ADAM12

Summary

ADAM12 (ADAM metallopeptidase domain 12, HGNC:190) is a protein-coding gene on chromosome 10q26.2, encoding Disintegrin and metalloproteinase domain-containing protein 12 (O43184). Involved in skeletal muscle regeneration, specifically at the onset of cell fusion.

This gene encodes a member of a family of proteins that are 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. Expression of this gene has been used as a maternal serum marker for pre-natal development. Alternative splicing results in multiple transcript variants encoding different isoforms. Shorter isoforms are secreted, while longer isoforms are membrane-bound form.

Source: NCBI Gene 8038 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 159 total — 9 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001288973

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:190
Approved symbol	ADAM12
Name	ADAM metallopeptidase domain 12
Location	10q26.2
Locus type	gene with protein product
Status	Approved
Aliases	MCMPMltna, MLTN
Ensembl gene	ENSG00000148848
Ensembl biotype	protein_coding
OMIM	602714
Entrez	8038

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding_CDS_not_defined, 3 protein_coding

ENST00000368676, ENST00000368679, ENST00000448723, ENST00000467145, ENST00000482291, ENST00000485388, ENST00000494661

RefSeq mRNA: 5 — MANE Select: NM_001288973 NM_001288973, NM_001288974, NM_001288975, NM_003474, NM_021641

CCDS: CCDS7653, CCDS7654, CCDS91373

Canonical transcript exons

ENST00000448723 — 23 exons

Exon	Start	End
ENSE00000987786	126118038	126118224
ENSE00000987787	126109775	126109840
ENSE00000987790	126098416	126098500
ENSE00000987792	126071477	126071654
ENSE00001016207	126038241	126038349
ENSE00001016209	126278915	126278988
ENSE00001016214	126043040	126043148
ENSE00001016215	126101072	126101241
ENSE00001016218	126036146	126036325
ENSE00001016219	126046055	126046132
ENSE00001099930	126049561	126049669
ENSE00001099950	126049253	126049451
ENSE00001190983	126039294	126039429
ENSE00001191046	126330412	126330509
ENSE00001191056	126019695	126019825
ENSE00001370088	126093985	126094133
ENSE00001384099	126135584	126135660
ENSE00003491013	126155227	126155305
ENSE00003493807	126066717	126066806
ENSE00003562372	126064806	126065001
ENSE00003670886	126108593	126108664
ENSE00003916311	126012391	126017339
ENSE00003920818	126388058	126388477

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 97.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.4673 / max 3898.3730, expressed in 1000 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111957	11.8711	814
111953	4.4096	745
111958	2.0548	460
111954	1.7954	578
111952	0.6717	373
111956	0.3467	165
111955	0.1863	93
111924	0.1316	67

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	97.32	gold quality
stromal cell of endometrium	CL:0002255	95.53	gold quality
buccal mucosa cell	CL:0002336	90.09	gold quality
tibia	UBERON:0000979	90.04	gold quality
type B pancreatic cell	CL:0000169	85.99	gold quality
olfactory bulb	UBERON:0002264	85.49	gold quality
diaphragm	UBERON:0001103	81.83	gold quality
decidua	UBERON:0002450	81.75	gold quality
mucosa of paranasal sinus	UBERON:0005030	81.21	gold quality
cartilage tissue	UBERON:0002418	81.11	gold quality
gall bladder	UBERON:0002110	81.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.98	gold quality
hair follicle	UBERON:0002073	78.07	gold quality
endometrium	UBERON:0001295	77.95	gold quality
cervix squamous epithelium	UBERON:0006922	77.45	gold quality
tendon of biceps brachii	UBERON:0008188	77.40	silver quality
skin of hip	UBERON:0001554	76.95	gold quality
mammary duct	UBERON:0001765	76.02	gold quality
epithelium of mammary gland	UBERON:0003244	75.82	gold quality
smooth muscle tissue	UBERON:0001135	75.53	gold quality
left ovary	UBERON:0002119	75.42	gold quality
periodontal ligament	UBERON:0008266	75.28	gold quality
adipose tissue	UBERON:0001013	75.26	gold quality
thoracic mammary gland	UBERON:0005200	75.14	gold quality
mammary gland	UBERON:0001911	75.06	gold quality
islet of Langerhans	UBERON:0000006	74.72	gold quality
connective tissue	UBERON:0002384	74.58	gold quality
amniotic fluid	UBERON:0000173	74.24	gold quality
ovary	UBERON:0000992	74.19	gold quality
palpebral conjunctiva	UBERON:0001812	74.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	85.34
E-MTAB-6678	yes	18.04
E-ANND-3	yes	9.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1, NFKB, RELA, SKIL

miRNA regulators (miRDB)

265 targeting ADAM12, 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-6867-5P	100.00	82.21	3464
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-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-3120-5P	100.00	65.56	965
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-34A-5P	99.99	71.21	1784

Literature-anchored findings (GeneRIF, showing 40)

• in liver cancers ADAM12 expression is associated with tumor aggressiveness and progression. (PMID:12717386)
• surface expression of ADAM12 alters the organization of the actin cytoskeleton and extracellular matrix (PMID:12915587)
• ADAM12 has a role in proHB-EGF shedding induced by TPA and angiotensin II requires PACSIN3 as an upregulator (PMID:12952982)
• The interaction between ADAM12 and integrin alpha7beta1 may be relevant to muscle development, function, and disease. We also conclude that laminin and the DC domain of ADAM12 represent two functional ligands for integrin alpha7beta1. (PMID:15242759)
• Expression in human colonic cell lines. (PMID:15358598)
• PKCepsilon plays a critical role in the regulation of ADAM12 cell-surface expression (PMID:15364951)
• ADAM 12 is a gelatinase, it can be detected in breast cancer patient urine, and increased urinary levels of this protein correlate with breast cancer progression (PMID:15381692)
• ADAM12m is highly expressed in human glioblastomas and may play a role in the prominent proliferation of the glioblastomas through shedding of heparin-binding epidermal growth factor (PMID:15509542)
• ADAM12 is instrumental in myogenic cell differentiation. (PMID:15574885)
• ADAM12 increases the apoptotic sensitivity of nonneoplastic cells in vitro while rendering tumor cells more resistant to apoptosis. (PMID:15930294)
• p70 s6 kinase is involved in upregulation of ADAM12 gene expression associated with hepatic stellate cell activation during liver injury contributing to liver fibrosis and liver tumor progression. (PMID:16139919)
• Cells deficient in beta1 integrin or overexpressing beta3 integrin can bind human ADAM12 via beta3 integrin. (PMID:16213489)
• the prodomain of human ADAM12-S is an integral domain of the mature molecule and as such might have specific biological functions in the extracellular space (PMID:16455653)
• results provide evidence for an overexpression of ADAM-12 and a lower expression of ADAMTS-1 in non-small-cell lung cancer suggest that these proteases play different functions in cancer progression (PMID:16495931)
• ADAM12-S stimulates bone growth by modulating chondrocyte proliferation and maturation through mechanisms probably involving both metalloprotease and adhesion activities. (PMID:16869727)
• The most significant statistical interaction is between rs3740473, a synonymous single nucleotide polymorphism (SNP) in SH3MD1 and rs11244787, an intronic SNP in ADAM12 (effect size = 2.1 for interaction term, P = 0.006). (PMID:17440933)
• ADAM 12 is an efficient second-trimester marker for Down syndrome. (PMID:17465398)
• ADAM12 contributes to TGFB signaling through interaction with the type II receptor. (PMID:17620406)
• ADAM12 may be a useful addition to early screening for trisomy 18 alongside other chromosomal anomalies, particularly if biochemical screening can occur before 10 weeks. (PMID:17701664)
• data show the possibility of levels of ADAM12s being altered in the first and second trimester of pregnancies with rare aneuploidies (PMID:17987603)
• These results indicate unique enzymatic properties of ADAM12 among the members of the ADAM family of metalloproteinases. (PMID:18081311)
• Breast cancer-associated mutations interfere with the intracellular trafficking of ADAM12 and result in loss of the functional ADAM12 at the cell surface. (PMID:18241035)
• ADAM12s may have the potential as an early screening marker for trisomy (PMID:18264948)
• ADAM12s in addition to being a potential marker of aneuploidy may also be a marker of pre-eclampsia. (PMID:18264967)
• There is a novel function of ADAM-12m in chondrocyte proliferation and cloning in osteoarthritic cartilage through enhanced bioavailability of IGF-1 from the IGF-1-IGFBP-5 complex by selective IGFBP-5 digestion. (PMID:18311789)
• Upregulated expression of ADAM12m by TM4SF3 might play a key role in TM4SF3-mediated invasion and metastasis of esophageal cancer (PMID:18365756)
• Ultra-low levels of ADAM12s in pregnancies affected by trisomy 21 prior to 10 weeks of gestation. (PMID:18382998)
• ADAM12 (a disintegrin and metalloproteinase domain 12) is unlikely to be of much additional value when screening for Trisomy 21 in the period 11-13 weeks (PMID:18395873)
• increased expression of ADAM12 in chronic wounds impairs wound healing through the inhibition of keratinocyte migration. (PMID:18604515)
• RACK1 is an ADAM12 interacting protein with a role in liver fibrogenesis (PMID:18621736)
• human heparanase, an enzyme also linked to tumorigenesis, can promote ADAM12 sheddase activity at the cell surface through cleavage of the inhibitory heparan sulfate (PMID:18801731)
• maternal ADAM12(a disintegrin and metalloproteinase 12) does not provide useful prediction of small for gestational age, preeclampsia, or spontaneous preterm delivery (PMID:18978109)
• Early prediction of fetuses being SGA is feasible with the combination of first trimester PAPP-A, beta-hCG and ADAM12. (PMID:19003798)
• ADAM-12 contributes to enhancing heparin-binding epidermal growth factor (EGF)-like growth factor shedding from plasma membranes leading to increased cell proliferation and reduced apoptosis in this bronchial epithelial cell line. (PMID:19040574)
• Up-regulation of ADAM-12 in airway epithelial cells increased the expression of alpha3 & alpha4 integrins, secretion of CXCL1 and CXCL8, and neutrophil recruitment. It decreased CD47. (PMID:19213876)
• Overexpression of ADAM 10, 12 and 17 immunoreactivity in deep invasion area of BCC indicates that these three proteases may play an important role in the locally invasive and highly destructive growth behavior of basal cell carcinoma (PMID:19278423)
• ADAM12s could be an additional biochemical marker for first-trimester screening for trisomies other than Down syndrome. (PMID:19544290)
• ADAM12-L mRNA expression is an independent prognostic factor in resected stage I lung adenocarcinoma, and is significantly correlated with tumor differentiation stage and postoperative cancer recurrence. (PMID:19544357)
• Four genes previously not examined in that respect in laryngeal carcinoma, occurred to be good markers of the neoplasm. They are: metal-proteinase ADAM12, cyclin-dependent kinase 2-CDK2, kinesin 14-KIF14, suppressor 1 of checkpoint-CHES1. (PMID:19609547)
• Adding ADAM12 as a parameter in Down screening did not cause radical changes in the risk value. (PMID:19736612)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	adam12b	ENSDARG00000079068
danio_rerio	adam12a	ENSDARG00000116062
mus_musculus	Adam12	ENSMUSG00000054555
rattus_norvegicus	Adam12	ENSRNOG00000018384

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), ADAM33 (ENSG00000149451), ADAM8 (ENSG00000151651), ADAM17 (ENSG00000151694), ADAM29 (ENSG00000168594), ADAM9 (ENSG00000168615), ADAM18 (ENSG00000168619), ADAM32 (ENSG00000197140)

Protein

Protein identifiers

Disintegrin and metalloproteinase domain-containing protein 12 — O43184 (reviewed: O43184)

Alternative names: Meltrin-alpha

All UniProt accessions (2): O43184, Q5JRP2

UniProt curated annotations — full annotation on UniProt →

Function. Involved in skeletal muscle regeneration, specifically at the onset of cell fusion. Also involved in macrophage-derived giant cells (MGC) and osteoclast formation from mononuclear precursors.

Subunit / interactions. Interacts with alpha-actinin-2 and with syndecans. Interacts with SH3PXD2A. Interacts with FST3. Interacts with RACK1; the interaction is required for PKC-dependent translocation of ADAM12 to the cell membrane.

Subcellular location. Cell membrane Secreted Secreted Secreted.

Tissue specificity. Isoform 1 is expressed in placenta and skeletal, cardiac, and smooth muscle. Isoform 2 seems to be expressed only in placenta or in embryo and fetus. Both forms were expressed in some tumor cells lines. Not detected in brain, lung, liver, kidney or pancreas.

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

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The cysteine-rich domain supports cell adhesion through syndecans and triggers signaling events that lead to beta-1 integrin-dependent cell spreading. In carcinomas cells the binding of this domain to syndecans does not allow the integrin-mediated cell spreading. The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.

Isoforms (4)

UniProt ID	Names	Canonical?
O43184-1	1, 12L	yes
O43184-2	2, 12S
O43184-3	3
O43184-4	4

RefSeq proteins (5): NP_001275902, NP_001275903, NP_001275904, NP_003465, NP_067673 (=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

Enzyme classification (BRENDA):

• EC 3.4.24.B10 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (44 total): disulfide bond 7, sequence variant 6, glycosylation site 5, splice variant 5, short sequence motif 4, binding site 4, domain 3, topological domain 2, signal peptide 1, propeptide 1, compositionally biased region 1, active site 1, chain 1, modified residue 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43184-F1	72.11	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): 351

Ligand- & substrate-binding residues (4): 179 (in inhibited form); 350; 354; 360

Post-translational modifications (1): 907

Disulfide bonds (7): 325–411, 367–395, 369–378, 482–502, 660–670, 664–676, 678–687

Glycosylation sites (5): 111, 149, 381, 452, 651

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-177929	Signaling by EGFR
R-HSA-8941237	Invadopodia formation
R-HSA-1474244	Extracellular matrix organization
R-HSA-162582	Signal Transduction
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 302 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, MULLIGHAN_NPM1_SIGNATURE_3_UP, FREAC2_01, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOMF_METALLOPEPTIDASE_ACTIVITY, GCANCTGNY_MYOD_Q6, AREB6_03, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, FOXO4_01, MODULE_329, AAAYRNCTG_UNKNOWN

GO Biological Process (5): proteolysis (GO:0006508), cell adhesion (GO:0007155), myoblast fusion (GO:0007520), positive regulation of angiogenesis (GO:0045766), integrin-mediated signaling pathway (GO:0007229)

GO Molecular Function (7): metalloendopeptidase activity (GO:0004222), metallopeptidase activity (GO:0008237), SH3 domain binding (GO:0017124), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (4): extracellular region (GO:0005576), nucleoplasm (GO:0005654), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	1
Extracellular matrix organization	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein metabolic process	1
cellular process	1
syncytium formation by cell-cell fusion	1
myotube differentiation	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
cell surface receptor signaling pathway	1
endopeptidase activity	1
metallopeptidase activity	1
peptidase activity	1
protein domain specific binding	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
nuclear lumen	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1340 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM12	SH3PXD2A	Q5TCZ1	896
ADAM12	TGFBR2	P37173	849
ADAM12	SDC1	P18827	787
ADAM12	ITGA7	Q13683	712
ADAM12	GRB2	P29354	702
ADAM12	HBEGF	Q99075	695
ADAM12	SDC4	P31431	676
ADAM12	LGALS13	Q9UHV8	668
ADAM12	PAPPA	Q13219	665
ADAM12	ITGA9	Q13797	658
ADAM12	PIK3R1	P27986	652
ADAM12	ACTN1	P12814	648
ADAM12	UTRN	P46939	646
ADAM12	FN1	P02751	632
ADAM12	MMP9	P14780	601

IntAct

27 interactions, top by confidence:

A	B	Type	Score
ADAM12	SRC	psi-mi:“MI:0407”(direct interaction)	0.560
ADAM12	LYN	psi-mi:“MI:0407”(direct interaction)	0.560
ADAM12	HCK	psi-mi:“MI:0407”(direct interaction)	0.560
ADAM12	AHI1	psi-mi:“MI:0407”(direct interaction)	0.560
ADAM12	SH3D19	psi-mi:“MI:0915”(physical association)	0.560
SH3D19	ADAM12	psi-mi:“MI:0403”(colocalization)	0.560
SH3D19	ADAM12	psi-mi:“MI:0915”(physical association)	0.560
ADAM12	NPHP1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM12	SH3PXD2A	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM12	SNX33	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM12	SNX9	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM12	GRB2	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM12	FYN	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM12	PIK3R1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM12	ITSN2	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM12	ITSN1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM12	RIMBP2	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM12	KRT8	psi-mi:“MI:0915”(physical association)	0.400
ADAM12	HOXA1	psi-mi:“MI:0915”(physical association)	0.370
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
ATF3	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (53): ADAM12 (Co-fractionation), PACSIN3 (Two-hybrid), ADAM12 (Reconstituted Complex), ADAM12 (Affinity Capture-Western), ADAM12 (Affinity Capture-Western), ILK (Affinity Capture-Western), ADAM12 (Two-hybrid), ADAM12 (Two-hybrid), ADAM12 (Two-hybrid), ADAM12 (Two-hybrid), ADAM12 (Two-hybrid), ADAM12 (Two-hybrid), ADAM12 (Two-hybrid), ADAM12 (Two-hybrid), SLC15A2 (Two-hybrid)

ESM2 similar proteins: A4IIA2, A5A6L1, D3Z5L9, O00622, O43184, O54775, O95388, O95389, P08833, P15473, P17936, P18406, P19336, P21743, P21744, P24591, P24593, P24594, P47876, P47878, P47879, P48745, P51609, P59384, P59511, P97857, Q05717, Q07079, Q28985, Q501P1, Q5XHC5, Q61824, Q64299, Q68SA9, Q6Q484, Q76HP2, Q76HP3, Q8BNJ2, Q8TE58, Q90WV8

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, O43184, O77780, O88839

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ADAM12	up-regulates	SDC4	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 21 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
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	144.2×	2e-08
Regulation of signaling by CBL	5	137.9×	2e-08
Signaling by CSF1 (M-CSF) in myeloid cells	6	115.3×	2e-09
Signaling by SCF-KIT	5	69.0×	4e-07
FCGR3A-mediated phagocytosis	5	52.0×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	5	105.3×	3e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	0
Uncertain significance	117
Likely benign	10
Benign	7

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
144259	GRCh38/hg38 10q26.13-26.3(chr10:125657472-133620674)x1	Pathogenic
150776	GRCh38/hg38 10q26.13-26.3(chr10:125021995-133620609)x1	Pathogenic
152830	GRCh38/hg38 10q26.13-26.3(chr10:125452905-133785874)x3	Pathogenic
1711096	GRCh37/hg19 10q26.13-26.3(chr10:126914469-135427143)x1	Pathogenic
1711099	GRCh37/hg19 10q26.13-26.3(chr10:127198625-135427143)x3	Pathogenic
3063149	GRCh37/hg19 10q26.13-26.3(chr10:126127397-135427143)x1	Pathogenic
442903	GRCh37/hg19 10q26.2-26.3(chr10:127658004-135427143)x1	Pathogenic
563794	GRCh37/hg19 10q26.13-26.3(chr10:127375792-135427143)x1	Pathogenic
58823	GRCh38/hg38 10q26.2-26.3(chr10:126256585-133613938)x1	Pathogenic

SpliceAI

5573 predictions. Top by Δscore:

Variant	Effect	Δscore
10:126017245:T:TA	donor_gain	1.0000
10:126043036:TGA:T	donor_loss	1.0000
10:126043037:GA:G	donor_loss	1.0000
10:126043038:A:AT	donor_loss	1.0000
10:126043039:C:CG	donor_loss	1.0000
10:126043153:C:CT	acceptor_gain	1.0000
10:126043158:C:CT	acceptor_gain	1.0000
10:126043159:A:T	acceptor_gain	1.0000
10:126046053:ACC:A	donor_gain	1.0000
10:126046054:CCC:C	donor_gain	1.0000
10:126049251:A:AC	donor_gain	1.0000
10:126049252:C:CC	donor_gain	1.0000
10:126066802:CATTC:C	acceptor_gain	1.0000
10:126101066:CCCTA:C	donor_loss	1.0000
10:126101067:CCTAC:C	donor_loss	1.0000
10:126101068:CTACC:C	donor_loss	1.0000
10:126101069:TACCT:T	donor_loss	1.0000
10:126101070:A:T	donor_loss	1.0000
10:126101071:C:CA	donor_loss	1.0000
10:126118036:AC:A	donor_gain	1.0000
10:126118037:CC:C	donor_gain	1.0000
10:126118037:CCCTT:C	donor_gain	1.0000
10:126118221:TCCC:T	acceptor_gain	1.0000
10:126118222:CCCC:C	acceptor_gain	1.0000
10:126118224:CCTGT:C	acceptor_gain	1.0000
10:126176730:AATT:A	donor_gain	1.0000
10:126278909:ACTT:A	donor_loss	1.0000
10:126278910:CTT:C	donor_loss	1.0000
10:126278911:TTACT:T	donor_loss	1.0000
10:126278912:TACTC:T	donor_loss	1.0000

AlphaMissense

5952 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:126049335:C:G	C615S	1.000
10:126049336:A:T	C615S	1.000
10:126049425:C:G	C585S	1.000
10:126049426:A:T	C585S	1.000
10:126049629:A:C	N553K	1.000
10:126049629:A:T	N553K	1.000
10:126064813:C:A	W537C	1.000
10:126064813:C:G	W537C	1.000
10:126064825:A:C	C533W	1.000
10:126046113:C:G	C649S	0.999
10:126046114:A:T	C649S	0.999
10:126049334:G:C	C615W	0.999
10:126049335:C:T	C615Y	0.999
10:126049336:A:G	C615R	0.999
10:126049424:A:C	C585W	0.999
10:126049426:A:G	C585R	0.999
10:126049440:C:G	C580S	0.999
10:126049441:A:G	C580R	0.999
10:126049441:A:T	C580S	0.999
10:126049570:C:G	C573S	0.999
10:126049571:A:T	C573S	0.999
10:126049603:C:G	C562S	0.999
10:126049604:A:T	C562S	0.999
10:126049609:C:T	G560D	0.999
10:126049610:C:A	G560C	0.999
10:126049642:A:C	F549C	0.999
10:126049644:G:C	C548W	0.999
10:126049645:C:G	C548S	0.999
10:126049645:C:T	C548Y	0.999
10:126049646:A:G	C548R	0.999

dbSNP variants (sampled 300 via entrez): RS1000016268 (10:126356628 G>A), RS1000037995 (10:126347868 G>C,T), RS1000043766 (10:126276004 C>G,T), RS1000047334 (10:126150198 T>A), RS1000049111 (10:126188831 T>C), RS1000051188 (10:126031050 C>G,T), RS1000051293 (10:126147478 C>T), RS1000052212 (10:126350589 G>A), RS1000060444 (10:126363075 A>G), RS1000076471 (10:126169048 G>A,T), RS1000078207 (10:126115970 C>T), RS1000081045 (10:126023167 G>T), RS1000082638 (10:126185477 C>T), RS1000096799 (10:126270270 A>C,G), RS1000103732 (10:126350470 C>T)

Disease associations

OMIM: gene MIM:602714 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001525_21	Visceral fat	6.000000e-06
GCST001821_9	Metabolite levels (5-HIAA/ MHPG Ratio)	8.000000e-06
GCST001859_27	Thiazide-induced adverse metabolic effects in hypertensive patients	9.000000e-06
GCST002218_2	Endometrial cancer	9.000000e-06
GCST002218_6	Endometrial cancer	8.000000e-06
GCST003030_3	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	1.000000e-06
GCST003124_18	Mild influenza (H1N1) infection	4.000000e-08
GCST003472_6	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	9.000000e-07
GCST003771_18	Loneliness	1.000000e-06
GCST004861_98	Itch intensity from mosquito bite	5.000000e-07
GCST005626_1	Extremely high intelligence	8.000000e-09
GCST005844_8	Placental abruption	4.000000e-06
GCST006394_74	Intraocular pressure	2.000000e-08
GCST006585_189	Blood protein levels	1.000000e-16
GCST006979_614	Heel bone mineral density	7.000000e-14
GCST012295_13	Schizophrenia, bipolar disorder or recurrent major depressive disorder x sex interaction	9.000000e-06
GCST012301_7	Schizophrenia, bipolar disorder or major depressive disorder x sex interaction	6.000000e-06
GCST90000025_185	Appendicular lean mass	2.000000e-10

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0005132	5-HIAA measurement
EFO:0005133	MHPG measurement
EFO:0004230	endometrial neoplasm
EFO:0007679	oppositional defiant disorder measurement
EFO:1001488	influenza A (H1N1)
EFO:0007865	loneliness measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0004337	intelligence
EFO:0004695	intraocular pressure measurement
EFO:0009270	heel bone mineral density
EFO:0004952	disease recurrence
EFO:0008343	sex interaction measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5030 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 12,065 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL19611	ILOMASTAT	2	12,065

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs868589	ADAM12		0.00	0

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
ilomastat	Inhibition	8.23	pIC50

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.23	IC50	5.93	nM	ILOMASTAT
7.78	IC50	16.7	nM	CHEMBL366034
7.61	IC50	24.8	nM	CHEMBL361087
7.39	IC50	40.5	nM	CHEMBL188414
7.37	IC50	42.3	nM	CHEMBL365261

PubChem BioAssay actives

5 with measured affinity, of 8 total; 5 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)-N’-hydroxy-N-[(2S)-3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl]-2-(2-methylpropyl)butanediamide	242091: Inhibition of A disintegrin and metalloprotease domain 12 (ADAM12) binding in cell based assay	ic50	0.0059	uM
2-[[(E)-3-(3-bromophenyl)-2-(furan-2-carbonylamino)prop-2-enoyl]amino]acetic acid	242091: Inhibition of A disintegrin and metalloprotease domain 12 (ADAM12) binding in cell based assay	ic50	0.0167	uM
2-[[(E)-2-[(5-bromofuran-2-carbonyl)amino]-3-(4-bromophenyl)prop-2-enoyl]amino]propanoic acid	242091: Inhibition of A disintegrin and metalloprotease domain 12 (ADAM12) binding in cell based assay	ic50	0.0248	uM
2-[[(E)-2-benzamido-3-(2-fluorophenyl)prop-2-enoyl]amino]-3-methylbutanoic acid	242091: Inhibition of A disintegrin and metalloprotease domain 12 (ADAM12) binding in cell based assay	ic50	0.0405	uM
2-[[(E)-2-(furan-2-carbonylamino)-3-(furan-2-yl)prop-2-enoyl]amino]propanoic acid	242091: Inhibition of A disintegrin and metalloprotease domain 12 (ADAM12) binding in cell based assay	ic50	0.0423	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	4
trichostatin A	increases expression, affects cotreatment, affects expression, decreases expression	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
Progesterone	affects cotreatment, decreases expression	3
entinostat	affects cotreatment, decreases expression	2
belinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Doxorubicin	decreases expression, increases expression	2
Colforsin	decreases expression	2
Nickel	increases expression	2
Valproic Acid	increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
salinomycin	decreases expression	1
arsenite	increases methylation	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
vinclozolin	increases expression	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	decreases methylation	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, affects expression	1
dimethylarsinous acid	increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
abrine	decreases expression	1
pyrachlostrobin	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL830979	Binding	Inhibition of A disintegrin and metalloprotease domain 12 (ADAM12) binding in cell based assay	Structure-based virtual screening and biological evaluation of potent and selective ADAM12 inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8H3	Ubigene HCT 116 ADAM12 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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