ADAM33

Summary

ADAM33 (ADAM metallopeptidase domain 33, HGNC:15478) is a protein-coding gene on chromosome 20p13, encoding Disintegrin and metalloproteinase domain-containing protein 33 (Q9BZ11).

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 protein is a type I transmembrane protein implicated in asthma and bronchial hyperresponsiveness. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 80332 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 172 total — 11 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_025220

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15478
Approved symbol	ADAM33
Name	ADAM metallopeptidase domain 33
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp434K0521, dJ964F7.1
Ensembl gene	ENSG00000149451
Ensembl biotype	protein_coding
OMIM	607114
Entrez	80332

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 21 protein_coding, 2 retained_intron

ENST00000350009, ENST00000356518, ENST00000379861, ENST00000466620, ENST00000483362, ENST00000882045, ENST00000882046, ENST00000882047, ENST00000882048, ENST00000882049, ENST00000882050, ENST00000882051, ENST00000882052, ENST00000882053, ENST00000959294, ENST00000959295, ENST00000959296, ENST00000959297, ENST00000959298, ENST00000959299, ENST00000959300, ENST00000959301, ENST00000959302

RefSeq mRNA: 3 — MANE Select: NM_025220 NM_001282447, NM_025220, NM_153202

CCDS: CCDS13058, CCDS63219

Canonical transcript exons

ENST00000356518 — 22 exons

Exon	Start	End
ENSE00000000319	3681908	3682010
ENSE00000990641	3674504	3674693
ENSE00001386761	3675027	3675105
ENSE00001598605	3672721	3672898
ENSE00001614585	3673354	3673496
ENSE00001709035	3673574	3673658
ENSE00001766750	3673745	3673911
ENSE00003042648	3671419	3671496
ENSE00003138563	3679492	3679571
ENSE00003165724	3677067	3677143
ENSE00003188976	3674219	3674284
ENSE00003204502	3674064	3674135
ENSE00003214806	3674773	3674849
ENSE00003482679	3671581	3671779
ENSE00003548381	3667975	3669000
ENSE00003565037	3671877	3671985
ENSE00003568863	3671006	3671153
ENSE00003591093	3671237	3671345
ENSE00003628071	3669546	3669637
ENSE00003636518	3672537	3672626
ENSE00003643148	3672134	3672329
ENSE00003674993	3669299	3669370

Expression profiles

Bgee: expression breadth ubiquitous, 240 present calls, max score 99.17.

FANTOM5 (CAGE): breadth broad, TPM avg 6.6585 / max 234.6001, expressed in 749 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186159	3.5861	685
186158	2.4640	484
186160	0.4262	249
186157	0.1555	88
186161	0.0267	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endocervix	UBERON:0000458	99.17	gold quality
body of uterus	UBERON:0009853	99.12	gold quality
left uterine tube	UBERON:0001303	98.74	gold quality
stromal cell of endometrium	CL:0002255	98.34	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.27	gold quality
ectocervix	UBERON:0012249	97.76	gold quality
lower esophagus	UBERON:0013473	97.75	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.75	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.69	gold quality
mucosa of stomach	UBERON:0001199	97.60	gold quality
descending thoracic aorta	UBERON:0002345	97.53	gold quality
lower esophagus mucosa	UBERON:0035834	97.13	gold quality
thoracic aorta	UBERON:0001515	97.08	gold quality
ascending aorta	UBERON:0001496	97.05	gold quality
myometrium	UBERON:0001296	96.82	gold quality
left ventricle myocardium	UBERON:0006566	96.61	silver quality
cardiac muscle of right atrium	UBERON:0003379	96.59	silver quality
tibial nerve	UBERON:0001323	96.47	gold quality
vagina	UBERON:0000996	96.45	gold quality
aorta	UBERON:0000947	96.42	gold quality
uterine cervix	UBERON:0000002	96.34	gold quality
right uterine tube	UBERON:0001302	96.25	gold quality
smooth muscle tissue	UBERON:0001135	96.21	gold quality
right ovary	UBERON:0002118	96.14	gold quality
fundus of stomach	UBERON:0001160	96.04	gold quality
tibial artery	UBERON:0007610	96.00	gold quality
right coronary artery	UBERON:0001625	95.98	gold quality
popliteal artery	UBERON:0002250	95.98	gold quality
buccal mucosa cell	CL:0002336	95.71	silver quality
upper arm skin	UBERON:0004263	95.53	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6142	no	49.63
E-MTAB-6058	no	4.46
E-MTAB-6678	no	3.69
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting ADAM33, 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-4282	99.99	75.36	6408
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-8052	99.17	65.01	719
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-5089-5P	98.45	66.06	1388
HSA-MIR-326	98.25	66.44	1565

Literature-anchored findings (GeneRIF, showing 40)

• The human protein shows homology with Xenopus ADAM13 (44%), human ADAM19 (40%), and human ADAM12 (39%). (PMID:11814695)
• genome-wide scan on 460 Caucasian families identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93) (PMID:12110844)
• Data describe the expression and processing of ADAM33 (PMID:12535637)
• Novel polymorphisms were identified in ADAM33. (PMID:12768445)
• This gene (and perhaps others that interact with it) is important in development and pathogenesis of asthma in these 4 asthma populations. (PMID:14564349)
• the crystal structure of the Adam33 catalytic domain in complex with the inhibitor marimastat reveals that the polypeptide fold and active site environment resemble that of other metalloproteases, but the substrate-binding site contains unique features (PMID:14659745)
• analysis of the catalytic properties of ADAM33 (PMID:14676211)
• Several protein isoforms of ADAM33 are expressed in primary airways fibroblasts, suggesting that it is a complex molecule that plays multiple roles within mesenchymal cells. (PMID:14742294)
• ADAM33 constitutes a novel asthma susceptibility gene. (PMID:15347848)
• ADAM33 might play a key role in predisposing to the reduced lung function characteristic of asthma, possibly by influencing airway wall remodelling. (PMID:15387895)
• Occurrence of ADAM33 in embryonic mesenchymal cells suggests that it may be involved in airway wall “remodeling” that contributes to the early life origins of asthma. (PMID:15709049)
• A substrate specificity profile is established for ADAM33, and enzymatic characterization of the metalloproteinase is reported. (PMID:15766253)
• Polymorphisms in ADAM33 predict impaired early-life lung function. The functionally relevant polymorphism is likely to be at the 5’ end of the gene. (PMID:15805180)
• SNPs in ADAM33 are associated with accelerated lung function decline in the general population. (PMID:15879414)
• ADAM33 is associated with asthma development, and the levels of ADAM protein are related to asthma severity. (PMID:16387804)
• The ability to identify novel disease genes by positional cloning led to the identification of a disintegrin and metalloprotease (ADAM)33 gene on chromosome 20p13 as a susceptibility gene for asthma. (PMID:16799089)
• No significant association was detected between three SNPs of ADAM33 and asthma susceptibility in the Chinese population (PMID:16893396)
• Sequence variations in ADAM33 are associated with susceptibility to aspirin-intolerant asthama in the Japanese population. (PMID:17061022)
• ADAM33 may contribute to the airway remodeling process that occurs with asthma progression. (PMID:17339047)
• The polymorphism of T(1) locus allele in ADAM33 gene is associated with the susceptibility to asthma in South China Han population. (PMID:17545039)
• The data provide for the first time a functional role for a disease-associated SNP in ADAM33 and begin to shed light on the deregulation of this gene in the pathophysiology of asthma (PMID:17640346)
• No consistent association was found between ADAM33 and asthma susceptibility. (PMID:17702965)
• identification of ADAM33 as a psoriasis susceptibility gene identified by positional cloning in an outbred population should provide insights into the pathogenesis and natural history of this common disease (PMID:17878941)
• Met764Thr locus polymorphism of ADAM33 is associated with susceptibility of asthma and clinical indexes of lung function of asthmatic subjects of Han nationality in Southern China. (PMID:17961406)
• The discovery that sADAM33 promotes angiogenesis defines it as a tissue remodeling gene with potential to affect airflow obstruction and lung function independently of inflammation (PMID:18410963)
• The ADAM33 gene contains a regulatory CpG island within its promoter, the methylation status of which tightly controls its expression in a cell type-specific manner (PMID:18423563)
• This is the first study that replicates an association between genetic variants in ADAM33 and psoriasis. Interestingly, 2 ADAM33 SNPs associated with psoriasis in this analysis were part of the 3-SNPs haplotypes showing the strongest associations earlier (PMID:18560587)
• The SNPs (V4 G/C, T2 A/G, T1 G/A, and Q - 1A/G) of the ADAM33 gene may be the causal variants in allergic rhinitis and asthma (PMID:18752037)
• Polymorphisms of the ADAM33 gene may modify individual susceptibility to AR and AS in a Chinese Han population (PMID:18778489)
• ADAM33, CDKAL1, and PTPN22 may be true psoriasis-risk genes (PMID:18923449)
• First epidemiological study on the relationship between polymorphisms in the ADAM33 gene and the risk of atopic dermatitis. The rs2853209 SNP in the ADAM33 gene was significantly associated with the risk of AD in Japanese children. (PMID:19146844)
• Smoke exposure interacts with ADAM33 polymorphisms in the development of lung function and hyperresponsiveness. (PMID:19236319)
• ADAM33 has a key role in gastric cancer pathogenesis by up-regulating the interleukin (IL)-18 secretion process, which results in increased cell migration and proliferation. (PMID:19265133)
• We suggest that ADAM33 promoter methylation may be a useful molecular marker for differentiating invasive lobular carcinoma and invasive ductal carcinoma (PMID:19267929)
• Adam33 polymorphisms are associated with chronic obstructive pulmonary disease and lung function in long-term tobacco smokers. (PMID:19284602)
• This study in a Thai population confirmed a positive association between ADAM33 polymorphisms and asthma susceptibility. (PMID:19317339)
• genetic polymorphism is associated with asthma and allergic sensitization in african-americans, hispanics and asians; contradictory data (PMID:19326508)
• These results support the note that Th2 cytokines can up-regulate the expression of ADAM33 mRNA and ADAM33 may play an important role in the development of airway remodeling in allergen-induced chronic airway inflammation. (PMID:19635592)
• Adam33/Adam33 shows 2 significant increments in expression during lung morphogenesis, suggesting important developmental regulation. (PMID:19665773)
• Our findings suggest a relevant role of ADAM33 in thepathogenesis of asthma in this population in Cartagena, Colombia. (PMID:19940503)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	adam19a	ENSDARG00000059693
mus_musculus	Adam33	ENSMUSG00000027318
rattus_norvegicus	Adam33	ENSRNOG00000021242
drosophila_melanogaster	mmd	FBGN0259110
caenorhabditis_elegans		WBGENE00006804

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

Protein

Protein identifiers

Disintegrin and metalloproteinase domain-containing protein 33 — Q9BZ11 (reviewed: Q9BZ11)

All UniProt accessions (2): Q9BZ11, A2A2L3

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Tissue specificity. Expressed in all tissues, except liver, with high expression in placenta, lung, spleen and veins.

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

Disease relevance. Asthma (ASTHMA) [MIM:600807] The most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. It is characterized by recurrent attacks of paroxysmal dyspnea, with wheezing due to spasmodic contraction of the bronchi. Disease susceptibility is associated with variants affecting the gene represented in this entry.

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.

Miscellaneous. By similarity with mouse isoform.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BZ11-1	1	yes
Q9BZ11-2	2
Q9BZ11-3	3

RefSeq proteins (3): NP_001269376, NP_079496, NP_694882 (=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 (66 total): sequence variant 15, helix 9, disulfide bond 7, strand 6, glycosylation site 5, binding site 4, turn 3, domain 3, region of interest 2, topological domain 2, splice variant 2, signal peptide 1, propeptide 1, short sequence motif 1, compositionally biased region 1, active site 1, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1R55	X-RAY DIFFRACTION	1.58
1R54	X-RAY DIFFRACTION	1.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZ11-F1	75.33	0.40

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): 133 (in inhibited form); 345; 349; 355

Disulfide bonds (7): 320–404, 360–388, 361–371, 475–495, 653–663, 657–669, 671–680

Glycosylation sites (5): 109, 145, 231, 276, 448

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-9762292	Regulation of CDH11 function
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: 73 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOMF_METALLOPEPTIDASE_ACTIVITY, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, LIAO_METASTASIS, WGGAATGY_TEF1_Q6, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, REACTOME_CELL_JUNCTION_ORGANIZATION, MEISSNER_ES_ICP_WITH_H3K4ME3_AND_H3K27ME3, MEISSNER_NPC_ICP_WITH_H3_UNMETHYLATED, LIU_PROSTATE_CANCER_DN, MIKKELSEN_IPS_ICP_WITH_H3K4ME3_AND_H327ME3, MIKKELSEN_ES_ICP_WITH_H3K4ME3_AND_H3K27ME3, MARTENS_TRETINOIN_RESPONSE_UP

GO Biological Process (1): proteolysis (GO:0006508)

GO Molecular Function (7): metalloendopeptidase activity (GO:0004222), zinc ion binding (GO:0008270), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (1): membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
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
protein metabolic process	1
endopeptidase activity	1
metallopeptidase activity	1
transition metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

874 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM33	PHF11	Q9UIL8	905
ADAM33	DPP10	Q8N608	787
ADAM33	NPSR1	Q6W5P4	698
ADAM33	ORMDL3	Q8N138	635
ADAM33	IL4R	P24394	633
ADAM33	SPINK5	Q9NQ38	620
ADAM33	HLA-G	P17693	580
ADAM33	PTGDR2	Q9Y5Y4	558
ADAM33	FCER1A	P12319	514
ADAM33	CDKAL1	Q5VV42	509
ADAM33	SCGB2A1	O75556	497
ADAM33	PLA2G7	Q13093	497
ADAM33	KCNS3	Q9BQ31	497
ADAM33	SCGB3A2	Q96PL1	493
ADAM33	CDSN	Q15517	493

IntAct

6 interactions, top by confidence:

A	B	Type	Score
ADAM33	LRP5	psi-mi:“MI:0914”(association)	0.530
ADAM33	SLC30A2	psi-mi:“MI:0915”(physical association)	0.370
ADAM33	ATXN7	psi-mi:“MI:0915”(physical association)	0.370
ADAM33	ADAM10	psi-mi:“MI:0914”(association)	0.350
UBQLN4	ADAM33	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (108): ADAM33 (Two-hybrid), ADAM33 (Two-hybrid), ASB7 (Affinity Capture-MS), ZDHHC6 (Affinity Capture-MS), HMOX1 (Affinity Capture-MS), SOAT1 (Affinity Capture-MS), TMEM39B (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), SLC27A3 (Affinity Capture-MS), NOTCH3 (Affinity Capture-MS), TMEM67 (Affinity Capture-MS), EGFL7 (Affinity Capture-MS), HLA-A (Affinity Capture-MS), TTC17 (Affinity Capture-MS), ITGB5 (Affinity Capture-MS)

ESM2 similar proteins: A6NGC4, A6NKX4, A6NM10, D3YZZ2, O35595, O46547, O60391, O77808, O95528, P30518, P43119, P46092, P46095, P48044, P48748, Q14626, Q3SYU3, Q3ZAV1, Q4U2R8, Q4W8A3, Q5RF19, Q5U419, Q64385, Q684M3, Q6UXD7, Q6UXT9, Q6YNI2, Q863Y8, Q86SM5, Q8CFZ5, Q8IXF9, Q8WUG5, Q91X56, Q924U0, Q96S37, Q99MF4, Q9BGL8, Q9BZ11, Q9H1Z9, Q9H228

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	1
Uncertain significance	123
Likely benign	13
Benign	8

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
149704	GRCh38/hg38 20p13-12.1(chr20:80106-13029401)x3	Pathogenic
150785	GRCh38/hg38 20p13-12.3(chr20:80093-6386012)x3	Pathogenic
152841	GRCh38/hg38 20p13-12.3(chr20:84402-6159078)x3	Pathogenic
155359	GRCh38/hg38 20p13-11.23(chr20:80928-18688031)x3	Pathogenic
1703638	GRCh37/hg19 20p13-12.2(chr20:3178539-11848383)	Pathogenic
2426797	NC_000020.10:g.(?3063276)(3903941_?)del	Pathogenic
253566	GRCh37/hg19 20p13-12.3(chr20:121521-5564937)x3	Pathogenic
2684899	GRCh37/hg19 20p13-12.2(chr20:61569-9542361)x3	Pathogenic
443885	GRCh37/hg19 20p13-12.3(chr20:2463101-8185680)x1	Pathogenic
57354	GRCh38/hg38 20p13-11.23(chr20:89939-19146279)x3	Pathogenic
59194	GRCh38/hg38 20p13(chr20:3059231-4187716)x3	Pathogenic
443774	GRCh37/hg19 20p13-12.2(chr20:61568-10486106)x3	Likely pathogenic

SpliceAI

3692 predictions. Top by Δscore:

Variant	Effect	Δscore
20:3671005:CCCA:C	donor_gain	1.0000
20:3671235:A:AC	donor_gain	1.0000
20:3671236:C:CC	donor_gain	1.0000
20:3671239:T:A	donor_gain	1.0000
20:3671344:ACC:A	acceptor_loss	1.0000
20:3671346:C:CA	acceptor_loss	1.0000
20:3671347:T:C	acceptor_loss	1.0000
20:3671575:GCTCA:G	donor_loss	1.0000
20:3671576:CTCA:C	donor_loss	1.0000
20:3671577:TCACC:T	donor_loss	1.0000
20:3671579:A:AC	donor_gain	1.0000
20:3671579:ACCA:A	donor_loss	1.0000
20:3671580:C:CC	donor_gain	1.0000
20:3671580:C:CG	donor_loss	1.0000
20:3671580:CCATT:C	donor_gain	1.0000
20:3671678:T:TA	donor_gain	1.0000
20:3671775:CATCC:C	acceptor_gain	1.0000
20:3671776:ATCC:A	acceptor_gain	1.0000
20:3671777:TCC:T	acceptor_gain	1.0000
20:3671778:CC:C	acceptor_gain	1.0000
20:3671778:CCC:C	acceptor_gain	1.0000
20:3671779:CC:C	acceptor_gain	1.0000
20:3671779:CCTGG:C	acceptor_loss	1.0000
20:3671780:C:CC	acceptor_gain	1.0000
20:3671780:C:T	acceptor_gain	1.0000
20:3671780:CTGGG:C	acceptor_loss	1.0000
20:3671875:ACCTC:A	donor_gain	1.0000
20:3671876:CCTCC:C	donor_gain	1.0000
20:3671879:C:A	donor_gain	1.0000
20:3673743:A:AC	donor_gain	1.0000

AlphaMissense

5278 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:3672877:G:C	F385L	0.986
20:3672877:G:T	F385L	0.986
20:3672879:A:G	F385L	0.986
20:3673861:C:A	W263C	0.986
20:3673861:C:G	W263C	0.986
20:3672865:G:C	S389R	0.984
20:3672865:G:T	S389R	0.984
20:3672867:T:G	S389R	0.984
20:3673863:A:G	W263R	0.984
20:3673863:A:T	W263R	0.984
20:3671768:C:G	C573S	0.983
20:3671769:A:T	C573S	0.983
20:3672154:C:G	C526S	0.983
20:3672155:A:T	C526S	0.983
20:3672878:A:C	F385C	0.983
20:3671753:C:G	C578S	0.982
20:3671754:A:T	C578S	0.982
20:3671958:A:C	F542C	0.981
20:3671290:C:G	C680S	0.980
20:3671291:A:T	C680S	0.980
20:3673804:G:C	F282L	0.979
20:3673804:G:T	F282L	0.979
20:3673805:A:C	F282C	0.979
20:3673805:A:G	F282S	0.979
20:3673806:A:G	F282L	0.979
20:3671290:C:T	C680Y	0.978
20:3672268:C:G	C488S	0.978
20:3672269:A:T	C488S	0.978
20:3672874:G:C	S386R	0.978
20:3672874:G:T	S386R	0.978

dbSNP variants (sampled 300 via entrez): RS1000021117 (20:3678930 G>A), RS1000061936 (20:3682961 C>T), RS1000183200 (20:3669216 TA>T), RS1000191147 (20:3678051 A>G), RS1000284688 (20:3680648 G>A,T), RS1000420724 (20:3679990 C>T), RS1000659117 (20:3675733 C>G,T), RS1000685618 (20:3675938 C>A), RS1000755269 (20:3679216 G>A), RS1000814251 (20:3678999 C>A,G,T), RS1001140936 (20:3673387 T>C), RS1001371888 (20:3678302 T>C), RS1001382550 (20:3673122 C>T), RS1001428218 (20:3681028 G>T), RS1001801687 (20:3678085 A>G)

Disease associations

OMIM: gene MIM:607114 | disease phenotypes: MIM:613850

GenCC curated gene-disease

Mondo (3): inosine triphosphatase deficiency (MONDO:0013461), 20p12.3 microdeletion syndrome (MONDO:0016841), breast ductal adenocarcinoma (MONDO:0005590)

Orphanet (2): 20p12.3 microdeletion syndrome (Orphanet:261295), NON RARE IN EUROPE: Inosine triphosphate pyrophosphatase deficiency (Orphanet:319684)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003542_159	Night sleep phenotypes	8.000000e-06
GCST90002401_307	Platelet distribution width	3.000000e-13
GCST90002405_438	Reticulocyte count	2.000000e-11
GCST90002407_640	White blood cell count	1.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width
EFO:0007986	reticulocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
C564127	Inosine Triphosphatase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6121 (SINGLE PROTEIN)

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2787094	ADAM33		0.00	0
rs2853209	ADAM33		0.00	0
rs3918396	ADAM33		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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
IK-862	Inhibition	7.82	pKi
INCB3619	Inhibition	5.99	pIC50

Binding affinities (BindingDB)

7 measured of 9 human assays (9 total across all organisms); most potent 7 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-N-hydroxy-2-morpholin-4-yl-3-[(4-phenylmethoxyphenyl)sulfonylamino]propanamide	IC50	147 nM	US-8772478: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
(2S)-N-hydroxy-3-[(4-phenylmethoxyphenyl)sulfonylamino]-2-piperidin-1-ylpropanamide	IC50	181 nM	US-8772478: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
(2S)-3-[[4-[(4-fluorophenyl)methoxy]phenyl]sulfonylamino]-N-hydroxy-2-piperidin-1-ylpropanamide	IC50	181 nM	US-8772478: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
(2S)-N-hydroxy-3-[[4-(naphthalen-2-ylmethoxy)phenyl]sulfonylamino]-2-piperidin-1-ylpropanamide	IC50	249 nM	US-8772478: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
(2S)-N-hydroxy-3-[(4-phenylmethoxyphenyl)sulfonylamino]-2-pyrrolidin-1-ylpropanamide	IC50	298 nM	US-8772478: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
(2S)-3-[[4-[(3,4-dichlorophenyl)methoxy]phenyl]sulfonylamino]-N-hydroxy-2-piperidin-1-ylpropanamide	IC50	328 nM	US-8772478: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
(2S)-3-[[4-[(3,5-dichlorophenyl)methoxy]phenyl]sulfonylamino]-N-hydroxy-2-piperidin-1-ylpropanamide	IC50	469 nM	US-8772478: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics

ChEMBL bioactivities

14 potent at pChembl≥5 of 14 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.82	Ki	15	nM	CHEMBL148169
7.62	IC50	24	nM	CHEMBL3643916
7.58	IC50	26	nM	CHEMBL3643914
7.42	IC50	38	nM	CHEMBL3643916
6.95	IC50	112	nM	CHEMBL3643914
6.83	IC50	147	nM	CHEMBL3643913
6.74	IC50	181	nM	CHEMBL3643910
6.74	IC50	181	nM	CHEMBL3643908
6.60	IC50	249	nM	CHEMBL3643911
6.53	IC50	298	nM	CHEMBL3643909
6.48	IC50	328	nM	CHEMBL3643912
6.33	IC50	469	nM	CHEMBL3643915
5.99	IC50	1026	nM	CHEMBL434567
5.38	IC50	4125	nM	CHEMBL497985

PubChem BioAssay actives

3 with measured affinity, of 5 total; 3 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-2-[(3S)-3-methyl-3-[4-[(2-methylquinolin-4-yl)methoxy]phenyl]-2-oxopyrrolidin-1-yl]propanamide	344620: Inhibition of ADAM33	ki	0.0150	uM
methyl (6S,7S)-7-(hydroxycarbamoyl)-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-azaspiro[2.5]octane-5-carboxylate	344620: Inhibition of ADAM33	ic50	1.0260	uM
(6S,7S)-N-hydroxy-5-methyl-6-[4-[5-(trifluoromethyl)-2-pyridinyl]piperazine-1-carbonyl]-5-azaspiro[2.5]octane-7-carboxamide	344620: Inhibition of ADAM33	ic50	4.1250	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	decreases expression	2
propionaldehyde	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
sulforaphane	decreases expression	1
2-ethyl-5-carboxypentyl phthalate	increases abundance, increases expression, increases methylation	1
mono(2-ethyl-5-oxohexyl)phthalate	increases abundance, increases expression, increases methylation	1
mono(2-ethyl-5-hydroxyhexyl) phthalate	increases abundance, increases expression, increases methylation	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Liraglutide	increases expression, decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	decreases methylation	1
Acetaminophen	decreases expression	1
Acetylcysteine	decreases reaction, increases expression	1
Aspirin	affects response to substance	1
Benomyl	increases expression, affects reaction	1
Benzo(a)pyrene	decreases methylation	1
Calcitriol	decreases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	decreases expression, affects cotreatment	1
Polychlorinated Biphenyls	affects expression	1
Tobacco Smoke Pollution	increases methylation	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1
1-Methyl-4-phenylpyridinium	increases expression	1
Antirheumatic Agents	increases expression	1
Endocrine Disruptors	increases abundance, increases expression, increases methylation	1
Particulate Matter	decreases reaction, increases 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
CHEMBL3706288	Binding	Enzymatic Assay: The products are solubilized in DMSO at a concentration of 10 mM. A serial 3-fold dilution over 10 points is carried out so as to have a concentration range of from 10 uM to 0.5 nM final concentration. The TACE enzyme is an	Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery