ADAM19

Summary

ADAM19 (ADAM metallopeptidase domain 19, HGNC:197) is a protein-coding gene on chromosome 5q33.3, encoding Disintegrin and metalloproteinase domain-containing protein 19 (Q9H013). Participates in the proteolytic processing of beta-type neuregulin isoforms which are involved in neurogenesis and synaptogenesis, suggesting a regulatory role in glial cell.

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. This member is a type I transmembrane protein and serves as a marker for dendritic cell differentiation. It has been demonstrated to be an active metalloproteinase, which may be involved in normal physiological processes such as cell migration, cell adhesion, cell-cell and cell-matrix interactions, and signal transduction. It is proposed to play a role in pathological processes, such as cancer, inflammatory diseases, renal diseases, and Alzheimer’s disease.

Source: NCBI Gene 8728 — RefSeq curated summary.

At a glance

• GWAS associations: 22
• Clinical variants (ClinVar): 169 total — 6 pathogenic
• MANE Select transcript: NM_033274

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:197
Approved symbol	ADAM19
Name	ADAM metallopeptidase domain 19
Location	5q33.3
Locus type	gene with protein product
Status	Approved
Aliases	MLTNB
Ensembl gene	ENSG00000135074
Ensembl biotype	protein_coding
OMIM	603640
Entrez	8728

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000257527, ENST00000517374, ENST00000517905, ENST00000517951, ENST00000519752, ENST00000929677, ENST00000929678, ENST00000957644

RefSeq mRNA: 1 — MANE Select: NM_033274 NM_033274

CCDS: CCDS4338

Canonical transcript exons

ENST00000257527 — 23 exons

Exon	Start	End
ENSE00001211136	157477304	157481002
ENSE00001356773	157481791	157481943
ENSE00003467089	157537913	157537991
ENSE00003480383	157518823	157518888
ENSE00003494398	157530807	157530883
ENSE00003494492	157492973	157493177
ENSE00003498064	157494687	157494795
ENSE00003509832	157502803	157502980
ENSE00003510111	157570895	157570980
ENSE00003532342	157513434	157513505
ENSE00003534297	157509301	157509467
ENSE00003546069	157505669	157505808
ENSE00003584244	157564373	157564443
ENSE00003599313	157496894	157497089
ENSE00003606157	157507056	157507140
ENSE00003613715	157488265	157488489
ENSE00003637737	157519839	157520031
ENSE00003640914	157491835	157491912
ENSE00003669445	157491615	157491723
ENSE00003685680	157489102	157489186
ENSE00003693518	157490310	157490454
ENSE00003694638	157499573	157499662
ENSE00003899522	157575603	157575775

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 93.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.1555 / max 448.3773, expressed in 1356 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64529	20.6482	1337
64528	2.5072	798

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	93.12	gold quality
stromal cell of endometrium	CL:0002255	91.43	gold quality
blood	UBERON:0000178	90.41	gold quality
secondary oocyte	CL:0000655	89.85	gold quality
sural nerve	UBERON:0015488	89.27	gold quality
vermiform appendix	UBERON:0001154	88.96	gold quality
saphenous vein	UBERON:0007318	88.59	gold quality
lymph node	UBERON:0000029	88.15	gold quality
caecum	UBERON:0001153	87.36	gold quality
granulocyte	CL:0000094	86.21	gold quality
placenta	UBERON:0001987	86.17	gold quality
decidua	UBERON:0002450	85.53	gold quality
colonic epithelium	UBERON:0000397	85.52	gold quality
bone marrow cell	CL:0002092	85.09	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.08	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.72	gold quality
lower esophagus	UBERON:0013473	84.66	gold quality
spleen	UBERON:0002106	84.18	gold quality
right atrium auricular region	UBERON:0006631	84.08	gold quality
epithelium of nasopharynx	UBERON:0001951	84.02	gold quality
nasopharynx	UBERON:0001728	84.00	gold quality
Brodmann (1909) area 10	UBERON:0013541	83.82	silver quality
leukocyte	CL:0000738	83.67	gold quality
cardiac atrium	UBERON:0002081	83.65	gold quality
monocyte	CL:0000576	83.25	gold quality
mononuclear cell	CL:0000842	83.21	gold quality
sigmoid colon	UBERON:0001159	83.04	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	82.85	gold quality
paraflocculus	UBERON:0005351	82.55	gold quality
smooth muscle tissue	UBERON:0001135	81.98	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	20.47
E-MTAB-6678	yes	17.31
E-MTAB-9067	yes	15.70
E-GEOD-83139	yes	7.34
E-MTAB-9801	yes	3.81
E-CURD-89	no	698.72

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
CDH1	Activation

Upstream regulators (CollecTRI, top): GLI2, NOTCH1, RBPJ

miRNA regulators (miRDB)

217 targeting ADAM19, 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-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3613-3P	100.00	76.36	7965
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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-150-5P	99.99	66.69	1976

Literature-anchored findings (GeneRIF, showing 30)

• activation by furin via one of two consecutive recognition sites (PMID:12006600)
• investigation of proteolytic activity (PMID:12393862)
• yeast two-hybrid screen performed in fetal brain cDNA library isolated four proteins that interact with the cytoplasmic tail of ADAM19 (PMID:12463424)
• A new autolytic processing site at Lys543-Val544 was identified in soluble mutants of ADAM19 when these cysteine residues were individually mutated to serine residues. (PMID:15242783)
• ChIP assays demonstrated high levels of acetylated histone H3 in the promoter region of the MADDAM gene in TSA-treated THP-1 cells/dendritic cells compared to macrophages, indicating an important role of histone acetylation in regulating the MADDAM gene. (PMID:15896713)
• ADAM19 may have a modulatory role in the dysfunctional renal allograft state (PMID:16827870)
• results suggest that ADAM19 has a constitutive alpha-secretase activity for amyloid precursor protein (PMID:17112471)
• ADAM19 correlates with the progress and prognosis of endometrial carcinoma. (PMID:18458692)
• we suggest that epigenetic dysregulation of ADAM19 may contribute to the neoplastic process in ovarian cancer. (PMID:18714391)
• ADAM19 may participate in the coordinated regulation of human trophoblast cell behaviors during the process of placentation. (PMID:19727588)
• These findings suggest that ADAM19 autolysis is activated by lipopolysaccharide and that ADAM19 promotes the secretion of CRIP2. (PMID:20460109)
• Single nucleotide polymorphisms in ADAM19 gene is associated with lymphoma. (PMID:21239057)
• Prorenin receptor is mainly localized in the subcellular organelles, such as the endoplasmic reticulum and Golgi apparatus, and the prorenin receptor is cleaved by ADAM19 in the Golgi, resulting in two fragments. (PMID:21270819)
• ADAM19 was upregulated in patients with ulcerative colitis and, to a lesser extent, in patients with Crohn’s disease compared with normal controls. In contrast, ADAM9 and ADAM10 expression did not differ between patients with IBD and controls. (PMID:23429442)
• ADAM19 rs1422795 and HTR4 rs11168048 are associated with pulmonary function. (PMID:24951661)
• four suggestive loci (PAX3, CCRN4L, PIGQ, and ADAM19)determinants of disease progression in Alzheimer’s disease. (PMID:25114068)
• MiR-153 has a role in inhibiting migration and invasion of human non-small-cell lung cancer by targeting ADAM19 (PMID:25475731)
• miR-30c inhibited colon cancer cells via targeting ADAM19. (PMID:25799050)
• these findings suggested that miR-145 functions as a tumor suppressor in RB by directly targeting ADAM19 in retinoblastoma cells (PMID:26823772)
• ADAM19 is a protective factor for human prostate cancer. Further, this study suggests that upregulation of ADAM19 expression could be of therapeutic potential in human prostate cancer. (PMID:26912236)
• 3 SNPs (rs4329505 and rs4845626 in interleukin 6 receptor [IL6R] and rs1422794 in a disintegrin and metalloproteinase domain 19 [ADAM19]) were associated with a lower risk of suffering the most severe stages of the disease. (PMID:27078193)
• MiR-874-3p suppresses cell proliferation and invasion by targeting ADAM19 in nasopharyngeal carcinoma. (PMID:31352763)
• ADAM19 hypermethylation was associated with more advanced gastric neoplasm (GC) as stage IV. (PMID:31675985)
• Circular RNA has_circ_0000034 accelerates retinoblastoma advancement through the miR-361-3p/ADAM19 axis. (PMID:32844346)
• Comparison of ADAM19 and CUEDC2 expression in EHCC and their clinicopathological significance. (PMID:32960074)
• The elevated transcription of ADAM19 by the oncohistone H2BE76K contributes to oncogenic properties in breast cancer. (PMID:33548228)
• MicroRNA-874-3p/ADAM (A Disintegrin and Metalloprotease) 19 Mediates Macrophage Activation and Renal Fibrosis After Acute Kidney Injury. (PMID:33775119)
• Synovial mesenchymal stem cell-derived exosomal miR-320c enhances chondrogenesis by targeting ADAM19. (PMID:34927445)
• ADAM19 and TUBB1 Correlate with Tumor Infiltrating Immune Cells and Predicts Prognosis in Osteosarcoma. (PMID:35388751)
• Human umbilical cord mesenchymal stem cell-derived exosomal miR-335-5p attenuates the inflammation and tubular epithelial-myofibroblast transdifferentiation of renal tubular epithelial cells by reducing ADAM19 protein levels. (PMID:35902972)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	adam19b	ENSDARG00000067545
rattus_norvegicus	Adam19	ENSRNOG00000042980

Paralogs (20): ADAM22 (ENSG00000008277), ADAM28 (ENSG00000042980), ADAM7 (ENSG00000069206), ADAM11 (ENSG00000073670), ADAM2 (ENSG00000104755), ADAM23 (ENSG00000114948), ADAM20 (ENSG00000134007), ADAMDEC1 (ENSG00000134028), ADAM30 (ENSG00000134249), ADAM10 (ENSG00000137845), ADAM21 (ENSG00000139985), ADAM15 (ENSG00000143537), ADAM12 (ENSG00000148848), ADAM33 (ENSG00000149451), ADAM8 (ENSG00000151651), ADAM17 (ENSG00000151694), ADAM29 (ENSG00000168594), ADAM9 (ENSG00000168615), ADAM18 (ENSG00000168619), ADAM32 (ENSG00000197140)

Protein

Protein identifiers

Disintegrin and metalloproteinase domain-containing protein 19 — Q9H013 (reviewed: Q9H013)

Alternative names: Meltrin-beta, Metalloprotease and disintegrin dendritic antigen marker

All UniProt accessions (3): E5RIS2, Q9H013, H0YC66

UniProt curated annotations — full annotation on UniProt →

Function. Participates in the proteolytic processing of beta-type neuregulin isoforms which are involved in neurogenesis and synaptogenesis, suggesting a regulatory role in glial cell. Also cleaves alpha-2 macroglobulin. May be involved in osteoblast differentiation and/or osteoblast activity in bone.

Subunit / interactions. Interacts with SH3PXD2A.

Subcellular location. Membrane.

Tissue specificity. Expressed in many normal organ tissues and several cancer cell lines.

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

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. 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.

Induction. By 1,25(OH)2VD3 in monocytes.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H013-1	A	yes
Q9H013-2	B

RefSeq proteins (1): NP_150377* (*=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 (39 total): disulfide bond 7, binding site 4, glycosylation site 4, sequence variant 4, compositionally biased region 3, sequence conflict 3, domain 3, short sequence motif 2, topological domain 2, signal peptide 1, propeptide 1, active site 1, chain 1, splice variant 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H013-F1	69.93	0.33

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): 346

Ligand- & substrate-binding residues (4): 132 (in inhibited form); 345; 349; 355

Disulfide bonds (7): 320–403, 360–387, 361–370, 474–494, 654–664, 658–670, 672–681

Glycosylation sites (4): 144, 444, 447, 645

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-8941237	Invadopodia formation
R-HSA-9762292	Regulation of CDH11 function
R-HSA-1474244	Extracellular matrix organization
R-HSA-1500931	Cell-Cell communication
R-HSA-418990	Adherens junctions interactions
R-HSA-421270	Cell-cell junction organization
R-HSA-446728	Cell junction organization
R-HSA-9759475	Regulation of CDH11 Expression and Function
R-HSA-9759476	Regulation of Homotypic Cell-Cell Adhesion
R-HSA-9764260	Regulation of Expression and Function of Type II Classical Cadherins

MSigDB gene sets: 410 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_REGULATION_OF_CELL_CELL_ADHESION_MEDIATED_BY_CADHERIN, MODULE_45, MODULE_16, CTATGCA_MIR153, LA_MEN1_TARGETS, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, GOBP_CELL_CELL_ADHESION, GTGCCTT_MIR506, MODULE_118, GOBP_PROTEIN_MATURATION, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, BOYLAN_MULTIPLE_MYELOMA_D_CLUSTER_DN

GO Biological Process (7): placenta development (GO:0001890), membrane protein ectodomain proteolysis (GO:0006509), positive regulation of gene expression (GO:0010628), protein processing (GO:0016485), amyloid precursor protein catabolic process (GO:0042987), positive regulation of cell-cell adhesion mediated by cadherin (GO:2000049), proteolysis (GO:0006508)

GO Molecular Function (8): metalloendopeptidase activity (GO:0004222), SH3 domain binding (GO:0017124), metal ion binding (GO:0046872), metalloendopeptidase activity involved in amyloid precursor protein catabolic process (GO:1902945), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Extracellular matrix organization	1
Regulation of CDH11 Expression and Function	1
Cell-cell junction organization	1
Cell junction organization	1
Cell-Cell communication	1
Regulation of Expression and Function of Type II Classical Cadherins	1
Adherens junctions interactions	1
Regulation of Homotypic Cell-Cell Adhesion	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	1
membrane protein proteolysis	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
proteolysis	1
protein maturation	1
amyloid precursor protein metabolic process	1
positive regulation of cell-cell adhesion	1
cell-cell adhesion mediated by cadherin	1
regulation of cell-cell adhesion mediated by cadherin	1
protein metabolic process	1
endopeptidase activity	1
metallopeptidase activity	1
protein domain specific binding	1
cation binding	1
metalloendopeptidase activity	1
amyloid precursor protein catabolic process	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

910 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM19	MAD2L2	Q9UI95	760
ADAM19	REV3L	O60673	672
ADAM19	MAD2L1	Q13257	669
ADAM19	REV1	Q9UBZ9	633
ADAM19	ADAM17	P78536	590
ADAM19	GSTCD	Q8NEC7	584
ADAM19	ITGB5	P18084	575
ADAM19	SNX9	Q9Y5X1	572
ADAM19	ADAM10	O14672	565
ADAM19	FAM13A	O94988	523
ADAM19	METTL14	Q9HCE5	518
ADAM19	SH3PXD2A	Q5TCZ1	516
ADAM19	METTL3	Q86U44	511
ADAM19	EPHA4	P54764	510
ADAM19	INTS12	Q96CB8	477

IntAct

38 interactions, top by confidence:

A	B	Type	Score
ADAM19	SH3PXD2A	psi-mi:“MI:0407”(direct interaction)	0.590
ADAM19	TSPOAP1	psi-mi:“MI:0407”(direct interaction)	0.560
ADAM19	EPS8L1	psi-mi:“MI:0407”(direct interaction)	0.560
ADAM19	ABI2	psi-mi:“MI:0915”(physical association)	0.510
ADAM19	SRC	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM19	SNX9	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM19	NCF1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM19	TEC	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM19	LYN	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM19	PIK3R1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM19	NPHP1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM19	SNX33	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM19	FNBP1L	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM19	HCK	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM19	NCK1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM19	ESF1	psi-mi:“MI:0915”(physical association)	0.370
UBC	ADAM19	psi-mi:“MI:0915”(physical association)	0.370
ADAM19	TSC22D2	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
LY86	TMEM131L	psi-mi:“MI:0914”(association)	0.350
NCR3	POTEF	psi-mi:“MI:0914”(association)	0.350
DNAJB9	POTEF	psi-mi:“MI:0914”(association)	0.350
CFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
MFAP4	QSOX1	psi-mi:“MI:0914”(association)	0.350
ELSPBP1	QSOX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (36): ADAM19 (Two-hybrid), KPTN (Affinity Capture-MS), ITFG2 (Affinity Capture-MS), TSC22D2 (Affinity Capture-MS), HSPA14 (Affinity Capture-MS), TUBB7P (Affinity Capture-MS), TSC22D3 (Affinity Capture-MS), SH3PXD2A (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), GKN2 (Affinity Capture-MS), NRBP1 (Affinity Capture-MS), TSC22D1 (Affinity Capture-MS), THUMPD3 (Affinity Capture-MS), ADAM19 (Affinity Capture-MS)

ESM2 similar proteins: A2VCU8, A6QR11, E1BMV3, O00339, O08746, O15232, O35674, O35701, O42401, O43184, O89029, O95460, P01130, P18337, P19336, P20063, P21743, P21941, P23142, P24591, P47876, P51942, P57110, P58335, P98110, Q08879, Q13219, Q14114, Q14393, Q4VC17, Q501P1, Q53RD9, Q61220, Q61581, Q61824, Q62179, Q62918, Q6AZ60, Q6DFX2, Q6Q484

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

2 interactions.

A	Effect	B	Mechanism
NOTCH	“up-regulates quantity by expression”	ADAM19	“transcriptional regulation”
NOTCH1	“up-regulates quantity by expression”	ADAM19	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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 CSF1 (M-CSF) in myeloid cells	5	61.8×	7e-06
FCGR3A-mediated phagocytosis	5	33.4×	3e-05
VEGFA-VEGFR2 Pathway	5	24.9×	1e-04
Signaling by Receptor Tyrosine Kinases	7	12.9×	6e-05
RHO GTPase cycle	5	10.7×	2e-03
Innate Immune System	10	9.1×	9e-06

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	5	51.4×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	0
Uncertain significance	122
Likely benign	11
Benign	8

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
149231	GRCh38/hg38 5q33.1-34(chr5:152443869-166104392)x1	Pathogenic
1808662	GRCh37/hg19 5q33.1-35.2(chr5:150535183-172906793)x3	Pathogenic
253504	GRCh37/hg19 5q33.2-35.1(chr5:154886174-169757448)x1	Pathogenic
4682633	GRCh37/hg19 5q33.2-34(chr5:154849998-164037131)x1	Pathogenic
58390	GRCh38/hg38 5q33.1-34(chr5:152761187-167248053)x1	Pathogenic
814756	GRCh37/hg19 5q33.3-35.1(chr5:156347980-169959880)x1	Pathogenic

SpliceAI

4431 predictions. Top by Δscore:

Variant	Effect	Δscore
5:157463089:TCCA:T	acceptor_loss	1.0000
5:157463091:CA:C	acceptor_loss	1.0000
5:157463092:AGGT:A	acceptor_loss	1.0000
5:157463330:GCTG:G	donor_gain	1.0000
5:157463332:TGGTA:T	donor_loss	1.0000
5:157463333:GGT:G	donor_loss	1.0000
5:157463334:G:C	donor_loss	1.0000
5:157463335:T:A	donor_loss	1.0000
5:157467047:A:AG	acceptor_gain	1.0000
5:157467048:G:GG	acceptor_gain	1.0000
5:157467106:G:GG	donor_gain	1.0000
5:157468796:C:G	donor_gain	1.0000
5:157471650:C:CA	acceptor_gain	1.0000
5:157471650:C:G	acceptor_gain	1.0000
5:157471655:A:AG	acceptor_gain	1.0000
5:157471656:G:GA	acceptor_gain	1.0000
5:157471656:GT:G	acceptor_gain	1.0000
5:157471656:GTGCC:G	acceptor_gain	1.0000
5:157472327:CAAA:C	acceptor_loss	1.0000
5:157472328:A:AG	acceptor_gain	1.0000
5:157472328:AAAG:A	acceptor_gain	1.0000
5:157472328:AAAGG:A	acceptor_gain	1.0000
5:157472329:AAG:A	acceptor_gain	1.0000
5:157472330:A:G	acceptor_gain	1.0000
5:157472330:AG:A	acceptor_gain	1.0000
5:157472330:AGGGT:A	acceptor_loss	1.0000
5:157472331:G:A	acceptor_gain	1.0000
5:157472331:G:GG	acceptor_gain	1.0000
5:157489096:TCTTA:T	donor_loss	1.0000
5:157489097:CTTAC:C	donor_loss	1.0000

AlphaMissense

6032 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:157493067:C:G	C605S	1.000
5:157493068:A:T	C605S	1.000
5:157493166:C:G	C572S	1.000
5:157493167:A:T	C572S	1.000
5:157494768:A:C	F541C	1.000
5:157505766:G:C	H345D	1.000
5:157491667:G:C	C681W	0.999
5:157491668:C:G	C681S	0.999
5:157491668:C:T	C681Y	0.999
5:157491669:A:T	C681S	0.999
5:157491694:G:C	C672W	0.999
5:157491695:C:G	C672S	0.999
5:157491696:A:T	C672S	0.999
5:157491719:C:G	C664S	0.999
5:157491720:A:T	C664S	0.999
5:157491848:C:G	C658S	0.999
5:157491849:A:T	C658S	0.999
5:157491893:C:G	C643S	0.999
5:157491894:A:T	C643S	0.999
5:157491907:G:C	C638W	0.999
5:157492986:C:G	C632S	0.999
5:157492987:A:T	C632S	0.999
5:157493066:G:C	C605W	0.999
5:157493068:A:G	C605R	0.999
5:157493151:C:G	C577S	0.999
5:157493152:A:G	C577R	0.999
5:157493152:A:T	C577S	0.999
5:157493163:C:T	G573E	0.999
5:157493164:C:A	G573W	0.999
5:157493165:A:C	C572W	0.999

dbSNP variants (sampled 300 via entrez): RS1000023822 (5:157507961 T>C), RS1000033536 (5:157544493 C>T), RS1000133080 (5:157497639 C>A), RS1000152354 (5:157509753 A>G), RS1000257267 (5:157526157 TAC>T), RS1000266019 (5:157503901 G>A), RS1000284263 (5:157538675 T>C), RS1000301990 (5:157484198 C>A,T), RS1000350155 (5:157556694 G>T), RS1000356371 (5:157514187 G>A), RS1000380486 (5:157516007 C>T), RS1000399173 (5:157509479 C>T), RS1000420503 (5:157478733 T>C), RS1000567598 (5:157483849 A>C,G), RS1000590398 (5:157550980 T>A)

Disease associations

OMIM: gene MIM:603640 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): lung adenocarcinoma (MONDO:0005061), squamous cell carcinoma (MONDO:0005096)

Orphanet (1): NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

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

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000542_8	Pulmonary function	1.000000e-10
GCST001784_2	Pulmonary function (smoking interaction)	2.000000e-11
GCST002740_86	Inflammatory skin disease	5.000000e-06
GCST004147_22	Chronic obstructive pulmonary disease	2.000000e-13
GCST004185_45	Lung function (FEV1/FVC)	3.000000e-11
GCST006585_584	Blood protein levels	1.000000e-21
GCST007430_109	Peak expiratory flow	5.000000e-25
GCST007431_103	Lung function (FEV1/FVC)	3.000000e-59
GCST007432_168	FEV1	6.000000e-25
GCST007692_21	Chronic obstructive pulmonary disease	6.000000e-11
GCST007692_46	Chronic obstructive pulmonary disease	8.000000e-10
GCST007692_55	Chronic obstructive pulmonary disease	1.000000e-16
GCST007941_17	Medication use (adrenergics, inhalants)	2.000000e-10
GCST008158_84	Body mass index	4.000000e-06
GCST009507_8	Triglyceride levels	6.000000e-07
GCST009798_48	Asthma	2.000000e-10
GCST010500_7	T-Cell Immunoglobulin and Mucin domain 1 levels	1.000000e-09
GCST011766_7	Chronic obstructive pulmonary disease	4.000000e-09
GCST011766_8	Chronic obstructive pulmonary disease	2.000000e-17
GCST90002382_134	Eosinophil percentage of white cells	3.000000e-09
GCST90002398_8	Neutrophil count	3.000000e-09
GCST90002399_429	Neutrophil percentage of white cells	1.000000e-09

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0009718	peak expiratory flow
EFO:0004314	forced expiratory volume
EFO:0009941	Inhalant adrenergic use measurement
EFO:0004340	body mass index
EFO:0004530	triglyceride measurement
EFO:0010812	T-cell immunoglobulin and mucin domain 1 measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002294	Carcinoma, Squamous Cell	C04.557.470.200.400; C04.557.470.700.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M12: Astacin/Adamalysin

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases expression	3
Valproic Acid	increases methylation, decreases expression, increases expression	3
(+)-JQ1 compound	affects cotreatment, decreases expression	2
Cisplatin	decreases expression, affects expression, affects cotreatment	2
Doxorubicin	decreases expression	2
Smoke	increases expression, decreases expression	2
Testosterone	increases expression	2
Tretinoin	increases expression	2
Cyclosporine	decreases expression, increases expression	2
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
quinocetone	increases expression	1
mirdametinib	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
Irinotecan	increases expression	1
Oxaliplatin	increases expression	1
Temozolomide	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02399566	PHASE4	UNKNOWN	Clinical Trial of Erlotinib and Pemetrexed for Maintenance Treatment in Lung Adenocarcinoma
NCT02804646	PHASE4	UNKNOWN	Endostar Durative Transfusion Combined With Chemotherapy in the Treatment of Advanced Lung Adenocarcinoma
NCT00868088	PHASE4	COMPLETED	Photodynamic Therapy to Treat Actinic Damage in Patients With Squamous Cell Carcinoma (SCC) of the Lip
NCT02088515	PHASE4	COMPLETED	Nedaplatin (Jiebaishu®) Combined With Docetaxel for Advanced Lung Squamous Cell Carcinoma
NCT02151149	PHASE4	COMPLETED	Safety and Efficacy Study of Abraxane in Combination With Carboplatin to Treat Advanced NSCL Cancer in the Elderly
NCT03388931	PHASE4	WITHDRAWN	Radiotherapy Dose Escalation in Locally Advanced Squamous Cell Carcinoma of the Larynx or Hypopharynx
NCT00002852	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Stage I Non-small Cell Lung Cancer
NCT00005838	PHASE3	COMPLETED	Combination Chemotherapy Plus Radiation Therapy With or Without AE-941 in Treating Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed By Surgery
NCT00020709	PHASE3	COMPLETED	Combination Chemotherapy and Radiation Therapy With or Without Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery
NCT00049543	PHASE3	COMPLETED	Gefitinib in Treating Patients With Stage IB, II, or IIIA Non-small Cell Lung Cancer That Was Completely Removed by Surgery
NCT00946712	PHASE3	TERMINATED	S0819: Carboplatin and Paclitaxel With or Without Bevacizumab and/or Cetuximab in Treating Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer
NCT01798485	PHASE3	TERMINATED	A Phase 3 Study of Ganetespib in Combination With Docetaxel Versus Docetaxel Alone in Patients With Advanced NSCLC
NCT02011997	PHASE3	UNKNOWN	Comparison of cVATS Segmentectomy Versus Lobectomy for Lung Adenocarcinoma in Situ and With Microinvasion
NCT03391869	PHASE3	ACTIVE_NOT_RECRUITING	Nivolumab and Ipilimumab With or Without Local Consolidation Therapy in Treating Patients With Stage IV Non-Small Cell Lung Cancer
NCT03676192	PHASE3	COMPLETED	To Compare Efficacy and Safety of CT-P16 and European Union-Approved Avastin as First-Line Treatment for Metastatic or Recurrent Non-Squamous Non-Small Cell Lung Cancer
NCT04339218	PHASE3	RECRUITING	Cryoablation in Combination (or Not) With Pembrolizumab and Pemetrexed-carboplatin in 1st-line Treatment for Patients With Metastatic Lung Adenocarcinoma
NCT05204758	PHASE3	COMPLETED	Prophylactic TCM for Mitigation of EGFR-TKI Related Dermatological Adverse Effect
NCT05717803	PHASE3	RECRUITING	Segmentectomy for Ground Glass-dominant Invasive Lung Cancer (ECTOP-1012)
NCT05943795	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Study of SI-B001 Combined With Docetaxel in the Treatment of Non-small Cell Lung Adenocarcinoma and Lung Squamous Cell Carcinoma
NCT06031181	PHASE3	RECRUITING	Sublobar Resection for Adenocarcinoma in Situ/Minimally Invasive Adenocarcinoma Diagnosed by Intraoperative Frozen Section (ECTOP-1019)
NCT06031246	PHASE3	RECRUITING	Selective Lymph Node Dissection for cT1N0M0 Invasive NSCLC With CTR>0.5 Located in the Apical Segment (ECTOP-1018)
NCT06634966	PHASE3	RECRUITING	Segmentectomy for Solid-dominant Lung Cancer
NCT07169903	PHASE3	NOT_YET_RECRUITING	Segmentectomy vs Lobectomy for 2 - 3cm IASLC Grade 1-2 Lung Adenocarcinoma: A Multi-center RCT
NCT07481786	PHASE3	RECRUITING	Bevacizumab Plus FSRT Versus Hippocampus-Avoidant WBRT in Lung Adenocarcinoma With Extensive Brain Metastases
NCT00101582	PHASE3	COMPLETED	Palifermin for the Reduction of Oral Mucositis in Patients With Locally Advanced Head and Neck Cancer
NCT00201279	PHASE3	COMPLETED	Chemoprevention Study of Oral Cavity Squamous Cell Carcinoma
NCT00201383	PHASE3	COMPLETED	Post-Operative Adjuvant Concurrent Chemoradiotherapy For High Risk Oral Cavity Squamous Cell Carcinoma Patients
NCT00382031	PHASE3	COMPLETED	Zalutumumab in Patients With Non-curable Head and Neck Cancer
NCT00472459	PHASE3	COMPLETED	Photodynamic Therapy (PDT) With Metvix® 160 Milligrams/Gram Cream in Organ Transplant Participants With Non-melanoma Skin Cancer
NCT00559351	PHASE3	TERMINATED	RCT on the Combined Modality Treatment of Squamous Cell Carcinoma of the Esophagus
NCT01161498	PHASE3	TERMINATED	Study of Safety and Efficacy of Talimogene Laherparepvec With Cisplatin and Radiotherapy for Treatment of Locally Advanced Head and Neck Cancer
NCT01363466	PHASE3	TERMINATED	Evaluation of Hysterectomy After Chemoradiation Therapy for Stage IB2/II Cervical Cancer
NCT01532453	PHASE3	TERMINATED	Prevention of UV-induced Carcinogenic Skin Alterations in Immunosuppressed Solid Organ Transplanted Patients
NCT01706939	PHASE3	ACTIVE_NOT_RECRUITING	The Quarterback Trial: Reduced Dose Radiotherapy for HPV+ Oropharynx Cancer
NCT03115476	PHASE3	TERMINATED	A Trial to Compare the Incidence of Squamous Cell Carcinoma (SCC) and Other Skin Neoplasia on Skin Areas Treated With Ingenol Disoxate Gel or Vehicle Gel for Actinic Keratosis on Face and Chest or Scalp
NCT03257267	PHASE3	COMPLETED	Study of Cemiplimab in Adults With Cervical Cancer
NCT00040794	PHASE2	COMPLETED	Combination Chemotherapy, Radiation Therapy, and Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer
NCT00087412	PHASE2	COMPLETED	S0341: Erlotinib in Treating Patients With Advanced Primary Non-Small Cell Lung Cancer
NCT00118144	PHASE2	COMPLETED	Bortezomib in Treating Patients With Stage IIIB or Stage IV Lung Cancer
NCT00118183	PHASE2	COMPLETED	Docetaxel With Either Cetuximab or Bortezomib as First-Line Therapy in Treating Patients With Stage III or Stage IV Non-Small Cell Lung Cancer