ADAM18

Summary

ADAM18 (ADAM metallopeptidase domain 18, HGNC:196) is a protein-coding gene on chromosome 8p11.22, encoding Disintegrin and metalloproteinase domain-containing protein 18 (Q9Y3Q7). Sperm surface membrane protein that may be involved in spermatogenesis and fertilization.

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 biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded preproprotein is proteolytically processed to generate the mature sperm surface protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed.

Source: NCBI Gene 8749 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 135 total — 25 pathogenic
• MANE Select transcript: NM_014237

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:196
Approved symbol	ADAM18
Name	ADAM metallopeptidase domain 18
Location	8p11.22
Locus type	gene with protein product
Status	Approved
Aliases	tMDCIII, ADAM27
Ensembl gene	ENSG00000168619
Ensembl biotype	protein_coding
OMIM	619495
Entrez	8749

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 3 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000265707, ENST00000379866, ENST00000520001, ENST00000520087, ENST00000520559, ENST00000520772, ENST00000523755, ENST00000524117

RefSeq mRNA: 3 — MANE Select: NM_014237 NM_001190956, NM_001320313, NM_014237

CCDS: CCDS55225, CCDS6113, CCDS83287

Canonical transcript exons

ENST00000265707 — 20 exons

Exon	Start	End
ENSE00001155617	39610529	39610706
ENSE00001196454	39648344	39648527
ENSE00002105724	39584568	39584677
ENSE00002126354	39729898	39730065
ENSE00003471438	39723748	39723907
ENSE00003481295	39609485	39609561
ENSE00003482365	39606307	39606362
ENSE00003490115	39637537	39637703
ENSE00003504543	39609042	39609120
ENSE00003516155	39638465	39638546
ENSE00003541723	39637264	39637335
ENSE00003542128	39692600	39692680
ENSE00003579590	39706790	39706904
ENSE00003592924	39585276	39585352
ENSE00003593112	39629374	39629439
ENSE00003595323	39677431	39677536
ENSE00003601234	39645338	39645474
ENSE00003607976	39663795	39663890
ENSE00003648572	39667998	39668196
ENSE00003663593	39680037	39680226

Expression profiles

Bgee: expression breadth broad, 25 present calls, max score 80.72.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1178 / max 78.0377, expressed in 14 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88586	0.0602	4
88585	0.0277	4
88587	0.0251	9
205161	0.0048	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
testis	UBERON:0000473	80.72	gold quality
left testis	UBERON:0004533	80.69	gold quality
right testis	UBERON:0004534	80.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.20	gold quality
monocyte	CL:0000576	41.19	gold quality
sural nerve	UBERON:0015488	41.19	gold quality
right coronary artery	UBERON:0001625	40.98	silver quality
leukocyte	CL:0000738	40.48	gold quality
cortical plate	UBERON:0005343	40.42	silver quality
apex of heart	UBERON:0002098	40.39	silver quality
heart left ventricle	UBERON:0002084	37.64	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
granulocyte	CL:0000094	35.39	gold quality
skeletal muscle tissue	UBERON:0001134	34.90	gold quality
heart	UBERON:0000948	33.54	gold quality
muscle tissue	UBERON:0002385	32.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
bone marrow	UBERON:0002371	31.74	gold quality
urinary bladder	UBERON:0001255	30.85	silver quality
fundus of stomach	UBERON:0001160	29.97	silver quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
endometrium	UBERON:0001295	29.48	gold quality
prefrontal cortex	UBERON:0000451	29.19	gold quality
lymph node	UBERON:0000029	28.86	gold quality
blood	UBERON:0000178	28.53	gold quality
duodenum	UBERON:0002114	28.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-99795	no	1.82
E-ANND-3	no	0.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

4 targeting ADAM18, 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-6835-3P	99.93	70.49	2904
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-154-5P	98.92	66.65	733
HSA-MIR-450A-2-3P	97.91	67.56	1459

Literature-anchored findings (GeneRIF, showing 1)

• we have determined the complete nucleotide sequence of human tMDC III cDNA , human tMDC III contains a putative integrin-binding glu-cys-asp (ECD) motif, the relevance of which is discussed in the context of a possible role in oolemma binding. (PMID:12200459)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	adam10b	ENSDARG00000015502
danio_rerio	adam10a	ENSDARG00000053468
danio_rerio	adam9b	ENSDARG00000057138
mus_musculus	Adam18	ENSMUSG00000031552
rattus_norvegicus	Adam18	ENSRNOG00000017683
drosophila_melanogaster	mmd	FBGN0259110
drosophila_melanogaster	kuz	FBGN0259984
caenorhabditis_elegans	sup-17	WBGENE00006324
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), ADAM33 (ENSG00000149451), ADAM8 (ENSG00000151651), ADAM17 (ENSG00000151694), ADAM29 (ENSG00000168594), ADAM9 (ENSG00000168615), ADAM32 (ENSG00000197140)

Protein

Protein identifiers

Disintegrin and metalloproteinase domain-containing protein 18 — Q9Y3Q7 (reviewed: Q9Y3Q7)

Alternative names: Transmembrane metalloproteinase-like, disintegrin-like, and cysteine-rich protein III

All UniProt accessions (3): Q9Y3Q7, E5RIP0, E5RK96

UniProt curated annotations — full annotation on UniProt →

Function. Sperm surface membrane protein that may be involved in spermatogenesis and fertilization. This is a non catalytic metalloprotease-like protein.

Subcellular location. Membrane.

Tissue specificity. Expressed specifically in testis.

Post-translational modifications. The prodomain and the metalloprotease-like domain are cleaved during the epididymal maturation of the spermatozoa.

Domain organisation. A tripeptide motif (ECD) within disintegrin-like domain could be involved in the binding to egg integrin receptor and thus could mediate sperm/egg binding.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y3Q7-1	1	yes
Q9Y3Q7-2	2
Q9Y3Q7-3	3

RefSeq proteins (3): NP_001177885, NP_001307242, NP_055052* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
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 (37 total): glycosylation site 12, disulfide bond 7, sequence variant 6, splice variant 3, domain 3, topological domain 2, signal peptide 1, propeptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3Q7-F1	78.24	0.37

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (7): 293–376, 335–360, 337–342, 450–471, 624–636, 630–642, 644–653

Glycosylation sites (12): 76, 122, 149, 156, 177, 294, 359, 465, 561, 611, 625, 36

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 75 (showing top): GOBP_SINGLE_FERTILIZATION, GOMF_METALLOPEPTIDASE_ACTIVITY, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_MALE_GAMETE_GENERATION, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, GOBP_SPERM_EGG_RECOGNITION, GOBP_SEX_DIFFERENTIATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_FERTILIZATION, GOBP_CELL_CELL_RECOGNITION, GOBP_BINDING_OF_SPERM_TO_ZONA_PELLUCIDA, WEBER_METHYLATED_ICP_IN_SPERM_DN, GOBP_MALE_SEX_DIFFERENTIATION, GOBP_DEVELOPMENT_OF_PRIMARY_SEXUAL_CHARACTERISTICS, YAGI_AML_WITH_11Q23_REARRANGED

GO Biological Process (6): proteolysis (GO:0006508), cell adhesion (GO:0007155), spermatogenesis (GO:0007283), binding of sperm to zona pellucida (GO:0007339), male gonad development (GO:0008584), cell differentiation (GO:0030154)

GO Molecular Function (2): metalloendopeptidase activity (GO:0004222), metallopeptidase activity (GO:0008237)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
cellular process	1
developmental process involved in reproduction	1
male gamete generation	1
sperm-egg recognition	1
gonad development	1
development of primary male sexual characteristics	1
cellular developmental process	1
endopeptidase activity	1
metallopeptidase activity	1
peptidase activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

278 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM18	TMEM121	Q9BTD3	472
ADAM18	ATAD3C	Q5T2N8	443
ADAM18	WDR88	Q6ZMY6	351
ADAM18	ACP6	Q9NPH0	350
ADAM18	SERPINI2	O75830	348
ADAM18	ZAN	Q9Y493	339
ADAM18	GDE1	Q9NZC3	336
ADAM18	PRM2	P04554	321
ADAM18	PRSS12	P56730	312
ADAM18	TOR1B	O14657	311
ADAM18	SPACA1	Q9HBV2	308
ADAM18	ZPBP2	Q6X784	291
ADAM18	ALPG	P10696	290
ADAM18	SEPTIN3	Q9UH03	279
ADAM18	RAI1	Q7Z5J4	270

IntAct

3 interactions, top by confidence:

A	B	Type	Score
PACSIN3	COBLL1	psi-mi:“MI:0914”(association)	0.530
ADAM18	WDR27	psi-mi:“MI:0914”(association)	0.350
ADAM18	OAF	psi-mi:“MI:0914”(association)	0.350

BioGRID (16): NT5C3A (Affinity Capture-MS), LMF1 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), MPC2 (Affinity Capture-MS), UFSP2 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS), RPS6KA3 (Affinity Capture-MS), C1orf27 (Affinity Capture-MS), WDR27 (Affinity Capture-MS), SIL1 (Affinity Capture-MS), OAF (Affinity Capture-MS), ADAM18 (Affinity Capture-MS), PCSK9 (Affinity Capture-MS), GPR56 (Affinity Capture-MS)

ESM2 similar proteins: A1A547, A6QPN6, D2GZV9, E1BPW0, O18956, O75356, O75594, O93295, P10852, P15396, P22413, P49961, P55772, P57110, P70665, P82450, P97535, P97687, Q0V8L2, Q0VB07, Q53H76, Q58CQ9, Q5E9H0, Q5R5M5, Q5RBQ5, Q5RFU0, Q67BJ4, Q6P6S9, Q6YGZ1, Q71RP1, Q794F9, Q8K0L2, Q8TE60, Q8VI78, Q95194, Q96LB8, Q96LB9, Q99JP7, Q99MZ4, Q9HAT2

Diamond homologs: A2CJE2, A2CJE3, A2CJE4, A8QL59, C0LZJ5, C5FUK3, D4B1G0, D4DCV9, E9NW26, F8VQ03, G5EFD5, J3S830, O13766, O35227, O42596, O73795, O75077, O75078, O77780, O93515, O93517, O93518, P0C6B6, P0C6E3, P0C6R9, P0C7B0, P0DJ87, P0DM87, P17497, P23323, P31989, P83912, Q05910, Q0NZX6, Q0NZX7, Q0NZX8, Q0NZX9, Q0NZY0, Q13443, Q13444

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	25
Likely pathogenic	0
Uncertain significance	93
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
145616	GRCh38/hg38 8p11.23-11.21(chr8:38065927-40341650)x1	Pathogenic
147303	GRCh38/hg38 8p23.1-11.21(chr8:12728904-40169194)x3	Pathogenic
147723	GRCh38/hg38 8p12-11.21(chr8:29362097-40231708)x1	Pathogenic
150770	GRCh38/hg38 8p12-q12.1(chr8:36580103-59618998)x3	Pathogenic
161033	GRCh38/hg38 8p23.1-11.21(chr8:12609975-42085703)x3	Pathogenic
1703665	Single allele	Pathogenic
1711134	Single allele	Pathogenic
2580355	GRCh37/hg19 8p11.23-q11.21(chr8:36763176-50929707)x3	Pathogenic
2659006	GRCh37/hg19 8p11.22-11.21(chr8:38602986-41615655)x1	Pathogenic
2671608	Single allele	Pathogenic
2684517	GRCh37/hg19 8p23.2-11.21(chr8:2201405-41723095)x3	Pathogenic
2684529	GRCh37/hg19 8p22-11.1(chr8:14240573-43824035)x3	Pathogenic
3063025	GRCh37/hg19 8p21.2-q21.3(chr8:27024288-89410121)x3	Pathogenic
3063038	GRCh37/hg19 8p21.3-11.1(chr8:20136266-43786723)x3	Pathogenic
3391848	GRCh37/hg19 8p11.23-q11.23(chr8:37551624-52934472)x3	Pathogenic
394647	GRCh37/hg19 8p23.1-11.1(chr8:12580132-43388233)x3	Pathogenic
442330	GRCh37/hg19 8p23.1-11.22(chr8:12528482-39593802)x3	Pathogenic
563546	GRCh37/hg19 8p12-11.21(chr8:31352498-41481295)x3	Pathogenic
57114	GRCh38/hg38 8p12-11.21(chr8:34312250-43158901)x1	Pathogenic
57237	GRCh38/hg38 8p21.2-q11.21(chr8:25832130-48521849)x3	Pathogenic
57312	GRCh38/hg38 8p12-q11.21(chr8:29719897-48521849)x3	Pathogenic
59764	GRCh38/hg38 8p23.1-11.1(chr8:12609975-43336172)x3	Pathogenic
59782	GRCh38/hg38 8p11.23-11.21(chr8:37899430-42371734)x3	Pathogenic
60360	GRCh38/hg38 8p11.23-11.21(chr8:38342177-40546982)x1	Pathogenic
997076	GRCh37/hg19 8p23.3-11.1(chr8:176814-43396776)	Pathogenic

SpliceAI

3064 predictions. Top by Δscore:

Variant	Effect	Δscore
8:39584674:GAAG:G	donor_gain	1.0000
8:39584675:AAGGT:A	donor_loss	1.0000
8:39584676:AGG:A	donor_loss	1.0000
8:39584678:G:GG	donor_gain	1.0000
8:39584678:GTAA:G	donor_loss	1.0000
8:39585350:A:T	donor_gain	1.0000
8:39585350:AAG:A	donor_loss	1.0000
8:39585351:AGG:A	donor_loss	1.0000
8:39585352:GGTA:G	donor_loss	1.0000
8:39585353:G:GA	donor_loss	1.0000
8:39606363:G:GG	donor_gain	1.0000
8:39637262:A:AG	acceptor_gain	1.0000
8:39637263:G:GA	acceptor_gain	1.0000
8:39637702:GT:G	donor_gain	1.0000
8:39637704:G:GG	donor_gain	1.0000
8:39645336:A:AG	acceptor_gain	1.0000
8:39645337:G:GG	acceptor_gain	1.0000
8:39645470:GCAGT:G	donor_gain	1.0000
8:39645473:GT:G	donor_gain	1.0000
8:39645475:G:GG	donor_gain	1.0000
8:39667996:A:AG	acceptor_gain	1.0000
8:39667997:G:GG	acceptor_gain	1.0000
8:39668192:AAAAG:A	donor_loss	1.0000
8:39668193:AAAG:A	donor_loss	1.0000
8:39668194:AAGG:A	donor_loss	1.0000
8:39668195:AG:A	donor_loss	1.0000
8:39668196:GGT:G	donor_loss	1.0000
8:39668197:G:GC	donor_loss	1.0000
8:39668198:T:G	donor_loss	1.0000
8:39677534:G:GT	donor_gain	1.0000

AlphaMissense

4914 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:39692666:T:A	C630S	0.986
8:39692667:G:C	C630S	0.986
8:39668061:T:A	C464S	0.982
8:39668062:G:C	C464S	0.982
8:39706817:T:A	C644S	0.982
8:39706818:G:C	C644S	0.982
8:39706844:T:A	C653S	0.982
8:39706845:G:C	C653S	0.982
8:39648507:T:A	C404S	0.981
8:39648508:G:C	C404S	0.981
8:39663816:T:A	C418S	0.981
8:39663817:G:C	C418S	0.981
8:39663855:T:A	C431S	0.979
8:39663856:G:C	C431S	0.979
8:39648369:A:C	S358R	0.977
8:39648371:C:A	S358R	0.977
8:39648371:C:G	S358R	0.977
8:39668043:T:A	C458S	0.977
8:39668044:G:C	C458S	0.977
8:39680212:T:A	C603S	0.976
8:39680213:G:C	C603S	0.976
8:39663873:T:A	C437S	0.975
8:39663874:G:C	C437S	0.975
8:39706798:T:A	N637K	0.975
8:39706798:T:G	N637K	0.975
8:39668019:T:A	C450S	0.974
8:39668020:G:C	C450S	0.974
8:39668082:T:A	C471S	0.973
8:39668083:G:C	C471S	0.973
8:39668154:T:A	C495S	0.973

dbSNP variants (sampled 300 via entrez): RS1000014978 (8:39718962 A>G), RS1000018972 (8:39640277 G>A), RS1000019785 (8:39599491 T>A), RS1000054092 (8:39634708 A>G), RS1000066218 (8:39592959 C>T), RS1000092910 (8:39692243 C>T), RS1000144216 (8:39675640 C>A), RS1000179892 (8:39701647 G>C), RS1000213264 (8:39628059 A>G), RS1000245324 (8:39646212 T>C), RS1000249773 (8:39660134 A>T), RS1000257476 (8:39701980 T>G), RS1000261468 (8:39600329 T>C), RS1000265014 (8:39709946 G>T), RS1000271616 (8:39618579 A>G)

Disease associations

OMIM: gene MIM:619495 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): 8p inverted duplication/deletion syndrome (MONDO:0019876)

Orphanet (1): 8p inverted duplication/deletion syndrome (Orphanet:96092)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001353_4	HIV-1 susceptibility	2.000000e-06
GCST003173_3	Visceral adipose tissue/subcutaneous adipose tissue ratio	2.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0004767	visceral:subcutaneous adipose tissue ratio

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

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
alpha phellandrene	decreases expression	1
potassium perchlorate	increases expression	1
CGP 52608	affects binding, increases reaction	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Folic Acid	increases expression	1
Tobacco Smoke Pollution	decreases methylation	1
Triclosan	increases expression	1
Valproic Acid	increases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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