ADAM8

Summary

ADAM8 (ADAM metallopeptidase domain 8, HGNC:215) is a protein-coding gene on chromosome 10q26.3, encoding Disintegrin and metalloproteinase domain-containing protein 8 (P78325). Possible involvement in extravasation of leukocytes.

This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The protein encoded by this gene may be involved in cell adhesion during neurodegeneration, and it is thought to be a target for allergic respiratory diseases, including asthma. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 101 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 248 total — 22 pathogenic, 3 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001109

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:215
Approved symbol	ADAM8
Name	ADAM metallopeptidase domain 8
Location	10q26.3
Locus type	gene with protein product
Status	Approved
Aliases	CD156, MS2, CD156A
Ensembl gene	ENSG00000151651
Ensembl biotype	protein_coding
OMIM	602267
Entrez	101

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 9 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000415217, ENST00000445355, ENST00000463298, ENST00000468964, ENST00000485491, ENST00000486609, ENST00000537099, ENST00000559018, ENST00000559180, ENST00000560135, ENST00000561175, ENST00000897045, ENST00000897046, ENST00000897047, ENST00000897048, ENST00000916032

RefSeq mRNA: 3 — MANE Select: NM_001109 NM_001109, NM_001164489, NM_001164490

CCDS: CCDS31319, CCDS58102, CCDS58103

Canonical transcript exons

ENST00000445355 — 23 exons

Exon	Start	End
ENSE00001893770	133262423	133263233
ENSE00002431587	133271806	133271954
ENSE00002466382	133270881	133271070
ENSE00002475412	133271528	133271705
ENSE00002490565	133268748	133268862
ENSE00002499610	133269897	133269974
ENSE00002501184	133269445	133269529
ENSE00002519127	133270736	133270805
ENSE00002521112	133267929	133268118
ENSE00002524787	133270360	133270510
ENSE00002535778	133271200	133271289
ENSE00003460874	133276772	133276868
ENSE00003470045	133273762	133273838
ENSE00003476925	133263688	133263765
ENSE00003489193	133274159	133274235
ENSE00003531507	133273951	133274029
ENSE00003543916	133267352	133267417
ENSE00003550483	133272798	133272866
ENSE00003552823	133272193	133272274
ENSE00003561471	133272957	133273019
ENSE00003579082	133272416	133272585
ENSE00003653215	133273254	133273443
ENSE00003691035	133275484	133275587

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 98.66.

FANTOM5 (CAGE): breadth broad, TPM avg 13.6373 / max 1419.5952, expressed in 608 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112102	10.7951	576
112101	2.6388	375
112100	0.2034	71

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.66	gold quality
blood	UBERON:0000178	97.17	gold quality
leukocyte	CL:0000738	93.12	gold quality
spleen	UBERON:0002106	93.00	gold quality
monocyte	CL:0000576	92.87	gold quality
mononuclear cell	CL:0000842	92.75	gold quality
bone marrow cell	CL:0002092	92.63	gold quality
pancreatic ductal cell	CL:0002079	92.52	silver quality
periodontal ligament	UBERON:0008266	91.46	silver quality
vermiform appendix	UBERON:0001154	89.62	gold quality
bone marrow	UBERON:0002371	88.84	gold quality
upper lobe of left lung	UBERON:0008952	87.91	gold quality
right lung	UBERON:0002167	87.69	gold quality
upper lobe of lung	UBERON:0008948	86.81	gold quality
oocyte	CL:0000023	86.52	gold quality
caecum	UBERON:0001153	85.33	gold quality
secondary oocyte	CL:0000655	85.08	gold quality
trabecular bone tissue	UBERON:0002483	84.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.86	gold quality
right lobe of liver	UBERON:0001114	84.31	gold quality
amniotic fluid	UBERON:0000173	83.23	silver quality
lymph node	UBERON:0000029	83.21	gold quality
epithelium of nasopharynx	UBERON:0001951	82.91	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.59	gold quality
left uterine tube	UBERON:0001303	82.54	gold quality
gall bladder	UBERON:0002110	81.77	gold quality
endometrium epithelium	UBERON:0004811	81.66	silver quality
cervix squamous epithelium	UBERON:0006922	81.47	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.75	gold quality
mucosa of urinary bladder	UBERON:0001259	80.61	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	79.91
E-MTAB-9067	yes	15.75
E-CURD-112	yes	11.42
E-ANND-3	yes	9.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting ADAM8, 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-4283	100.00	66.42	2097
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-129-1-3P	98.86	68.41	779
HSA-MIR-129-2-3P	98.86	68.41	779
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-4294	97.86	65.72	1110
HSA-MIR-4741	97.69	64.14	883
HSA-MIR-4675	97.69	64.82	774
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-596	97.48	63.13	469
HSA-MIR-342-5P	97.25	64.10	817
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-4484	96.35	64.08	382
HSA-MIR-10396B-5P	94.99	63.57	358

Literature-anchored findings (GeneRIF, showing 40)

• Overexpression of ADAM8 is associated with lung cancer progression (PMID:15623614)
• ADAM8 may contribute to the airway remodeling process that occurs with asthma progression. (PMID:17339047)
• All these data support a potential relevant role for ADAM-8 in the function of neutrophils during inflammatory response. (PMID:17548643)
• ADAM8 is overexpressed in pancreatic ductal adenocarcinoma, influences cancer cell invasiveness and correlates with reduced survival. (PMID:17979891)
• ADAM8 may have a role as a hypoxia-dependent protein in the pathogenesis and evolution of pancreatic cancer (PMID:18566576)
• ADAM8 might be a therapeutic target for allergic respiratory diseases. (PMID:18691140)
• ADAM8 and EGFR are overexpressed in non-small cell lung cancer. (PMID:18710625)
• Autoactivation of ADAM8: a novel pre-processing step is required for catalytic activity. (PMID:18811590)
• ADAM8 is up-regulated upon formation of multinuclear giant cells after HPIV2 induction. (PMID:19284887)
• The structure, function & expression of ADAM8 and its role in asthma are reviewed. Review. (PMID:19397475)
• Increasing trend for ADAM8 expression is associated with early to advanced stages of myelodysplastic syndrome. (PMID:19469654)
• ADAM8 is a promising candidate to be involved in atherosclerosis, and its 2662 T/G allelic variant significantly associates with advanced atherosclerotic lesion areas and myocardial infarction. (PMID:19575316)
• ADAM-8 as a fibronectinase in human osteoarthritis chondrocytes. (PMID:19714641)
• the effects of pH on substrate cleavage by ADAM8 beyond autocatalysis (PMID:19766586)
• expression of truncated forms of ADAM8 by the lung cancer cells may result in the specific upregulation of their invasive and osteoclastogenic activities in the bone microenvironment (PMID:20453887)
• It regulates onset of blood circulation. (review) (PMID:21077325)
• variation in the ADAM8 gene may affect serum sADAM8 concentrations and the risk of myocardial infarction (PMID:21640993)
• increased expression in allergic rhinitis (PMID:21679521)
• gene expressions for ADAM8 and ADAM15 were notably lower in ascending aorta as compared with aortic dissection (PMID:21728902)
• These findings suggest for the first time that ADAM8 is frequently overexpressed in human gliomas and is closely associated with poor clinical outcome. (PMID:21983884)
• Upregulation of a disintegrin and metalloprotease 8 influences tumor metastasis with osteosarcoma. (PMID:22215309)
• ADAM8 is both associated with PSGL-1 through the ezrin-radixin-moesin actin-binding proteins and able to cause the proteolytic cleavage of this adhesion receptor. (PMID:22229154)
• ADAM8 was highly expressed in 54.3% of hepatocellular carcinoma patients. ADAM8 expression was closely associated with tumor size, histological differentiation, recurrence, metastasis, and stage. High levels of ADAM8 resulted in poor prognosis. (PMID:22878099)
• High expression of ADAM8 is associated with hepatocellular carcinoma. (PMID:22941466)
• ADAM8 mRNA & protein were highly expressed in medulloblastoma tissues when compared with normal cerebellum. This correlated with advanced stage, aggressive type, undifferentiated tumor & decreased survival. (PMID:22959284)
• We used immunohistochemistry to compare ADAM8 protein expression in HCC and normal liver tissues and further analyze the ADAM8 protein expression in 105 HCC cases. Studied knocked down expression of ADAM8 in HepG2 cells. (PMID:22965687)
• ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients (PMID:23670189)
• ADAM8 expression is increased in both severe asthma and COPD and associated with sputum total cell count and neutrophils. ADAM8 may facilitate neutrophil migration to the airways in severe asthma and COPD. (PMID:24147597)
• Data show that Cu2+-generated reactive oxygen species (ROS), human ADAM8, ADAM10, and ADAM17 are all capable of cleaving mouse PrP (MoPrP). (PMID:24247244)
• ADAM8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue. (PMID:24375628)
• High ADAM8 expression is associated with pancreatic adenocarcinoma. (PMID:24526468)
• Data indicate that fibronectin fragments (FN-fs) are present in adult ntervertebral disc (IVD) from adult subjects, and ADAM-8, known to cleave FN, is present at the pericellular matrix of disc cells. (PMID:25010013)
• Results show that ADAM8 is overexpressed in colorectal cancer and promotes cell growth. (PMID:25098630)
• N-glycosylation is essential for processing, localization, stability, and activity of ADAM8. (PMID:25336660)
• ADAM8 and endostatin play a role in osteosarcoma progression. (PMID:25481287)
• ADAM8 expression is associated with increased migration and invasiveness of pancreatic ductal adenocarcinoma cells. (PMID:25629724)
• ADAM8 causes temozolomide resistance in glioblastoma cells by enhancing pAkt/PI3K, pERK1/2, and cleavage of CD44 and HGF R/c-met (PMID:25825051)
• ADAM8 promotes GC cell proliferation and invasion, and its expression is positively correlated with poor survival, indicating that it might be a promising target in GC therapy (PMID:26024798)
• miR-720 is elevated in serum of patients with ADAM8-high TNBC and, in a group with other miRNAs downstream of ADAM8, holds promise as a biomarker for early detection of or treatment response of ADAM8-positive triple-negative breast cancer (PMID:27039296)
• ADAM8 on leukocytes holds a proinflammatory function in acute lung inflammation by promoting alveolar leukocyte recruitment. (PMID:28596294)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	adam8a	ENSDARG00000001452
danio_rerio	adam8b	ENSDARG00000057644
mus_musculus	Adam8	ENSMUSG00000025473
rattus_norvegicus	Adam8	ENSRNOG00000017897

Paralogs (20): ADAM22 (ENSG00000008277), ADAM28 (ENSG00000042980), ADAM7 (ENSG00000069206), ADAM11 (ENSG00000073670), ADAM2 (ENSG00000104755), ADAM23 (ENSG00000114948), ADAM20 (ENSG00000134007), ADAMDEC1 (ENSG00000134028), ADAM30 (ENSG00000134249), ADAM19 (ENSG00000135074), ADAM10 (ENSG00000137845), ADAM21 (ENSG00000139985), ADAM15 (ENSG00000143537), ADAM12 (ENSG00000148848), ADAM33 (ENSG00000149451), ADAM17 (ENSG00000151694), ADAM29 (ENSG00000168594), ADAM9 (ENSG00000168615), ADAM18 (ENSG00000168619), ADAM32 (ENSG00000197140)

Protein

Protein identifiers

Disintegrin and metalloproteinase domain-containing protein 8 — P78325 (reviewed: P78325)

Alternative names: Cell surface antigen MS2

All UniProt accessions (3): P78325, H0YKZ1, H0YMT6

UniProt curated annotations — full annotation on UniProt →

Function. Possible involvement in extravasation of leukocytes.

Subunit / interactions. Interacts with FST3.

Subcellular location. Membrane.

Tissue specificity. Expressed on neutrophils and monocytes.

Cofactor. Binds 1 zinc ion per subunit.

Isoforms (3)

UniProt ID	Names	Canonical?
P78325-1	1	yes
P78325-2	2
P78325-3	3

RefSeq proteins (3): NP_001100, NP_001157961, NP_001157962 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR001590	Peptidase_M12B	Domain
IPR001762	Disintegrin_dom	Domain
IPR002870	Peptidase_M12B_N	Domain
IPR006586	ADAM_Cys-rich	Domain
IPR018358	Disintegrin_CS	Conserved_site
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR034027	Reprolysin_adamalysin	Domain
IPR036436	Disintegrin_dom_sf	Homologous_superfamily

Pfam: PF00200, PF01421, PF01562, PF08516

UniProt features (63 total): disulfide bond 12, helix 8, splice variant 6, sequence variant 6, sequence conflict 5, strand 5, glycosylation site 4, binding site 3, domain 3, compositionally biased region 2, topological domain 2, region of interest 2, signal peptide 1, chain 1, active site 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4DD8	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78325-F1	74.28	0.34

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): 335

Ligand- & substrate-binding residues (3): 334; 338; 344

Disulfide bonds (12): 310–395, 351–379, 353–362, 435–457, 448–454, 466–486, 473–503, 498–508, 566–613, 613–623, 617–629, 631–640

Glycosylation sites (4): 67, 91, 436, 612

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-6798695	Neutrophil degranulation
R-HSA-1474244	Extracellular matrix organization
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 496 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_MATURATION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_LYMPHOCYTE_APOPTOTIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, GNF2_MSN, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION

GO Biological Process (32): cell morphogenesis (GO:0000902), angiogenesis (GO:0001525), leukocyte migration involved in inflammatory response (GO:0002523), positive regulation of acute inflammatory response (GO:0002675), positive regulation of cellular extravasation (GO:0002693), proteolysis (GO:0006508), inflammatory response (GO:0006954), canonical NF-kappaB signal transduction (GO:0007249), positive regulation of epithelial to mesenchymal transition (GO:0010718), positive regulation of protein processing (GO:0010954), regulation of cell-cell adhesion (GO:0022407), extracellular matrix disassembly (GO:0022617), signal release (GO:0023061), positive regulation of T cell differentiation in thymus (GO:0033089), positive regulation of MAPK cascade (GO:0043410), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of innate immune response (GO:0045089), positive regulation of bone resorption (GO:0045780), positive regulation of cell adhesion (GO:0045785), lymphocyte chemotaxis (GO:0048247), positive regulation of protein secretion (GO:0050714), positive regulation of membrane protein ectodomain proteolysis (GO:0051044), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive regulation of thymocyte apoptotic process (GO:0070245), cellular response to hypoxia (GO:0071456), cell-cell adhesion (GO:0098609), positive regulation of tumor necrosis factor (ligand) superfamily member 11 production (GO:2000309), positive regulation of neutrophil extravasation (GO:2000391), positive regulation of fibronectin-dependent thymocyte migration (GO:2000415), positive regulation of eosinophil migration (GO:2000418), positive regulation of inflammatory response (GO:0050729), positive regulation of T cell migration (GO:2000406)

GO Molecular Function (12): metalloendopeptidase activity (GO:0004222), serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), metallopeptidase activity (GO:0008237), zinc ion binding (GO:0008270), tumor necrosis factor receptor superfamily binding (GO:0032813), immunoglobulin receptor binding (GO:0034987), cell adhesion molecule binding (GO:0050839), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (13): podosome (GO:0002102), cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell surface (GO:0009986), phagolysosome (GO:0032010), dense core granule membrane (GO:0032127), specific granule membrane (GO:0035579), specific granule (GO:0042581), tertiary granule (GO:0070820), tertiary granule membrane (GO:0070821), alpha9-beta1 integrin-ADAM8 complex (GO:0071133), ficolin-1-rich granule membrane (GO:0101003), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Extracellular matrix organization	1
Innate Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
secretory granule membrane	4
cellular anatomical structure	3
positive regulation of multicellular organismal process	2
regulation of cell adhesion	2
endopeptidase activity	2
secretory granule	2
tertiary granule	2
anatomical structure morphogenesis	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
inflammatory response	1
leukocyte migration	1
acute inflammatory response	1
regulation of acute inflammatory response	1
positive regulation of inflammatory response	1
positive regulation of leukocyte migration	1
regulation of cellular extravasation	1
cellular extravasation	1
protein metabolic process	1
defense response	1
intracellular signaling cassette	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of cell differentiation	1
protein processing	1
positive regulation of proteolysis	1
regulation of protein processing	1
positive regulation of protein maturation	1
cell-cell adhesion	1
cellular component disassembly	1
extracellular matrix organization	1
cell-cell signaling	1
secretion by cell	1
T cell differentiation in thymus	1
regulation of T cell differentiation in thymus	1
positive regulation of T cell differentiation	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
negative regulation of apoptotic process	1

Protein interactions and networks

STRING

1444 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM8	MRPL13	Q9BYD1	825
ADAM8	ASB17	Q8WXJ9	724
ADAM8	CP	P00450	692
ADAM8	TGM6	O95932	552
ADAM8	ASB2	Q96Q27	543
ADAM8	EIF3J	O75822	497
ADAM8	ATP2A1	O14983	452
ADAM8	PTAFR	P25105	452
ADAM8	SRC	P12931	434
ADAM8	MMP28	Q9H239	410
ADAM8	MMP9	P14780	408
ADAM8	ADAM10	O14672	391
ADAM8	MMP25	Q9NPA2	386
ADAM8	UTF1	Q5T230	376
ADAM8	ORMDL2	Q53FV1	369

IntAct

17 interactions, top by confidence:

A	B	Type	Score
ADAM8	FNBP1L	psi-mi:“MI:0407”(direct interaction)	0.560
ADAM8	TRIP10	psi-mi:“MI:0407”(direct interaction)	0.560
ADAM8	TEC	psi-mi:“MI:0407”(direct interaction)	0.560
ADAM8	NCF1	psi-mi:“MI:0407”(direct interaction)	0.560
ADAM8	SNX33	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM8	SNX9	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM8	SRC	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM8	OSTF1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM8	SNX18	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM8	FNBP1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM8	FST	psi-mi:“MI:0407”(direct interaction)	0.440
FSTL3	ADAM8	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (5): ADAM8 (Co-fractionation), ADAM8 (Affinity Capture-RNA), ADAM8 (Proximity Label-MS), ADAM8 (Cross-Linking-MS (XL-MS)), ADAM8 (Protein-RNA)

ESM2 similar proteins: O35674, O43184, O43506, O75173, O88839, O95450, P57110, P58459, P59384, P59511, P70505, P78325, P79331, P97857, Q05910, Q13443, Q13444, Q14114, Q1EHB3, Q4VC17, Q5RFQ8, Q60813, Q61072, Q61824, Q62179, Q64151, Q68SA9, Q69Z28, Q8BNJ2, Q8C9W3, Q8TE57, Q8TE58, Q8TE60, Q8WXS8, Q924X6, Q9ESP7, Q9H013, Q9H324, Q9JI76, Q9JLN6

Diamond homologs: A0A0B4U9L8, A0A6B7FMR5, A2CJE2, A2CJE3, A2CJE4, A3R0T9, A4PBQ9, A8QL48, A8QL49, A8QL59, B8K1W0, C0LZJ5, C5H5D1, C5H5D2, C5H5D3, C5H5D4, C5H5D5, C5H5D6, C9E1R8, C9E1S0, D3TTC1, D3TTC2, D5LMJ3, D6PXE8, D8VNS0, F8RKV9, F8RKW0, F8RKW1, F8S108, G5EFD5, J3S829, J3S830, J3SDW6, J3SDW8, O35227, O35674, O42138, O75077, O93517, O93518

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 12 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Clathrin-mediated endocytosis	5	38.7×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
endocytosis	5	39.7×	5e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	3
Uncertain significance	158
Likely benign	47
Benign	5

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
144558	GRCh38/hg38 10q26.2-26.3(chr10:126730896-133620609)x1	Pathogenic
1456992	NC_000010.10:g.(?134916201)(135439108_?)del	Pathogenic
146073	GRCh38/hg38 10q26.3(chr10:132178475-133620674)x1	Pathogenic
146234	GRCh38/hg38 10q26.3(chr10:129549258-133620674)x1	Pathogenic
147736	GRCh38/hg38 10q26.3(chr10:128872419-133564028)x3	Pathogenic
148897	GRCh38/hg38 10q26.3(chr10:129427520-133622588)x1	Pathogenic
149101	GRCh38/hg38 10q26.2-26.3(chr10:128549913-133622588)x1	Pathogenic
1527616	GRCh37/hg19 10q26.2-26.3(chr10:128465436-135427143)	Pathogenic
1527622	GRCh37/hg19 10q26.2-26.3(chr10:129914228-135427143)	Pathogenic
155174	GRCh38/hg38 10q26.2-26.3(chr10:127435985-133622588)x1	Pathogenic
1808640	GRCh37/hg19 10q26.2-26.3(chr10:130043370-135345340)x1	Pathogenic
2685391	GRCh37/hg19 10q26.2-26.3(chr10:128925940-135427143)x1	Pathogenic
3063154	GRCh37/hg19 10q26.3(chr10:131398569-135427143)x1	Pathogenic
395021	GRCh37/hg19 10q26.3(chr10:132468363-135367666)x1	Pathogenic
443505	GRCh37/hg19 10q26.2-26.3(chr10:129007673-135427143)x3	Pathogenic
4682767	GRCh37/hg19 10q26.2-26.3(chr10:128423873-135126133)x1	Pathogenic
4682769	GRCh37/hg19 10q26.3(chr10:131515269-135427143)x1	Pathogenic
57314	GRCh38/hg38 10q26.3(chr10:131457361-133620674)x1	Pathogenic
58825	GRCh38/hg38 10q26.3(chr10:129673966-133613938)x1	Pathogenic
58853	GRCh38/hg38 10q26.3(chr10:131914873-133613938)x1	Pathogenic
58854	GRCh38/hg38 10q26.3(chr10:132475849-133620674)x1	Pathogenic
815387	GRCh37/hg19 10q26.2-26.3(chr10:129381095-135427143)x1	Pathogenic
155695	GRCh38/hg38 10q26.3(chr10:131424682-133613639)x1	Likely pathogenic
442210	GRCh37/hg19 10q26.3(chr10:134624870-135427143)x1	Likely pathogenic
442485	GRCh37/hg19 10q26.2-26.3(chr10:129825453-135427143)x1	Likely pathogenic

SpliceAI

3771 predictions. Top by Δscore:

Variant	Effect	Δscore
10:133268114:CGTTC:C	acceptor_gain	1.0000
10:133268120:T:A	acceptor_loss	1.0000
10:133268742:CCTCA:C	donor_loss	1.0000
10:133268743:CTCA:C	donor_loss	1.0000
10:133268744:TCA:T	donor_loss	1.0000
10:133268745:CACCT:C	donor_loss	1.0000
10:133268747:CCTG:C	donor_gain	1.0000
10:133268858:GGACG:G	acceptor_gain	1.0000
10:133268859:GACG:G	acceptor_gain	1.0000
10:133268860:ACG:A	acceptor_gain	1.0000
10:133268861:CG:C	acceptor_gain	1.0000
10:133268861:CGC:C	acceptor_gain	1.0000
10:133268862:GC:G	acceptor_loss	1.0000
10:133268863:C:A	acceptor_loss	1.0000
10:133268863:C:CC	acceptor_gain	1.0000
10:133268864:T:G	acceptor_loss	1.0000
10:133270354:GCTCA:G	donor_loss	1.0000
10:133270355:CTCAC:C	donor_loss	1.0000
10:133270356:TCAC:T	donor_loss	1.0000
10:133270358:A:AC	donor_gain	1.0000
10:133270359:C:CA	donor_loss	1.0000
10:133270359:C:CC	donor_gain	1.0000
10:133270359:CCTT:C	donor_gain	1.0000
10:133270506:CAGCC:C	acceptor_gain	1.0000
10:133270512:T:A	acceptor_loss	1.0000
10:133270802:CCAC:C	acceptor_gain	1.0000
10:133270803:CACC:C	acceptor_gain	1.0000
10:133270805:CCTG:C	acceptor_loss	1.0000
10:133270806:CTGTG:C	acceptor_loss	1.0000
10:133270967:T:A	donor_gain	1.0000

AlphaMissense

5353 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:133271685:A:C	F376C	0.997
10:133271672:G:C	S380R	0.995
10:133271672:G:T	S380R	0.995
10:133271674:T:G	S380R	0.995
10:133271684:G:C	F376L	0.994
10:133271684:G:T	F376L	0.994
10:133271686:A:G	F376L	0.994
10:133269488:C:A	W635C	0.993
10:133269488:C:G	W635C	0.993
10:133271270:C:G	C435S	0.993
10:133271271:A:T	C435S	0.993
10:133271900:G:C	H338D	0.993
10:133272246:C:A	G302W	0.993
10:133270484:C:G	C554S	0.992
10:133270485:A:T	C554S	0.992
10:133270901:C:G	C515S	0.992
10:133270902:A:T	C515S	0.992
10:133271681:A:C	S377R	0.992
10:133271681:A:T	S377R	0.992
10:133271682:C:A	S377I	0.992
10:133271683:T:G	S377R	0.992
10:133271820:C:A	M364I	0.992
10:133271820:C:G	M364I	0.992
10:133271820:C:T	M364I	0.992
10:133271915:C:G	A333P	0.992
10:133270373:C:G	C591S	0.991
10:133270374:A:T	C591S	0.991
10:133271547:C:G	C422S	0.991
10:133271548:A:T	C422S	0.991
10:133271912:G:C	H334D	0.991

dbSNP variants (sampled 300 via entrez): RS1000143110 (10:133275409 G>A,T), RS1000248904 (10:133270265 G>A,C,T), RS1000431446 (10:133275213 G>A), RS1001187199 (10:133265663 C>G,T), RS1001426999 (10:133267156 G>A,C), RS1001769343 (10:133278239 C>G,T), RS1001788133 (10:133269421 C>G,T), RS1001818127 (10:133270150 G>A), RS1001914805 (10:133278383 C>T), RS1002147972 (10:133273670 G>A), RS1002148990 (10:133268466 A>C), RS1002270379 (10:133267089 G>A), RS1002438265 (10:133273407 G>A,C), RS1002603390 (10:133266709 A>T), RS1002804739 (10:133268504 C>G,T)

Disease associations

OMIM: gene MIM:602267 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007250_1	Nonunion in individuals with fractures	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009707	fractures, ununited

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5665 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M12: Astacin/Adamalysin

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
INCB3619	Inhibition	6.0	pIC50

ChEMBL bioactivities

24 potent at pChembl≥5 of 24 total, top 24 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.92	IC50	12	nM	CHEMBL2431028
7.39	IC50	41	nM	CHEMBL5267938
7.14	IC50	73	nM	CHEMBL5283335
6.92	IC50	120	nM	CHEMBL2431028
6.85	IC50	142	nM	CHEMBL3828456
6.80	IC50	157	nM	CHEMBL3828497
6.74	IC50	182	nM	CHEMBL3827850
6.72	IC50	192	nM	CHEMBL3827732
6.66	IC50	220	nM	CHEMBL3827980
6.62	IC50	240	nM	CHEMBL3827893
6.59	IC50	256	nM	CHEMBL3827446
6.46	IC50	350	nM	CHEMBL5283335
6.43	IC50	368	nM	CHEMBL3827091
6.42	IC50	378	nM	CHEMBL3827647
6.38	IC50	420	nM	CHEMBL3828432
6.34	IC50	452	nM	CHEMBL3827027
6.25	IC50	567	nM	CHEMBL5276957
6.10	IC50	800	nM	CHEMBL5276957
6.05	IC50	890	nM	CHEMBL3827271
6.00	IC50	1000	nM	CHEMBL434567
5.91	IC50	1245	nM	CHEMBL3828603
5.78	IC50	1645	nM	CHEMBL3827625
5.65	IC50	2250	nM	CHEMBL5575976
5.63	IC50	2345	nM	CHEMBL3827487

PubChem BioAssay actives

23 with measured affinity, of 37 total; 20 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R)-5-(carbamoylamino)-2-[[4-[(3,5-dibromophenyl)methoxy]phenyl]sulfonylamino]-N-hydroxypentanamide	1926173: Inhibition of human recombinant ADAM8 using PepDAB13 as substrate preincubated with enzyme for 45 mins followed by substrate addition and measured for 6 hrs by fluorometric assay	ic50	0.0120	uM
1-N,3-N-bis[4-[[(4R)-4-[[4-[(3,5-dibromophenyl)methoxy]phenyl]sulfonylamino]-5-(hydroxyamino)-5-oxopentyl]amino]-4-oxobutyl]benzene-1,3-dicarboxamide	1926173: Inhibition of human recombinant ADAM8 using PepDAB13 as substrate preincubated with enzyme for 45 mins followed by substrate addition and measured for 6 hrs by fluorometric assay	ic50	0.0410	uM
1-N,3-N-bis[(4R)-4-[[4-[(3,5-dibromophenyl)methoxy]phenyl]sulfonylamino]-5-(hydroxyamino)-5-oxopentyl]benzene-1,3-dicarboxamide	1926173: Inhibition of human recombinant ADAM8 using PepDAB13 as substrate preincubated with enzyme for 45 mins followed by substrate addition and measured for 6 hrs by fluorometric assay	ic50	0.0730	uM
2-[(2S,5S,8S,11S,14S,17R)-2,8-bis(4-aminobutyl)-11-[3-(diaminomethylideneamino)propyl]-17-(hydroxymethyl)-14-(3-methylbutyl)-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	0.1420	uM
2-[(2S,5S,8S,11S,14S,17R)-2,8-bis(4-aminobutyl)-11-[3-(diaminomethylideneamino)propyl]-17-(hydroxymethyl)-14-(2-methylpropyl)-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	0.1570	uM
2-[(2S,5S,8S,11S,14R,17S)-5,17-bis(4-aminobutyl)-8-[3-(diaminomethylideneamino)propyl]-14-(hydroxymethyl)-11-(2-methylpropyl)-3,6,9,12,15,18-hexaoxo-1,4,7,10,13,16-hexazacyclooctadec-2-yl]acetic acid	1314102: Inhibition of recombinant ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 24 hrs by ELISA	ic50	0.1820	uM
2-[(2S,5S,8S,11S,14S,17R)-2,8-bis(4-aminobutyl)-11-[3-(carbamoylamino)propyl]-17-(hydroxymethyl)-14-(2-methylpropyl)-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	0.1920	uM
2-[(2S,5S,8S,11S,14S)-2,8-bis(4-aminobutyl)-11-[3-(diaminomethylideneamino)propyl]-14-(3-methylbutyl)-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	0.2200	uM
2-[(2S,5S,8S,11S,14S,17S)-5,17-bis(4-aminobutyl)-8-[3-(diaminomethylideneamino)propyl]-14-(hydroxymethyl)-11-(2-methylpropyl)-3,6,9,12,15,18-hexaoxo-1,4,7,10,13,16-hexazacyclooctadec-2-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	0.2400	uM
2-[(2S,5S,8S,11S,14S)-2,8-bis(4-aminobutyl)-11-[3-(diaminomethylideneamino)propyl]-14-(2,2-dimethylpropyl)-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	0.2560	uM
2-[(2S,5S,8S,11S,14S,17R)-2,8-bis(4-aminobutyl)-11-[4-(diaminomethylideneamino)butyl]-17-(hydroxymethyl)-14-(2-methylpropyl)-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	0.3680	uM
2-[(2S,5S,8S,11S,14S)-2,8-bis(4-aminobutyl)-14-butyl-11-[3-(diaminomethylideneamino)propyl]-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	0.3780	uM
(2S,5S,8S,11S,14S,17S)-2,8-bis(4-aminobutyl)-5-(carboxymethyl)-11-[3-(diaminomethylideneamino)propyl]-14-(2-methylpropyl)-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadecane-17-carboxylic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	0.4200	uM
2-[(2S,5S,8S,11S,14S)-2,8-bis(4-aminobutyl)-11-[3-(diaminomethylideneamino)propyl]-3,6,9,12,15,19-hexaoxo-14-propyl-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	0.4520	uM
(2R)-2-[[4-[(3,5-dibromophenyl)methoxy]phenyl]sulfonylamino]-5-[[(4R)-4-[[4-[(3,5-dibromophenyl)methoxy]phenyl]sulfonylamino]-5-(hydroxyamino)-5-oxopentyl]carbamoylamino]-N-hydroxypentanamide	1926173: Inhibition of human recombinant ADAM8 using PepDAB13 as substrate preincubated with enzyme for 45 mins followed by substrate addition and measured for 6 hrs by fluorometric assay	ic50	0.5670	uM
2-[(2S,5S,8S,11S,14S)-2,8-bis(4-aminobutyl)-11-[3-(carbamoylamino)propyl]-14-(2-methylpropyl)-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	0.8900	uM
methyl (6S,7S)-7-(hydroxycarbamoyl)-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-azaspiro[2.5]octane-5-carboxylate	344631: Inhibition of ADAM8	ic50	1.0000	uM
2-[(2S,5S,8S,11S,14S,17R)-2,8-bis(4-aminobutyl)-11-[3-[[amino(nitramido)methylidene]amino]propyl]-17-(hydroxymethyl)-14-(2-methylpropyl)-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	1.2450	uM
2-[(2S,5S,8S,11S,14S)-2,8-bis(4-aminobutyl)-11-[3-(diaminomethylideneamino)propyl]-14-(2-methylpropyl)-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	1.6450	uM
2-[(2S,5S,8S,11S,14S)-2,8-bis(4-aminobutyl)-11-[3-[[amino(nitramido)methylidene]amino]propyl]-14-(2-methylpropyl)-3,6,9,12,15,19-hexaoxo-1,4,7,10,13,16-hexazacyclononadec-5-yl]acetic acid	1314103: Inhibition of ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 6 hrs by ELISA	ic50	2.3450	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, increases expression	3
Silicon Dioxide	increases expression	3
sodium arsenite	decreases expression, increases expression	2
Ozone	affects expression, increases abundance, increases expression	2
Rotenone	decreases expression, increases expression	2
Particulate Matter	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
peficitinib	decreases reaction, increases expression, increases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	decreases expression	1
deguelin	decreases expression	1
entinostat	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
pyrachlostrobin	decreases expression	1
picoxystrobin	decreases expression	1
Temozolomide	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Calcitriol	decreases expression	1
Endosulfan	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Methotrexate	decreases expression	1
Nickel	increases expression	1
Phenytoin	decreases expression	1
Smoke	decreases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, affects expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3829986	Binding	Inhibition of recombinant ADAM8 (unknown origin) expressed in African green monkey COS7 cells co-expressing CD23 assessed as inhibition of CD23 shedding after 24 hrs by ELISA	Synthesis and biological evaluation of analogues of the potent ADAM8 inhibitor cyclo(RLsKDK) for the treatment of inflammatory diseases and cancer metastasis. — Bioorg Med Chem

Clinical trials (associated diseases)

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