ADAMTS8

Summary

ADAMTS8 (ADAM metallopeptidase with thrombospondin type 1 motif 8, HGNC:224) is a protein-coding gene on chromosome 11q24.3, encoding A disintegrin and metalloproteinase with thrombospondin motifs 8 (Q9UP79). Has anti-angiogenic properties.

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 enzyme. This enzyme contains two C-terminal TS motifs, and disrupts angiogenesis in vivo. A number of disorders have been mapped in the vicinity of this gene, most notably lung neoplasms. Reduced expression of this gene has been observed in multiple human cancers and this gene has been proposed as a potential tumor suppressor.

Source: NCBI Gene 11095 — RefSeq curated summary.

At a glance

• GWAS associations: 40 (top 3% of genes corpus-wide)
• Clinical variants (ClinVar): 173 total — 1 pathogenic
• Regional missense constraint (gnomAD): 1 of 5 regions constrained (≈2% of expected missense variation)
• GTEx eGene: eQTL in 23 tissues, sQTL in 3 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.08 (unconstrained)
• MANE Select transcript: NM_007037
• Notable: 173 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:224
Approved symbol	ADAMTS8
Name	ADAM metallopeptidase with thrombospondin type 1 motif 8
Location	11q24.3
Locus type	gene with protein product
Status	Approved
Aliases	METH2, FLJ41712, ADAM-TS8
Ensembl gene	ENSG00000134917
Ensembl biotype	protein_coding
OMIM	605175
Entrez	11095

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000257359

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1

ENST00000257359, ENST00000531752, ENST00000875535, ENST00000912959, ENST00000912960, ENST00000912961, ENST00000912962, ENST00000912963, ENST00001028465, ENST00001071611, ENST00001105712, ENST00001116165, ENST00001116166, ENST00001142150

RefSeq mRNA: 1 — MANE Select: NM_007037 NM_007037

CCDS: CCDS41732

Canonical transcript exons

ENST00000257359 — 9 exons

Exon	Start	End
ENSE00000749792	130416163	130416330
ENSE00000749793	130416940	130417075
ENSE00000990547	130419053	130419292
ENSE00000990549	130411417	130411600
ENSE00001001443	130427567	130428609
ENSE00001001447	130414531	130414832
ENSE00003475319	130408464	130408639
ENSE00003536668	130404923	130406128
ENSE00003545213	130408768	130408940

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 93.16.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1057 / max 14.3536, expressed in 52 samples.

Highest expression (Bgee): middle temporal gyrus, upper lobe of left lung, upper lobe of lung, endothelial cell, lower lobe of lung.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ADAMTS8 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 26 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Spinal cord cervical c-1	eqtl	4.0e-15	+1.79	11:130429850:C:T
Brain Caudate basal ganglia	eqtl	1.1e-13	-0.40	11:130892162:G:A
Brain Putamen basal ganglia	eqtl	1.3e-09	-0.35	11:130890099:T:C
Adipose Visceral Omentum	eqtl	1.2e-07	+0.23	11:130400960:T:C
Artery Aorta	eqtl	2.7e-07	+0.21	11:130398252:G:C
Testis	eqtl	3.9e-06	-0.31	11:130401783:T:G
Brain Nucleus accumbens basal ganglia	eqtl	1.1e-05	-0.23	11:130890599:A:T
Brain Hippocampus	eqtl	5.9e-05	+0.98	11:130458972:C:T
Brain Frontal Cortex BA9	eqtl	9.2e-05	-0.19	11:130431884:TAGAA:T
Pituitary	eqtl	1.5e-04	-0.31	11:130409029:T:G
Lung	eqtl	2.3e-04	-0.13	11:130423999:G:A
Lung	sqtl	5.6e-04	+0.31	11:130393052:C:T
Artery Tibial	eqtl	5.7e-04	-0.12	11:130403335:A:T
Brain Cortex	eqtl	7.0e-04	-0.18	11:130406384:G:C
Brain Hypothalamus	eqtl	8.3e-04	-0.31	11:130435710:A:G
Esophagus Muscularis	eqtl	2.7e-03	+0.16	11:130909773:T:C
Colon Transverse	sqtl	7.1e-03	-0.98	11:129754941:T:C
Esophagus Mucosa	eqtl	9.0e-03	+0.14	11:130896205:G:T
Brain Substantia nigra	eqtl	9.5e-03	+1.23	11:130458972:C:T
Adipose Subcutaneous	eqtl	1.3e-02	+0.21	11:130393052:C:T

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
123172	0.0658	32
123173	0.0400	17

Top tissues by expression

showing 100 of 271 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	93.16	gold quality
upper lobe of left lung	UBERON:0008952	92.71	gold quality
upper lobe of lung	UBERON:0008948	91.91	gold quality
endothelial cell	CL:0000115	91.56	gold quality
lower lobe of lung	UBERON:0008949	90.91	gold quality
right lung	UBERON:0002167	88.79	gold quality
lung	UBERON:0002048	87.07	gold quality
lower esophagus mucosa	UBERON:0035834	85.89	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.70	gold quality
entorhinal cortex	UBERON:0002728	83.54	gold quality
lower esophagus	UBERON:0013473	83.23	gold quality
lower esophagus muscularis layer	UBERON:0035833	83.22	gold quality
cauda epididymis	UBERON:0004360	82.95	gold quality
right coronary artery	UBERON:0001625	82.61	gold quality
visceral pleura	UBERON:0002401	82.33	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.33	gold quality
ascending aorta	UBERON:0001496	81.91	gold quality
superior frontal gyrus	UBERON:0002661	81.88	gold quality
thoracic aorta	UBERON:0001515	81.53	gold quality
prefrontal cortex	UBERON:0000451	80.99	gold quality
postcentral gyrus	UBERON:0002581	80.78	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	80.51	gold quality
vermiform appendix	UBERON:0001154	80.38	gold quality
frontal cortex	UBERON:0001870	79.70	gold quality
blood vessel layer	UBERON:0004797	79.61	gold quality
parietal lobe	UBERON:0001872	79.28	gold quality
caecum	UBERON:0001153	79.07	gold quality
caput epididymis	UBERON:0004358	78.76	gold quality
right frontal lobe	UBERON:0002810	78.48	gold quality
primary visual cortex	UBERON:0002436	78.20	gold quality
neocortex	UBERON:0001950	77.85	gold quality
coronary artery	UBERON:0001621	77.59	gold quality
aorta	UBERON:0000947	77.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	77.32	gold quality
left coronary artery	UBERON:0001626	77.10	gold quality
cerebral cortex	UBERON:0000956	76.82	gold quality
esophagus	UBERON:0001043	76.71	gold quality
descending thoracic aorta	UBERON:0002345	76.27	gold quality
endometrium	UBERON:0001295	76.09	gold quality
parotid gland	UBERON:0001831	76.02	gold quality
telencephalon	UBERON:0001893	75.94	gold quality
temporal lobe	UBERON:0001871	75.77	gold quality
left uterine tube	UBERON:0001303	75.48	gold quality
Brodmann (1909) area 9	UBERON:0013540	75.46	gold quality
occipital lobe	UBERON:0002021	75.41	gold quality
putamen	UBERON:0001874	75.38	gold quality
vena cava	UBERON:0004087	75.22	gold quality
nucleus accumbens	UBERON:0001882	75.21	gold quality
caudate nucleus	UBERON:0001873	74.83	gold quality
seminal vesicle	UBERON:0000998	74.68	gold quality
anterior cingulate cortex	UBERON:0009835	74.55	gold quality
cingulate cortex	UBERON:0003027	74.44	gold quality
tibial artery	UBERON:0007610	74.26	gold quality
corpus epididymis	UBERON:0004359	74.25	gold quality
popliteal artery	UBERON:0002250	74.20	gold quality
buccal mucosa cell	CL:0002336	74.14	gold quality
medial globus pallidus	UBERON:0002477	73.91	silver quality
cerebellar vermis	UBERON:0004720	73.83	gold quality
adult organism	UBERON:0007023	73.74	gold quality
prostate gland	UBERON:0002367	73.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.47	silver quality
Ammon’s horn	UBERON:0001954	73.17	gold quality
forebrain	UBERON:0001890	72.89	gold quality
Brodmann (1909) area 46	UBERON:0006483	72.58	gold quality
smooth muscle tissue	UBERON:0001135	72.50	gold quality
globus pallidus	UBERON:0001875	72.45	silver quality
fundus of stomach	UBERON:0001160	72.32	gold quality
body of stomach	UBERON:0001161	72.32	gold quality
nipple	UBERON:0002030	72.11	gold quality
myometrium	UBERON:0001296	71.89	gold quality
colon	UBERON:0001155	71.83	gold quality
uterus	UBERON:0000995	71.71	gold quality
urinary bladder	UBERON:0001255	71.54	gold quality
esophagus mucosa	UBERON:0002469	71.53	gold quality
large intestine	UBERON:0000059	71.44	gold quality
mucosa of stomach	UBERON:0001199	71.22	gold quality
decidua	UBERON:0002450	70.69	silver quality
amygdala	UBERON:0001876	70.63	gold quality
stomach	UBERON:0000945	70.50	gold quality
brain	UBERON:0000955	69.94	gold quality
gall bladder	UBERON:0002110	69.44	gold quality
dorsal root ganglion	UBERON:0000044	69.41	gold quality
intestine	UBERON:0000160	69.36	gold quality
pleura	UBERON:0000977	69.33	gold quality
tibial nerve	UBERON:0001323	69.18	gold quality
right atrium auricular region	UBERON:0006631	69.01	gold quality
transverse colon	UBERON:0001157	68.63	gold quality
superficial temporal artery	UBERON:0001614	68.45	gold quality
saphenous vein	UBERON:0007318	68.27	silver quality
cardia of stomach	UBERON:0001162	68.17	silver quality
body of uterus	UBERON:0009853	68.17	gold quality
placenta	UBERON:0001987	67.80	gold quality
cardiac atrium	UBERON:0002081	67.58	gold quality
hindlimb stylopod muscle	UBERON:0004252	67.39	gold quality
pharyngeal mucosa	UBERON:0000355	67.35	gold quality
body of tongue	UBERON:0011876	67.33	gold quality
pylorus	UBERON:0001166	67.06	silver quality
pericardium	UBERON:0002407	66.83	gold quality
urethra	UBERON:0000057	66.75	gold quality
inferior vagus X ganglion	UBERON:0005363	66.65	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.79

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 69 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Lung	tissue	12.3	not detected
Appendix	tissue	9.5	not detected
Nucleus accumbens	tissue	9.0
Hippocampus	tissue	6.7	not detected
Cerebral cortex	tissue	5.8	low
Retrosplenial and cingulate cortex	tissue	5.8
Prefrontal cortex	tissue	5.7
Hippocampal formation	tissue	5.7
Postcentral gyrus	tissue	5.6
Insular cortex	tissue	5.3
Motor cortex	tissue	5.0
Amygdala	tissue	4.8
Retrosplenial cortex	tissue	4.8
Seminal vesicle	tissue	4.6	not detected
Temporal cortex	tissue	4.5
Smooth muscle	tissue	3.9	not detected
Urinary bladder	tissue	3.9	low
Entorhinal cortex	tissue	3.8
Locus coeruleus	tissue	3.0
Esophagus	tissue	2.8	not detected
Olfactory bulb	tissue	2.8
Somatosensory cortex	tissue	2.6
Placenta	tissue	2.5	not detected
Frontal cortex	tissue	2.0
Colon	tissue	1.9	low
Occipital cortex	tissue	1.8
Adipose tissue	tissue	1.7	not detected
Gallbladder	tissue	1.5	not detected
Endometrium 1	tissue	1.4	not detected
Spinal cord	tissue	1.3
Prostate	tissue	1.3	not detected
Fallopian tube	tissue	1.3	not detected
Vagina	tissue	1.1	not detected
Duodenum	tissue	1.1	not detected
Septum	tissue	1.1
Stomach 1	tissue	0.9	not detected
Epididymis	tissue	0.9	not detected
Basal ganglia	tissue	0.9	not detected
Choroid plexus	tissue	0.9
Ventral forebrain	tissue	0.8
Cervix	tissue	0.7	not detected
Pons	tissue	0.7
Pancreas	tissue	0.7	not detected
Thalamus	tissue	0.7
Small intestine	tissue	0.7	not detected
Heart muscle	tissue	0.6	not detected
Midbrain	tissue	0.6
Caudate putamen	tissue	0.6
Breast	tissue	0.5	not detected
Rectum	tissue	0.5	not detected
Skeletal muscle	tissue	0.5	not detected
Hypothalamus	tissue	0.5
Superior colliculi	tissue	0.5
Substantia nigra	tissue	0.5
Tongue	tissue	0.4
Spleen	tissue	0.4	not detected
Ovary	tissue	0.3	not detected
Putamen	tissue	0.3
Medulla oblongata	tissue	0.3
Pituitary gland	tissue	0.2

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Blood vessel (12.7), Olfactory area (12.5), Perirhinal gyrus (12.4), Lingual gyrus (11.5), Temporo-occipital transitional zone (11.1).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ADAMTS8 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 53 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-143-5P	98.98	68.87	946

Functional genomics

gnomAD constraint: pLI 1.15e-15, LOEUF 1.08, missense Z -0.69 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000257359 splits into 5 regions with different missense tolerance; 1 is missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
11:130,405,561–130,405,922	147 / 154.1	0.95	no
11:130,405,923–130,405,966	4 / 18.2	0.22	yes (p 8.7e-04)
11:130,405,967–130,411,575	290 / 297.8	0.97	no
11:130,411,576–130,414,570	10 / 27.4	0.37	no
11:130,414,571–130,428,286	741 / 710.6	1.04	no

Literature-anchored findings (GeneRIF, showing 17)

• Ability of ADAMTS-8 to cleave aggrecan at aggrecanase-susceptible Glu373-Ala374 peptide bond. Presence of ADAMTS-8 mRNA transcripts in normal and osteoarthritic human cartilage. (ADAMTS-8) (PMID:15296936)
• Downdownregulation of METH-2 expression in primary NSCLC, often associated with promoter hypermethylation, is a frequent event, which may be related to the development of the disease. (PMID:15328519)
• ADAMTS8 and ADAMTS15 have emerged as novel predictors of survival in patients with breast carcinoma (PMID:16152618)
• Immunohistochemistry and Western analysis indicated downregulation of ADAMTS-8 protein in >77% brain tumours. A role for ADAMTS-8 in brain tumorigenesis, warranting further investigation into its role in regulation of tumour angiogenesis. (PMID:16570050)
• ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of atherosclerotic plaques (PMID:17606262)
• Study uncovers the tumor suppressive function of ADAMTS8 and its frequent methylation in certain tumors could be developed as a potential biomarker. (PMID:24184540)
• ADAMTS 8, CCL23, and TNFSF15 are implicated in anti-angiogenic activities (PMID:24384427)
• ADAMTS8 hypermethylation is associated with decreased expression in gastric cancer. (PMID:27493958)
• This study showed that ADAMTS1, 8, and 18 are highly expressed in GC and its nodal metastases, suggesting important roles of these proteases in carcinogenesis and lymphatic metastasis. The findings from the present study indicate that these proteases may be promising candidates for novel and alternative treatments in GC (gastric cancer) (PMID:28814085)
• Study revealed upregulation of ADAMTS8 and downregulation of FRAS1 and SOSTDC1 in primary fibroblasts from linear morphoea (LM) lesions. SOSTDC1 knock-down recapitulated the reduced TGF -beta1 responsiveness and LM fibroblast migration, while overexpression of ADAMTS 8 induced myofibroblast markers. (PMID:30367460)
• The expression level of ADAMTS8 mRNA increased 3.5 fold in Hip Degenerative Arthritis group when compared with Femoral neck fractures group. (PMID:30655094)
• ADAMTS8 is frequently down-regulated in colorectal cancer and functions as a tumor suppressor. (PMID:32033751)
• Post-translational regulation and proteolytic activity of the metalloproteinase ADAMTS8. (PMID:34687701)
• ADAMTS8 inhibited lung cancer progression through suppressing VEGFA. (PMID:35149432)
• The Prognostic Value of ADAMTS8 and Its Role as a Tumor Suppressor in Breast Cancer. (PMID:36346393)
• ADAMTS8 inhibits glioma development in vitro and in vivo. (PMID:37587889)
• HSFAS mediates fibroblast proliferation, migration, trans-differentiation and apoptosis in hypertrophic scars via interacting with ADAMTS8. (PMID:38006215)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	adamts8a	ENSDARG00000007709
danio_rerio		ENSDARG00000058252
mus_musculus	Adamts8	ENSMUSG00000031994
rattus_norvegicus	Adamts8	ENSRNOG00000005574

Paralogs (25): ADAMTS6 (ENSG00000049192), ADAMTS2 (ENSG00000087116), PAPLN (ENSG00000100767), 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)

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5RFQ8	98.7%	Diamond
Bos taurus	Q9TT92	98.1%	Diamond
Xenopus laevis	P35448	80.9%	Diamond
Gallus gallus	P35440	80.4%	Diamond
Oryctolagus cuniculus	P98136	75.9%	Diamond
Caenorhabditis elegans	O76840	58.8%	Diamond
Acropora millepora	B3EWY9	53.5%	Diamond
Drosophila melanogaster	Q868Z9	48.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR8052	ncRNA	102466873
ADAMTS15	protein-coding	170689
ZBTB44	protein-coding	29068
ZBTB44-DT	ncRNA	646383
APLP2	protein-coding	334
ST14	protein-coding	6768

Protein

Protein identifiers

A disintegrin and metalloproteinase with thrombospondin motifs 8 — Q9UP79 (reviewed: Q9UP79)

Alternative names: METH-2, METH-8

All UniProt accessions (1): Q9UP79

UniProt curated annotations — full annotation on UniProt →

Function. Has anti-angiogenic properties.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Highly expressed in adult and fetal lung, lower expression in brain, placenta, heart, stomach and fetal brain and kidney.

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.

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.

RefSeq proteins (1): NP_008968* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR001590	Peptidase_M12B	Domain
IPR002870	Peptidase_M12B_N	Domain
IPR006586	ADAM_Cys-rich	Domain
IPR010294	ADAMTS_spacer1	Domain
IPR013273	ADAMTS/ADAMTS-like	Family
IPR013277	Pept_M12B_ADAM-TS8	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 (37 total): disulfide bond 11, sequence conflict 6, glycosylation site 5, domain 4, binding site 3, compositionally biased region 2, region of interest 2, signal peptide 1, propeptide 1, active site 1, chain 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UP79-F1	80.22	0.48

Human Protein Atlas

Protein class: Predicted secreted proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, UniProt - Evidence at transcript level

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

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)

Position	Role
364

Ligand- & substrate-binding residues (3)

Position	Role
363	Zn(2+)
367	Zn(2+)
373	Zn(2+)

Disulfide bonds (11)

Type	Positions
Disulfide bond	294–347, 323–329, 341–424, 379–408, 452–477, 463–486, 472–507, 501–512, 538–575, 542–580, 553–565

Glycosylation sites (5)

Type	Positions
N-linked (glcnac…) asparagine	344, 400, 465, 490, 599

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 11; 5 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

11 pathways:

ID	Pathway	Evidence
R-HSA-5083635	Defective B3GALTL causes PpS ⚕	curated
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-3906995	Diseases associated with O-glycosylation of proteins ⚕	—
R-HSA-3781865	Diseases of glycosylation ⚕	—
R-HSA-5668914	Diseases of metabolism ⚕	—
R-HSA-1474228	Degradation of the extracellular matrix	electronic
R-HSA-1474244	Extracellular matrix organization	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-5173105	O-linked glycosylation	—
R-HSA-597592	Post-translational protein modification	—

MSigDB gene sets: 124 (showing top): MYOGENIN_Q6, GOMF_METALLOPEPTIDASE_ACTIVITY, GCANCTGNY_MYOD_Q6, RACCACAR_AML_Q6, CAGCTG_AP4_Q5, INAMURA_LUNG_CANCER_SCC_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GOMF_GLYCOSAMINOGLYCAN_BINDING, KIM_GASTRIC_CANCER_CHEMOSENSITIVITY, AML1_01, GOMF_SIGNALING_RECEPTOR_BINDING, GOMF_HEPARIN_BINDING, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_PROTEOLYSIS, OSF2_Q6

GO Biological Process (4): proteolysis (GO:0006508), negative regulation of cell population proliferation (GO:0008285), extracellular matrix organization (GO:0030198), transmembrane transport (GO:0055085)

GO Molecular Function (9): metalloendopeptidase activity (GO:0004222), integrin binding (GO:0005178), heparin binding (GO:0008201), metallopeptidase activity (GO:0008237), zinc ion binding (GO:0008270), low-affinity phosphate transmembrane transporter activity (GO:0009673), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (1): extracellular matrix (GO:0031012)

Reactome top-level categories

8 top-level categories:

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

23 GO namespaces:

Category	Terms
protein metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
extracellular structure organization	1
external encapsulating structure organization	1
transport	1
cellular process	1
endopeptidase activity	1
metallopeptidase activity	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
peptidase activity	1
transition metal ion binding	1
phosphate transmembrane transporter activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1
external encapsulating structure	1

Protein interactions and networks

STRING

showing 15 of 580 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAMTS8	COL18A1	P39060	762
ADAMTS8	BCAN	Q96GW7	598
ADAMTS8	ACAN	P16112	476
ADAMTS8	ADAMTS7	Q9UKP4	441
ADAMTS8	EXOC2	Q96KP1	390
ADAMTS8	FMOD	Q06828	390
ADAMTS8	TSR1	Q2NL82	385
ADAMTS8	ADAMTS12	P58397	384
ADAMTS8	IL1A	P01583	381
ADAMTS8	HAPLN2	Q9GZV7	376
ADAMTS8	THBS1	P07996	373
ADAMTS8	SLC13A2	Q13183	367
ADAMTS8	SLC36A2	Q495M3	367
ADAMTS8	MMP11	P24347	366
ADAMTS8	TMPRSS11D	O60235	364

IntAct

Human interaction partners of ADAMTS8 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
DSCR9	physical association	0.000	1

BioGRID (4 interactions; top human partners by supporting records): ADAMTS4 (Negative Genetic), DCAF6 (Proximity Label-MS), DSCR9 (Two-hybrid), PARP16 (Proximity Label-MS)

Disease & clinical

Genetic variants

Variant evidence for ADAMTS8: 173 ClinVar records (1 pathogenic / likely pathogenic); 40 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	158
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
625560	GRCh37/hg19 11q24.2-24.3(chr11:126809705-130289168)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ADAMTS8’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 668):

Position(s)	Effect	Δscore	Sites
11:130406131	acceptor_gain	1.0000
11:130408492	donor_gain	1.0000
11:130408640–130408641	acceptor_loss	1.0000	3
11:130408766–130408767	donor_loss	1.0000	5
11:130408941–130408942	acceptor_loss	1.0000	5
11:130416938–130416939	donor_loss	1.0000	3
11:130417076–130417077	acceptor_loss	1.0000	6
11:130417080	acceptor_gain	1.0000
11:130417085	acceptor_gain	1.0000
11:130419052	donor_loss	1.0000	2

AlphaMissense

1,532 missense substitutions predicted likely pathogenic (of 5,770 scored), across 394 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M392	9	0.862	0.972
D312	8	0.947	0.978
D644	8	0.940	0.991
D228	8	0.926	0.977
D374	8	0.922	0.970
F293	8	0.921	0.988
N745	8	0.911	0.992
F126	8	0.907	0.989
F638	8	0.887	0.983
F74	8	0.880	0.970
H367	8	0.874	0.950
S346	8	0.867	0.993
D352	8	0.861	0.961
H363	8	0.841	0.943
D621	8	0.767	0.906
H373	8	0.751	0.883
D418	8	0.712	0.861
C656	7	0.997	0.998
C592	7	0.996	0.999
C623	7	0.996	0.999

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Uterine Corpus Endometrial Carcinoma)

Disease associations

OMIM: gene MIM:605175 | disease phenotypes:

GWAS associations

showing 30 of 40 associations:

Study	Trait	p-value
GCST007096_134	Pulse pressure	8e-69
GCST011390_5	Corneal resistance factor	5e-54
GCST006168_11	Pulse pressure x alcohol consumption interaction (2df test)	1e-52
GCST006168_35	Pulse pressure x alcohol consumption interaction (2df test)	7e-48
GCST011391_4	Corneal hysteresis	6e-30
GCST90000654_24	Central corneal thickness	3e-29
GCST009724_18	Vertical cup-disc ratio (multi-trait analysis)	2e-28
GCST005667_1	Central corneal thickness	1e-26
GCST005580_61	Intraocular pressure	4e-25
GCST009723_24	Vertical cup-disc ratio (adjusted for vertical disc diameter)	1e-21
GCST007097_46	Pulse pressure	3e-21
GCST90011770_57	Glaucoma (primary open-angle)	1e-20
GCST007097_47	Pulse pressure	3e-17
GCST005580_88	Intraocular pressure	4e-17
GCST011496_7	Abdominal aortic aneurysm	7e-16
GCST007099_125	Systolic blood pressure	6e-15
GCST007094_2	Diastolic blood pressure	1e-12
GCST004775_31	Pulse pressure	2e-12
GCST009412_11	Vertical cup-disc ratio	1e-11
GCST010703_66	Brain morphology (MOSTest)	3e-10
GCST90020025_1379	Waist-to-hip ratio adjusted for BMI	7e-10
GCST009414_21	Central corneal thickness	2e-9
GCST90020027_347	Waist-hip index	2e-9
GCST90020028_1499	Hip circumference adjusted for BMI	2e-9
GCST004075_1	Vertical cup-disc ratio	3e-9
GCST008276_3	Corneal resistance factor	3e-9
GCST008277_2	Corneal hysteresis	4e-9
GCST002626_9	Vertical cup-disc ratio	5e-9
GCST004075_2	Vertical cup-disc ratio	7e-9
GCST004074_6	Intraocular pressure	2e-8

EFO canonical traits (from GWAS)

14 canonical traits:

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0004695	intraocular pressure measurement
EFO:0006939	cup-to-disc ratio measurement
EFO:0005213	central corneal thickness
EFO:0004329	alcohol drinking
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:1002040	Corneal astigmatism
EFO:0010067	corneal resistance factor
EFO:0010066	corneal hysteresis
EFO:0010446	2-hydroxyglutaric acid measurement
EFO:0004346	neuroimaging measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M12: Astacin/Adamalysin

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, increases expression, decreases expression	3
Progesterone	affects cotreatment, increases expression, decreases expression	3
Acetaminophen	decreases expression, increases expression	2
Doxorubicin	increases expression	2
Nickel	increases expression	2
bisphenol A	decreases methylation, affects cotreatment, increases methylation	1
sodium arsenite	affects methylation	1
butyraldehyde	increases expression	1
aflatoxin B2	increases methylation	1
pentanal	increases expression	1
rofecoxib	affects expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
abrine	decreases expression	1
bisphenol S	increases methylation	1
(+)-JQ1 compound	decreases expression	1
Decitabine	affects expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	affects expression	1
Ibuprofen	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
8-Bromo Cyclic Adenosine Monophosphate	decreases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

2 trials:

NCT	Phase	Status	Title
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes