein localization	1
establishment of protein localization	1
cellular process	1
extracellular structure organization	1
external encapsulating structure organization	1
pigment cell differentiation	1
aorta development	1
artery morphogenesis	1
melanocyte differentiation	1
regulation of melanocyte differentiation	1
positive regulation of pigment cell differentiation	1
eye morphogenesis	1
cell-matrix adhesion	1
sprouting angiogenesis	1
negative regulation of angiogenesis	1
regulation of sprouting angiogenesis	1
developmental pigmentation	1
regulation of pigmentation	1
endopeptidase activity	1
metallopeptidase activity	1
transition metal ion binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1
cytoplasm	1
endomembrane system	1

Protein interactions and networks

STRING

1262 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAMTS9	CDKAL1	Q5VV42	783
ADAMTS9	ACAN	P16112	775
ADAMTS9	CDC123	O75794	720
ADAMTS9	JAZF1	Q86VZ6	697
ADAMTS9	TSPAN8	P19075	661
ADAMTS9	B3GLCT	Q6Y288	652
ADAMTS9	CAMK1D	Q8IU85	642
ADAMTS9	FURIN	P09958	638
ADAMTS9	VCAN	P13611	610
ADAMTS9	SCARB2	Q14108	602
ADAMTS9	SLC30A8	Q8IWU4	602
ADAMTS9	CD36	P16671	600
ADAMTS9	MTNR1B	P49286	588
ADAMTS9	HHEX	Q03014	583
ADAMTS9	WFS1	O76024	578

IntAct

4 interactions, top by confidence:

A	B	Type	Score
NOTCH2	ZNF320	psi-mi:“MI:0914”(association)	0.350
DYRK1A	ADAMTS9	psi-mi:“MI:0915”(physical association)	0.000
ADAMTS9	LIMS1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): ADAMTS9 (Affinity Capture-MS), ADAMTS9 (Two-hybrid), ADAMTS9 (Affinity Capture-MS), ADAMTS9 (Two-hybrid), ADAMTS9 (Affinity Capture-MS)

ESM2 similar proteins: A5A6L1, B3F211, D3Z5L9, O00622, O15072, O54775, O95388, O95450, P08833, P18406, P19336, P24593, P24594, P47876, P51609, P59384, P59510, P59511, P79331, P97857, Q05717, Q07079, Q1EHB3, Q28985, Q4VC17, Q5XHC5, Q64299, Q68SA9, Q69Z28, Q7T3Q2, Q8AWW5, Q8C9W3, Q8CJ69, Q8N8U9, Q8TE57, Q8TE58, Q8TE60, Q8WXS8, Q90WV8, Q91713

Diamond homologs: A0A0G2K2P5, A2VEC9, B3EWY9, B3EWZ3, B3EWZ8, C0HL12, C5IAW9, D3YXF5, D3YXG0, D3ZTD8, E9Q6D8, F1LW30, G5ECS8, O08721, O08722, O08747, O14514, O15072, O60241, O60242, O75173, O95185, O95450, O97758, P07357, P07358, P07996, P10643, P11680, P13671, P27918, P35440, P35441, P35442, P35448, P39447, P55314, P57110, P58397, P59384

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — PCM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	323
Likely benign	91
Benign	112

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1341307	GRCh37/hg19 3p14.2-13(chr3:59332508-70686155)x1	Pathogenic
3062713	GRCh37/hg19 3p14.2-13(chr3:62188399-71663248)x1	Pathogenic
1344639	NM_182920.2(ADAMTS9):c.4575_4576del (p.Gln1525fs)	Likely pathogenic

SpliceAI

5719 predictions. Top by Δscore:

Variant	Effect	Δscore
3:64533269:CC:C	acceptor_gain	1.0000
3:64533270:CC:C	acceptor_gain	1.0000
3:64536471:TAG:T	donor_gain	1.0000
3:64536472:AGA:A	donor_gain	1.0000
3:64539291:GTGG:G	acceptor_gain	1.0000
3:64539295:C:CC	acceptor_gain	1.0000
3:64541086:CTAA:C	donor_gain	1.0000
3:64541089:A:AC	donor_gain	1.0000
3:64541090:C:CC	donor_gain	1.0000
3:64541090:CTTA:C	donor_gain	1.0000
3:64541093:A:AC	donor_gain	1.0000
3:64541094:C:CT	donor_gain	1.0000
3:64541094:CTG:C	donor_gain	1.0000
3:64541538:T:A	donor_gain	1.0000
3:64541836:A:AC	donor_gain	1.0000
3:64541837:C:CC	donor_gain	1.0000
3:64541969:CA:C	acceptor_gain	1.0000
3:64541971:C:CC	acceptor_gain	1.0000
3:64551059:TGCA:T	acceptor_gain	1.0000
3:64551061:CA:C	acceptor_gain	1.0000
3:64551063:C:CC	acceptor_gain	1.0000
3:64568534:CA:C	acceptor_gain	1.0000
3:64568536:C:CC	acceptor_gain	1.0000
3:64594254:GTAC:G	donor_loss	1.0000
3:64594255:TA:T	donor_loss	1.0000
3:64594257:CCGAG:C	donor_gain	1.0000
3:64594279:C:CA	donor_gain	1.0000
3:64594430:GTGCA:G	acceptor_gain	1.0000
3:64594431:TGCA:T	acceptor_gain	1.0000
3:64594432:GCA:G	acceptor_gain	1.0000

AlphaMissense

12757 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:64596851:C:A	W1386C	1.000
3:64596851:C:G	W1386C	1.000
3:64601965:C:A	W1332C	1.000
3:64601965:C:G	W1332C	1.000
3:64601967:A:G	W1332R	1.000
3:64601967:A:T	W1332R	1.000
3:64613366:C:A	W1111C	1.000
3:64613366:C:G	W1111C	1.000
3:64633476:C:G	C724S	1.000
3:64633477:A:T	C724S	1.000
3:64633490:A:C	C719W	1.000
3:64633492:A:G	C719R	1.000
3:64633577:G:C	C690W	1.000
3:64633579:A:G	C690R	1.000
3:64633590:C:G	C686S	1.000
3:64633591:A:G	C686R	1.000
3:64633591:A:T	C686S	1.000
3:64633717:C:A	W673C	1.000
3:64633717:C:G	W673C	1.000
3:64633719:A:G	W673R	1.000
3:64633719:A:T	W673R	1.000
3:64633775:C:G	C654S	1.000
3:64633776:A:T	C654S	1.000
3:64633856:C:G	C627S	1.000
3:64633857:A:T	C627S	1.000
3:64641860:C:G	C615S	1.000
3:64641861:A:G	C615R	1.000
3:64641861:A:T	C615S	1.000
3:64641989:C:G	C572S	1.000
3:64641990:A:T	C572S	1.000

dbSNP variants (sampled 300 via entrez): RS1000002276 (3:64681927 G>T), RS1000028209 (3:64640368 G>A), RS1000048023 (3:64605999 C>T), RS1000050823 (3:64568031 G>A), RS1000052612 (3:64670785 C>A,T), RS1000117550 (3:64565852 A>G), RS1000149794 (3:64640131 C>T), RS1000150319 (3:64549382 G>A), RS1000152896 (3:64677559 G>C,T), RS1000178378 (3:64616785 T>C), RS1000189988 (3:64650500 G>A), RS1000196226 (3:64523747 G>A), RS1000198632 (3:64625583 G>A,C), RS1000210109 (3:64645266 G>A), RS1000223445 (3:64650296 C>A,G,T)

Disease associations

OMIM: gene MIM:605421 | disease phenotypes: MIM:256100

GenCC curated gene-disease

Disease	Classification	Inheritance
nephropathy-associated ciliopathy	Moderate	Autosomal recessive
nephronophthisis 1	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ciliopathy	Limited	AR

Mondo (3): nephronophthisis (MONDO:0019005), nephronophthisis 1 (MONDO:0009728), (MONDO:0022409)

Orphanet (1): Nephronophthisis (Orphanet:655)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000090	Nephronophthisis

GWAS associations

75 associations (top):

Study	Trait	p-value
GCST000167_16	Type 2 diabetes	1.000000e-08
GCST000829_8	Waist-hip ratio	1.000000e-13
GCST001280_2	Alzheimer’s disease (age of onset)	3.000000e-06
GCST001523_17	Visceral adipose tissue adjusted for BMI	8.000000e-06
GCST001524_18	Visceral adipose tissue/subcutaneous adipose tissue ratio	2.000000e-07
GCST001524_40	Visceral adipose tissue/subcutaneous adipose tissue ratio	2.000000e-07
GCST001764_2	White matter integrity (bipolar disorder risk interaction)	2.000000e-06
GCST001884_9	Age-related macular degeneration	5.000000e-09
GCST002063_3	Sexual dimorphism in anthropometric traits	2.000000e-06
GCST002207_10	Liver enzyme levels (alanine transaminase)	7.000000e-06
GCST002208_1	Liver enzyme levels (aspartate transaminase)	2.000000e-06
GCST002782_205	Waist-to-hip ratio adjusted for body mass index	1.000000e-26
GCST002782_206	Waist-to-hip ratio adjusted for body mass index	2.000000e-20
GCST002782_207	Waist-to-hip ratio adjusted for body mass index	2.000000e-29
GCST002782_208	Waist-to-hip ratio adjusted for body mass index	1.000000e-22
GCST002875_5	Diisocyanate-induced asthma	1.000000e-06
GCST003176_1	Asthma	1.000000e-07
GCST004063_27	Waist circumference adjusted for body mass index	2.000000e-09
GCST004063_86	Waist circumference adjusted for body mass index	8.000000e-17
GCST004064_10	Waist-hip ratio	4.000000e-18
GCST004064_37	Waist-hip ratio	3.000000e-10
GCST004066_27	Hip circumference	2.000000e-06
GCST004066_75	Hip circumference	3.000000e-08
GCST004138_2	Early-onset Parkinson’s disease	6.000000e-44
GCST004500_67	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	5.000000e-13
GCST004501_3	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	1.000000e-11
GCST004504_23	Waist circumference adjusted for BMI in non-smokers	2.000000e-09
GCST004505_11	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	1.000000e-22
GCST004505_12	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	5.000000e-18
GCST004507_28	Waist-to-hip ratio adjusted for BMI (joint analysis main effects and smoking interaction)	1.000000e-15

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0004343	waist-hip ratio
EFO:0004847	age at onset
EFO:0004340	body mass index
EFO:0004767	visceral:subcutaneous adipose tissue ratio
EFO:0004641	white matter integrity
EFO:0005951	sexual dimorphism
EFO:0004736	aspartate aminotransferase measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0006995	response to diisocyanate
EFO:0007789	BMI-adjusted waist circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0008343	sex interaction measurement
EFO:0008007	age at assessment
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537699	Nephronophthisis, familial juvenile (supp.)

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 — M12: Astacin/Adamalysin

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	decreases expression, affects cotreatment	3
Acetaminophen	decreases expression, increases expression	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
Valproic Acid	affects cotreatment, decreases expression	3
bisphenol A	increases expression, affects cotreatment	2
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation, increases expression	2
sodium arsenite	affects methylation, increases expression	2
entinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	increases expression, increases methylation	2
Dexamethasone	increases expression, affects cotreatment	2
Progesterone	affects cotreatment, decreases expression, increases expression	2
Tetrachlorodibenzodioxin	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
3,4-dichloroaniline	increases expression	1
o,p’-DDT	increases expression	1
2-amino-9H-pyrido(2,3-b)indole	increases expression	1
stearic acid	increases 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, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases methylation	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Vorinostat	decreases expression, affects cotreatment	1
Arbutin	decreases expression	1
Arsenicals	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Calcitriol	increases expression	1
Cytarabine	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06648044	Not specified	RECRUITING	Research of Therapeutic Targets in the Frame of Nephronophthisis and Renal Associated Ciliopathies
NCT01022957	Not specified	COMPLETED	Nephronophthisis : Clinical and Genetic Study
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT05286632	Not specified	COMPLETED	KidneYou - Innovative Digital Therapy
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases