ADAMTS2

Summary

ADAMTS2 (ADAM metallopeptidase with thrombospondin type 1 motif 2, HGNC:218) is a protein-coding gene on chromosome 5q35.3, encoding A disintegrin and metalloproteinase with thrombospondin motifs 2 (O95450). Cleaves the propeptides of type I and II collagen prior to fibril assembly.

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. The encoded preproprotein is proteolytically processed to generate the mature procollagen N-proteinase. This proteinase excises the N-propeptide of the fibrillar procollagens types I-III and type V. Mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed.

Source: NCBI Gene 9509 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Ehlers-Danlos syndrome, dermatosparaxis type (Definitive, GenCC)
• GWAS associations: 22
• Clinical variants (ClinVar): 2,126 total — 64 pathogenic, 69 likely-pathogenic
• Phenotypes (HPO): 72
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_014244

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:218
Approved symbol	ADAMTS2
Name	ADAM metallopeptidase with thrombospondin type 1 motif 2
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	ADAMTS-3, hPCPNI, PCINP, ADAM-TS2, NPI
Ensembl gene	ENSG00000087116
Ensembl biotype	protein_coding
OMIM	604539
Entrez	9509

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000251582, ENST00000274609, ENST00000518335, ENST00000522937, ENST00000523450, ENST00000698889, ENST00000957641

RefSeq mRNA: 2 — MANE Select: NM_014244 NM_014244, NM_021599

CCDS: CCDS34311, CCDS4444

Canonical transcript exons

ENST00000251582 — 22 exons

Exon	Start	End
ENSE00000387854	179139890	179140035
ENSE00000387859	179129932	179130098
ENSE00000770318	179127959	179128118
ENSE00000770319	179125998	179126130
ENSE00000770321	179124973	179125180
ENSE00000770323	179122644	179122773
ENSE00000853537	179272911	179273064
ENSE00000973031	179154049	179154192
ENSE00000973032	179153491	179153623
ENSE00000973036	179132230	179132310
ENSE00001055567	179343767	179344161
ENSE00001095829	179137769	179137944
ENSE00001095836	179135909	179136042
ENSE00001095839	179132777	179132900
ENSE00001194320	179110853	179114324
ENSE00001350993	179158723	179158879
ENSE00001350999	179207513	179207715
ENSE00002514040	179181072	179181155
ENSE00002518076	179152142	179152255
ENSE00002527178	179154814	179154919
ENSE00003641249	179121661	179121750
ENSE00003847948	179345190	179345461

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 92.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.1803 / max 279.5366, expressed in 943 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65198	9.9154	899
65197	2.4408	519
65199	0.2374	130
65196	0.2352	132
65195	0.2056	123
65194	0.1458	71

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	92.74	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.49	gold quality
adipose tissue	UBERON:0001013	91.29	gold quality
omental fat pad	UBERON:0010414	91.23	gold quality
right lung	UBERON:0002167	90.77	gold quality
right coronary artery	UBERON:0001625	90.10	gold quality
spleen	UBERON:0002106	88.67	gold quality
left coronary artery	UBERON:0001626	88.03	gold quality
upper lobe of left lung	UBERON:0008952	87.94	gold quality
mucosa of stomach	UBERON:0001199	87.79	gold quality
myometrium	UBERON:0001296	87.71	gold quality
right atrium auricular region	UBERON:0006631	87.22	gold quality
left uterine tube	UBERON:0001303	87.01	gold quality
placenta	UBERON:0001987	86.97	gold quality
endocervix	UBERON:0000458	86.54	gold quality
smooth muscle tissue	UBERON:0001135	86.41	gold quality
mammary gland	UBERON:0001911	85.83	gold quality
thoracic mammary gland	UBERON:0005200	85.83	gold quality
body of uterus	UBERON:0009853	85.80	gold quality
lung	UBERON:0002048	84.49	gold quality
ectocervix	UBERON:0012249	84.47	gold quality
uterus	UBERON:0000995	84.20	gold quality
ascending aorta	UBERON:0001496	84.05	gold quality
thoracic aorta	UBERON:0001515	83.98	gold quality
vagina	UBERON:0000996	83.74	gold quality
gall bladder	UBERON:0002110	83.68	gold quality
tibial nerve	UBERON:0001323	83.36	gold quality
tibial artery	UBERON:0007610	82.80	gold quality
popliteal artery	UBERON:0002250	82.79	gold quality
right ovary	UBERON:0002118	82.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.66

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

81 targeting ADAMTS2, 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-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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 17)

• when conditioned media of TSP2-transfectants were added to cultures of bovine pulmonary microvascular endothelial cells (BPMEC), the BPMEC proliferation was significantly inhibited; suggesting that human TSP2 is a potential inhibitor of angiogenesis (PMID:11788898)
• Although exons 3-5 or 14-16 encode protein domains that have not been recognized as crucial for ADAMTS-2 activity, the aminoprocollagen processing was strongly impaired, providing evidence for the requirement of these domains for proper enzyme function (PMID:15373769)
• Determination of the processing, activity and cleavage specificity of the bovine ADAMTS2 protein. (PMID:16046392)
• Data show that ADAMTS-2 is able to reduce proliferation of endothelial cells, and to induce their retraction and detachment from the substrate resulting in apoptosis. (PMID:20574651)
• ADAMTS-2, -3, and -13 expression, but not that of ADAMTS-14, are increased in plaques causing AMI compared those associated with stable angina. (PMID:22205175)
• Pathway inhibition studies revealed that ADAMTS-2 upregulation by IL-6 was mediated by JNK pathway. (PMID:24752352)
• ADAMTS2 was significantly overexpressed in Fibrous dysplasia (FD) tissues, but rarely expressed in normal bone tissues, suggesting that ADAMTS2 could be a potential biomarker for FD (PMID:25674217)
• Data indicate that ADAMTS2 and 3 cleave the amino-propeptide of fibrillar collagens and regulate blood vessels homeostasis and lymphangiogenesis. Also, ADAMTS2 deficiency leads to the dermatosparactic type of Ehlers-Danlos syndrome. [review] (PMID:25863161)
• IL-1a is a strong positive regulator of ADAMTS-2 and ADAMTS-3 expression. (PMID:26232334)
• We identified three novel homozygous loss-of-function mutations (c.2927_2928delCT, p.(Pro976Argfs*42); c.669_670dupG, p.(Pro224Argfs*24); and c.2751-2A>T) and one compound heterozygous mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from four unrelated families (PMID:26765342)
• ADAMTS-2, collagen type-1, TIMP-3 and papilin levels of the uterosacral ligament play essential roles in the etiopathogenesis of pelvic organ prolapse among postmenopausal women without stress urinary incontinence. (PMID:30388611)
• Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics. (PMID:31740729)
• Our research revealed that partial microduplication of ADAMTS2 (chr5:178728830-178997692) might be benign and not correlate with disorders. And there might exist phenotypic diversities of 5q35.3 duplications. (PMID:31804359)
• ADAMTS12, a new candidate gene for pediatric stroke. (PMID:32817637)
• Mutations in the TBX15-ADAMTS2 pathway associate with a novel soft palate dysplasia. (PMID:36124393)
• Genome-wide association study of early ischaemic stroke risk in Brazilian individuals with sickle cell disease implicates ADAMTS2 and CDK18 and uncovers novel loci. (PMID:36602125)
• Opposing roles for ADAMTS2 and ADAMTS14 in myofibroblast differentiation and function. (PMID:37929635)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	adamts2a	ENSDARG00000075930
danio_rerio	adamts2b	ENSDARG00000100772
danio_rerio		ENSDARG00000115504
mus_musculus	Adamts2	ENSMUSG00000036545
rattus_norvegicus	Adamts2	ENSRNOG00000061484

Paralogs (25): ADAMTS6 (ENSG00000049192), 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), ADAMTS9 (ENSG00000163638), ADAMTS15 (ENSG00000166106), ADAMTS20 (ENSG00000173157), ADAMTSL1 (ENSG00000178031), ADAMTSL5 (ENSG00000185761), THSD4 (ENSG00000187720), ADAMTSL2 (ENSG00000197859)

Protein

Protein identifiers

A disintegrin and metalloproteinase with thrombospondin motifs 2 — O95450 (reviewed: O95450)

Alternative names: Procollagen I N-proteinase, Procollagen I/II amino propeptide-processing enzyme, Procollagen N-endopeptidase

All UniProt accessions (3): O95450, A0A1B0GTY3, A0A8V8TMU7

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves the propeptides of type I and II collagen prior to fibril assembly. Does not act on type III collagen. Cleaves lysyl oxidase LOX at a site downstream of its propeptide cleavage site to produce a short LOX form with reduced collagen-binding activity.

Subunit / interactions. May belong to a multimeric complex. Binds specifically to collagen type XIV.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed at high level in skin, bone, tendon and aorta and at low levels in thymus and brain.

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

Disease relevance. Ehlers-Danlos syndrome, dermatosparaxis type (EDSDERMS) [MIM:225410] A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. EDSDERMS is an autosomal recessive form characterized by extreme skin fragility and easy bruising, large fontanels, blue sclerae, puffy eyelids, micrognathia, umbilical hernia, and short fingers. Joint hypermobility becomes more important with age. The disease is caused by variants affecting the gene represented in this entry.

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.

Miscellaneous. Has no significant N-procollagen peptidase activity.

Isoforms (2)

UniProt ID	Names	Canonical?
O95450-1	LpNPI	yes
O95450-2	SpNPI

RefSeq proteins (2): NP_055059, NP_067610 (=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
IPR013275	Pept_M12B_ADAM-TS2	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

Enzyme classification (BRENDA):

• EC 3.4.24.14 — procollagen N-endopeptidase (BRENDA: 10 organisms, 94 substrates, 74 inhibitors, 17 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PROCOLLAGEN I	—	12
PNCOLLAGEN, CARBOXYMETHYLATED	0.0028	1
PROCOLLAGEN II	0.0002	1
PROPEPTIDE OF COLLAGEN ALPHA-1 CHAIN	0.001	1
PROPEPTIDE OF COLLAGEN ALPHA-2 CHAIN	0.001	1

UniProt features (49 total): disulfide bond 13, glycosylation site 8, domain 7, sequence variant 7, binding site 3, region of interest 2, splice variant 2, sequence conflict 2, signal peptide 1, propeptide 1, short sequence motif 1, active site 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95450-F1	71.59	0.15

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): 409

Ligand- & substrate-binding residues (3): 408; 412; 418

Disulfide bonds (13): 343–392, 386–465, 425–451, 492–517, 503–526, 512–545, 539–550, 573–610, 577–615, 588–600, 987–1023, 991–1028, 1002–1012

Glycosylation sites (8): 112, 251, 949, 993, 1031, 1098, 1145, 1150

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
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-1474290	Collagen formation
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: 314 (showing top): RNGTGGGC_UNKNOWN, E2F_Q4, E2F_Q4_01, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, E2F4DP1_01, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_MALE_GAMETE_GENERATION, CAGCTG_AP4_Q5, BROWNE_HCMV_INFECTION_48HR_DN, E2F1DP1_01, GOBP_PROTEIN_MATURATION, E2F_Q3, E2F1DP2_01, WU_ALZHEIMER_DISEASE_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP

GO Biological Process (8): proteolysis (GO:0006508), spermatogenesis (GO:0007283), protein processing (GO:0016485), extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), lung development (GO:0030324), collagen catabolic process (GO:0030574), skin development (GO:0043588)

GO Molecular Function (6): metalloendopeptidase activity (GO:0004222), metallopeptidase activity (GO:0008237), zinc ion binding (GO:0008270), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): extracellular region (GO:0005576), extracellular matrix (GO:0031012), obsolete collagen-containing extracellular matrix (GO:0062023)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Collagen formation	1
Diseases associated with O-glycosylation of proteins	1
O-linked glycosylation	1
Extracellular matrix organization	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
animal organ development	2
protein metabolic process	1
developmental process involved in reproduction	1
male gamete generation	1
proteolysis	1
protein maturation	1
extracellular structure organization	1
external encapsulating structure organization	1
extracellular matrix organization	1
respiratory tube development	1
respiratory system development	1
catabolic process	1
collagen metabolic process	1
endopeptidase activity	1
metallopeptidase activity	1
peptidase activity	1
transition metal ion binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1
cellular anatomical structure	1
external encapsulating structure	1

Protein interactions and networks

STRING

1358 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAMTS2	COL1A2	P02464	873
ADAMTS2	CCBE1	Q6UXH8	852
ADAMTS2	COL1A1	P02452	851
ADAMTS2	EFEMP2	O95967	813
ADAMTS2	ATP6V0A2	Q9Y487	786
ADAMTS2	FBLN5	Q9UBX5	779
ADAMTS2	COL3A1	P02461	758
ADAMTS2	LOX	P28300	658
ADAMTS2	FBN1	P35555	639
ADAMTS2	PYCR1	P32322	625
ADAMTS2	ADAMTSL2	Q86TH1	617
ADAMTS2	TIMP3	P35625	614
ADAMTS2	BMP1	P13497	590
ADAMTS2	BGN	P13247	588
ADAMTS2	COL5A1	P20908	586

IntAct

49 interactions, top by confidence:

A	B	Type	Score
CD1B	TOR1B	psi-mi:“MI:0914”(association)	0.530
PLA2G10	CHEK1	psi-mi:“MI:0914”(association)	0.530
FUT3	C1QL1	psi-mi:“MI:0914”(association)	0.530
TCTN3	GPAA1	psi-mi:“MI:0914”(association)	0.480
ADAMTS2	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
HLA-DQA1	TMEM223	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
ST8SIA4	FAM234B	psi-mi:“MI:0914”(association)	0.350
TCTN2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
PSCA	METTL15	psi-mi:“MI:0914”(association)	0.350
KLRC1	METTL15	psi-mi:“MI:0914”(association)	0.350
SUSD4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
RLN1	RTL8C	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
PRG2	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
TAS1R2	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
GPIHBP1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
IGFL3	CBX4	psi-mi:“MI:0914”(association)	0.350
CST9L	QSOX1	psi-mi:“MI:0914”(association)	0.350
LYPD4	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
DEFB136	MANBA	psi-mi:“MI:0914”(association)	0.350
DEFB135	MANBA	psi-mi:“MI:0914”(association)	0.350
SLURP1	MANBA	psi-mi:“MI:0914”(association)	0.350
C1orf54	AGRN	psi-mi:“MI:0914”(association)	0.350
HFE	PODXL	psi-mi:“MI:0914”(association)	0.350
CLEC12A	GOSR2	psi-mi:“MI:0914”(association)	0.350
ADAM33	ADAM10	psi-mi:“MI:0914”(association)	0.350
TMPRSS11B	ADAM10	psi-mi:“MI:0914”(association)	0.350

BioGRID (71): ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ADAMTS2 (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: 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

2126 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	64
Likely pathogenic	69
Uncertain significance	715
Likely benign	1005
Benign	114

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069859	NC_000005.9:g.(?178699902)(178772339_?)del	Pathogenic
1070257	NM_014244.5(ADAMTS2):c.227C>A (p.Ser76Ter)	Pathogenic
1369667	NM_014244.5(ADAMTS2):c.21del (p.Ala8fs)	Pathogenic
1453000	NM_014244.5(ADAMTS2):c.274del (p.Val92fs)	Pathogenic
1455817	NM_014244.5(ADAMTS2):c.591dup (p.Leu198fs)	Pathogenic
1456924	NM_014244.5(ADAMTS2):c.310dup (p.Glu104fs)	Pathogenic
1458940	NM_014244.5(ADAMTS2):c.2716A>T (p.Arg906Ter)	Pathogenic
152731	GRCh38/hg38 5q35.1-35.3(chr5:169334755-181285301)x3	Pathogenic
153687	GRCh38/hg38 5q35.2-35.3(chr5:175536771-181292788)x1	Pathogenic
154581	GRCh38/hg38 5q35.2-35.3(chr5:176700128-181269805)x1	Pathogenic
1711097	GRCh37/hg19 5q35.1-35.3(chr5:170350336-180719789)x3	Pathogenic
2021562	NM_014244.5(ADAMTS2):c.1903G>T (p.Glu635Ter)	Pathogenic
2026724	NM_014244.5(ADAMTS2):c.3026_3027delinsAA (p.Phe1009Ter)	Pathogenic
2033273	NM_014244.5(ADAMTS2):c.11del (p.Pro4fs)	Pathogenic
2033315	NM_014244.5(ADAMTS2):c.1612_1613del (p.Met538fs)	Pathogenic
2088004	NM_014244.5(ADAMTS2):c.2569G>T (p.Glu857Ter)	Pathogenic
2090934	NM_014244.5(ADAMTS2):c.1476C>A (p.Cys492Ter)	Pathogenic
2104599	NM_014244.5(ADAMTS2):c.1034G>A (p.Trp345Ter)	Pathogenic
2118709	NM_014244.5(ADAMTS2):c.471C>G (p.Tyr157Ter)	Pathogenic
2130165	NM_014244.5(ADAMTS2):c.1845C>A (p.Cys615Ter)	Pathogenic
2423423	NC_000005.9:g.(?178408658)(178772329_?)del	Pathogenic
2425918	NC_000005.9:g.(?178634504)(178634726_?)del	Pathogenic
2425919	NC_000005.9:g.(?178770758)(178772339_?)del	Pathogenic
2700680	NM_014244.5(ADAMTS2):c.431del (p.Gly144fs)	Pathogenic
2747336	NM_014244.5(ADAMTS2):c.107del (p.Asn36fs)	Pathogenic
2754968	NM_014244.5(ADAMTS2):c.1803_1827del (p.Gly602fs)	Pathogenic
2760679	NM_014244.5(ADAMTS2):c.3007del (p.Arg1003fs)	Pathogenic
2763468	NM_014244.5(ADAMTS2):c.1925_1934del (p.His642fs)	Pathogenic
2826263	NM_014244.5(ADAMTS2):c.97_130dup (p.Asp44fs)	Pathogenic
2836229	NM_014244.5(ADAMTS2):c.2768G>A (p.Trp923Ter)	Pathogenic

SpliceAI

6186 predictions. Top by Δscore:

Variant	Effect	Δscore
5:179121659:A:AC	donor_gain	1.0000
5:179121660:C:CC	donor_gain	1.0000
5:179121662:TG:T	donor_gain	1.0000
5:179122642:A:AC	donor_gain	1.0000
5:179122643:C:CC	donor_gain	1.0000
5:179122668:T:TA	donor_gain	1.0000
5:179125180:CCTG:C	acceptor_loss	1.0000
5:179129927:CTCA:C	donor_loss	1.0000
5:179129928:TCAC:T	donor_loss	1.0000
5:179129929:CACCA:C	donor_loss	1.0000
5:179129930:A:AC	donor_gain	1.0000
5:179129931:C:CC	donor_gain	1.0000
5:179129931:C:G	donor_loss	1.0000
5:179130096:CGG:C	acceptor_gain	1.0000
5:179130099:C:CC	acceptor_gain	1.0000
5:179132317:T:C	acceptor_gain	1.0000
5:179132320:A:AC	acceptor_gain	1.0000
5:179132322:G:GC	acceptor_gain	1.0000
5:179132776:CCATG:C	donor_gain	1.0000
5:179132896:ACCTT:A	acceptor_gain	1.0000
5:179132897:CCTTC:C	acceptor_gain	1.0000
5:179132898:CTT:C	acceptor_gain	1.0000
5:179132899:TT:T	acceptor_gain	1.0000
5:179132901:C:CC	acceptor_gain	1.0000
5:179132902:T:G	acceptor_loss	1.0000
5:179137767:ACCAT:A	donor_gain	1.0000
5:179137768:CCATC:C	donor_gain	1.0000
5:179150236:G:C	donor_gain	1.0000
5:179153484:CACT:C	donor_loss	1.0000
5:179153486:CTCA:C	donor_loss	1.0000

AlphaMissense

7949 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:179124979:C:A	W984C	1.000
5:179124979:C:G	W984C	1.000
5:179124994:C:A	W979C	1.000
5:179124994:C:G	W979C	1.000
5:179125162:C:A	W923C	1.000
5:179125162:C:G	W923C	1.000
5:179125177:C:A	W918C	1.000
5:179125177:C:G	W918C	1.000
5:179127987:C:A	W863C	1.000
5:179127987:C:G	W863C	1.000
5:179128002:C:A	W858C	1.000
5:179128002:C:G	W858C	1.000
5:179139964:C:A	W567C	1.000
5:179139964:C:G	W567C	1.000
5:179140030:A:C	C545W	1.000
5:179152155:C:G	C539S	1.000
5:179152156:A:T	C539S	1.000
5:179152193:G:C	C526W	1.000
5:179152194:C:G	C526S	1.000
5:179152194:C:T	C526Y	1.000
5:179152195:A:G	C526R	1.000
5:179152195:A:T	C526S	1.000
5:179152220:G:C	C517W	1.000
5:179152221:C:G	C517S	1.000
5:179152222:A:G	C517R	1.000
5:179152222:A:T	C517S	1.000
5:179152223:C:A	W516C	1.000
5:179152223:C:G	W516C	1.000
5:179152235:G:C	C512W	1.000
5:179152236:C:G	C512S	1.000

dbSNP variants (sampled 300 via entrez): RS1000000335 (5:179191439 T>C), RS1000009733 (5:179328954 G>A,T), RS1000011783 (5:179139725 G>A), RS1000012677 (5:179257765 C>A,T), RS1000024537 (5:179195974 G>A), RS1000040306 (5:179161422 T>C,G), RS1000048503 (5:179156239 C>G), RS1000063591 (5:179131723 A>G), RS1000066205 (5:179333860 C>G), RS1000068852 (5:179328166 G>A), RS1000110969 (5:179289891 C>T), RS1000118375 (5:179334144 GC>G), RS1000144061 (5:179333126 G>A), RS1000152747 (5:179195632 C>G,T), RS1000167061 (5:179295240 T>G)

Disease associations

OMIM: gene MIM:604539 | disease phenotypes: MIM:225410, MIM:130000

GenCC curated gene-disease

Disease	Classification	Inheritance
Ehlers-Danlos syndrome, dermatosparaxis type	Definitive	Autosomal recessive

Mondo (3): Ehlers-Danlos syndrome, dermatosparaxis type (MONDO:0009161), Ehlers-Danlos syndrome (MONDO:0020066), 5q35 microduplication syndrome (MONDO:0016461)

Orphanet (3): Dermatosparaxis Ehlers-Danlos syndrome (Orphanet:1901), Ehlers-Danlos syndrome (Orphanet:98249), 5q35 microduplication syndrome (Orphanet:228415)

HPO phenotypes

72 total (30 of 72 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000212	Gingival overgrowth
HP:0000222	Gingival hyperkeratosis
HP:0000225	Gingival bleeding
HP:0000232	Everted lower lip vermilion
HP:0000260	Wide anterior fontanel
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus
HP:0000545	Myopia
HP:0000592	Blue sclerae
HP:0000668	Hypodontia
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000963	Thin skin
HP:0000974	Hyperextensible skin
HP:0000978	Bruising susceptibility
HP:0001001	Abnormality of subcutaneous fat tissue
HP:0001007	Hirsutism
HP:0001027	Soft, doughy skin
HP:0001030	Fragile skin
HP:0001058	Poor wound healing
HP:0001075	Atrophic scars
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001367	Abnormal joint morphology

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000280_11	Attention deficit hyperactivity disorder (time to onset)	8.000000e-06
GCST001523_45	Visceral adipose tissue adjusted for BMI	9.000000e-06
GCST001689_1	Stroke (pediatric)	8.000000e-06
GCST002647_131	Height	6.000000e-11
GCST003824_2	Depression in response to interferon-based therapy in chronic hepatitis C	8.000000e-08
GCST005580_168	Intraocular pressure	1.000000e-08
GCST005580_297	Intraocular pressure	3.000000e-09
GCST005667_7	Central corneal thickness	4.000000e-08
GCST007158_5	Refractive astigmatism	3.000000e-06
GCST007294_118	Body fat distribution (trunk fat ratio)	1.000000e-17
GCST007294_78	Body fat distribution (trunk fat ratio)	7.000000e-18
GCST007295_174	Body fat distribution (leg fat ratio)	3.000000e-14
GCST007295_42	Body fat distribution (leg fat ratio)	2.000000e-14
GCST008759_52	Intake of total sugars	5.000000e-06
GCST009413_4	Intraocular pressure	6.000000e-06
GCST009415_5	Intraocular pressure and central corneal thickness (multi-trait analysis)	1.000000e-07
GCST012297_10	Schizophrenia, bipolar disorder or major depressive disorder	2.000000e-06
GCST012300_4	Schizophrenia, bipolar disorder or major depressive disorder	5.000000e-07
GCST90013406_80	Liver enzyme levels (alkaline phosphatase)	6.000000e-11
GCST90020029_1287	Waist circumference adjusted for body mass index	8.000000e-09
GCST90020029_1510	Waist circumference adjusted for body mass index	1.000000e-09
GCST90020029_1511	Waist circumference adjusted for body mass index	8.000000e-14

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007006	depressive symptom measurement
EFO:0007859	response to interferon
EFO:0004695	intraocular pressure measurement
EFO:0005213	central corneal thickness
EFO:0004341	body fat distribution
EFO:0010158	sugar consumption measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
C567527	Ehlers-Danlos Syndrome, Type VII, Autosomal Recessive (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

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, decreases expression, affects cotreatment, increases abundance	3
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, increases methylation	2
Cadmium Chloride	increases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
sodium arsenite	increases abundance, affects cotreatment, decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	affects methylation	1
mercuric bromide	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	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
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methapyrilene	affects methylation	1
Paraquat	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Plant Oils	increases expression	1
Progesterone	increases expression	1
Smoke	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT03686748	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Two Point Discrimination
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00270686	Not specified	COMPLETED	Studies of Heritable Disorders of Connective Tissue
NCT01322165	Not specified	COMPLETED	National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions
NCT01356134	Not specified	COMPLETED	Vascular Fundus Changes in Patients With High Probability of Chronic Cerebrospinal Venous Insufficiency (CCSVI)
NCT01367977	Not specified	COMPLETED	Head Circumference Growth in Children With Ehlers-Danlos Syndrome Who Develop Dysautonomia Later in Life
NCT02050113	Not specified	RECRUITING	Complex Aortic Aneurysm Repair Using Physician Modified Endografts and Custom Made Devices
NCT02435745	Not specified	COMPLETED	Obstructive Sleep Apnoea in Ehlers-Danlos Syndrome
NCT02721797	Not specified	UNKNOWN	Origins and Impact of EDS in Connective Tissues and Skin
NCT02985710	Not specified	COMPLETED	Assessment of Small Fiber Neuropathy in Rare Diseases Using Sudoscan
NCT03093493	Not specified	COMPLETED	Genetics of Ehlers-Danlos Syndrome
NCT03330977	Not specified	UNKNOWN	Efficiency Clinical Study of NOVATEX MEDICAL Compression Garments in Patients With Ehlers-Danlos Syndrome
NCT03575182	Not specified	UNKNOWN	Gait Retraining in Patients With Joint Hypermobility Syndrome/Hypermobile Ehlers Danlos Syndrome
NCT03596437	Not specified	UNKNOWN	Study of Arterial Properties by Ultra-high Frequency Ultrasound in Fibromuscular Dysplasia and Vascular Ehlers-Danlos Syndrome
NCT03602482	Not specified	COMPLETED	Standing Cognition and Co-morbidities of POTS Evaluation
NCT03681080	Not specified	COMPLETED	Concentration and Attentional Deficits in POTS and Other Autonomic Neuropathies
NCT03986229	Not specified	COMPLETED	Evaluation of the Effect of Custom Compression Garments on Standing Static Balance in Ehlers Danlos Syndrome
NCT04036305	Not specified	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT04133272	Not specified	RECRUITING	Registry of Ehlers-Danlos Syndrome
NCT04437589	Not specified	COMPLETED	Opioid-Free Anesthesia for Patients With Joint Hypermobility Syndrome Undergoing Craneo-Cervical Fixation: A Case-series
NCT04680793	Not specified	COMPLETED	Effects of a Multidisciplinary Outpatient Rehabilitation Program in Patients With Ehlers-Danlos Syndrome.
NCT04734041	Not specified	COMPLETED	Integrative Medicine for Hypermobility Spectrum Disorder and Ehlers-Danlos Syndromes (IMforHSDandEDS)
NCT04742803	Not specified	COMPLETED	Straberi Epistamp Needling Treatment For Skin Rejuvenation
NCT04806620	Not specified	RECRUITING	Unhide® Project: A Digital Health Platform to Collect Lifestyle Data for Brain Inflammation Research
NCT05137379	Not specified	COMPLETED	Evaluation of a Cohort of Patients With Ehlers-Danlos Syndrome Treated With Orthopedic Surgery (SED-eval)
NCT05366114	Not specified	UNKNOWN	Vision-based Assessment of Joint Extensibility in Ehlers Danlos Syndrome
NCT05389865	Not specified	ACTIVE_NOT_RECRUITING	Proximal Aortopathy in Scotland - Epidemiology and Surgical Outcomes
NCT05429996	Not specified	UNKNOWN	Ultrastructural Collagen Markers in Ehlers Danlos Syndromes
NCT05434728	Not specified	UNKNOWN	Characterization of Bleeding Disorders in EDS
NCT05516043	Not specified	COMPLETED	Safety and Performance of POLYTHESE® Vascular Prosthesis
NCT05561270	Not specified	RECRUITING	Light Exposure on Pain in Hypermobile Ehlers-Danlos Syndrome
NCT05720923	Not specified	ACTIVE_NOT_RECRUITING	Analysis of Muscular Properties in Patients With MFS and EDS
NCT05871216	Not specified	RECRUITING	Functional Instability in Patients Suffering From Collagen Disease and Joint Hypermobility
NCT05945784	Not specified	COMPLETED	Exploring Accessible Beauty for Individuals With Upper Extremity Deficits
NCT06074276	Not specified	RECRUITING	The Effects of Almond on Facial Skin Collagen and Wrinkles
NCT06105541	Not specified	COMPLETED	Hypermobile Ehlers-Danlos Syndrome - Transcutaneous Auricular Neuromodulation