ADAM21

Summary

ADAM21 (ADAM metallopeptidase domain 21, HGNC:200) is a protein-coding gene on chromosome 14q24.2, encoding Disintegrin and metalloproteinase domain-containing protein 21 (Q9UKJ8). May be involved in sperm maturation and/or 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 biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The expression of this gene expression is testis-specific.

Source: NCBI Gene 8747 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 114 total
• Regional missense constraint (gnomAD): 1 of 4 regions constrained (≈5% of expected missense variation)
• GTEx eGene: eQTL in 22 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.14 (intermediate), LOEUF 1.91 (unconstrained)
• MANE Select transcript: NM_003813
• Notable: 114 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:200
Approved symbol	ADAM21
Name	ADAM metallopeptidase domain 21
Location	14q24.2
Locus type	gene with protein product
Status	Approved
Aliases	ADAM31
Ensembl gene	ENSG00000139985
Ensembl biotype	protein_coding
OMIM	603713
Entrez	8747

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

MANE Select: ENST00000603540

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 3: 1

ENST00000603540, ENST00000679631, ENST00000942462, ENST00000942463, ENST00001139660

RefSeq mRNA: 1 — MANE Select: NM_003813 NM_003813

CCDS: CCDS9804

Canonical transcript exons

ENST00000603540 — 2 exons

Exon	Start	End
ENSE00002452332	70452174	70452263
ENSE00003575393	70457349	70459905

Expression profiles

Bgee: expression breadth ubiquitous, 121 present calls, max score 94.51.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0146 / max 13.9836, expressed in 3 samples.

Highest expression (Bgee): sperm, male germ cell, male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, testis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ADAM21 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 22 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 22 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	3.2e-22	+0.39	14:70455425:C:A
Thyroid	eqtl	3.9e-10	-0.57	14:70514449:A:C
Artery Tibial	eqtl	3.5e-09	-0.47	14:70580348:AT:A
Skin Sun Exposed Lower leg	eqtl	1.1e-05	-0.32	14:70587667:T:C
Esophagus Muscularis	eqtl	7.0e-05	-0.36	14:70581841:C:T
Esophagus Gastroesophageal Junction	eqtl	8.2e-05	-0.47	14:70579708:A:G
Nerve Tibial	eqtl	3.5e-04	-0.27	14:70568360:G:GA
Pancreas	eqtl	7.5e-04	-0.52	14:70595715:T:C
Pituitary	eqtl	9.5e-04	-0.49	14:70595715:T:C
Artery Aorta	eqtl	9.9e-04	-0.27	14:70457532:A:G
Testis	eqtl	1.3e-03	-0.12	14:70457532:A:G
Breast Mammary Tissue	eqtl	1.6e-03	-0.43	14:70574785:T:C
Skin Not Sun Exposed Suprapubic	eqtl	1.7e-03	-0.37	14:70576840:C:T
Brain Frontal Cortex BA9	eqtl	1.7e-03	+0.25	14:70425508:C:T
Adipose Visceral Omentum	eqtl	2.6e-03	-0.24	14:70202285:A:G
Small Intestine Terminal Ileum	eqtl	1.4e-02	-0.43	14:70291860:T:C
Brain Cortex	eqtl	2.1e-02	-0.25	14:70457532:A:G
Muscle Skeletal	eqtl	3.6e-02	+0.32	14:70439006:G:A
Brain Caudate basal ganglia	eqtl	4.0e-02	-0.24	14:70457532:A:G
Brain Cerebellar Hemisphere	eqtl	4.4e-02	-0.31	14:70305157:A:G

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
140401	0.0146	3

Top tissues by expression

showing 100 of 259 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	94.51	gold quality
male germ cell	CL:0000015	90.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.61	gold quality
secondary oocyte	CL:0000655	76.53	gold quality
right testis	UBERON:0004534	71.38	gold quality
left testis	UBERON:0004533	71.10	gold quality
testis	UBERON:0000473	70.10	gold quality
ileal mucosa	UBERON:0000331	68.09	gold quality
tibialis anterior	UBERON:0001385	67.96	silver quality
buccal mucosa cell	CL:0002336	63.72	gold quality
oocyte	CL:0000023	61.10	silver quality
stromal cell of endometrium	CL:0002255	60.48	gold quality
pancreatic ductal cell	CL:0002079	59.03	silver quality
tendon of biceps brachii	UBERON:0008188	58.08	gold quality
decidua	UBERON:0002450	56.55	gold quality
endothelial cell	CL:0000115	56.53	gold quality
hair follicle	UBERON:0002073	56.04	gold quality
prefrontal cortex	UBERON:0000451	55.86	gold quality
right adrenal gland cortex	UBERON:0035827	54.73	gold quality
deltoid	UBERON:0001476	54.35	silver quality
tendon	UBERON:0000043	54.06	silver quality
right adrenal gland	UBERON:0001233	53.81	gold quality
left adrenal gland	UBERON:0001234	53.32	gold quality
lower lobe of lung	UBERON:0008949	53.12	gold quality
islet of Langerhans	UBERON:0000006	52.73	gold quality
calcaneal tendon	UBERON:0003701	52.39	silver quality
left adrenal gland cortex	UBERON:0035825	52.11	gold quality
quadriceps femoris	UBERON:0001377	52.07	gold quality
adrenal cortex	UBERON:0001235	51.78	gold quality
bone marrow cell	CL:0002092	51.66	gold quality
muscle tissue	UBERON:0002385	51.47	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	51.09	gold quality
epithelial cell of pancreas	CL:0000083	51.03	silver quality
adrenal gland	UBERON:0002369	50.80	gold quality
metanephric glomerulus	UBERON:0004736	50.80	gold quality
vastus lateralis	UBERON:0001379	50.73	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
frontal cortex	UBERON:0001870	50.38	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
adult organism	UBERON:0007023	50.25	silver quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
oviduct epithelium	UBERON:0004804	50.03	gold quality
Brodmann (1909) area 9	UBERON:0013540	49.62	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
muscle organ	UBERON:0001630	49.29	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
gastrocnemius	UBERON:0001388	48.89	gold quality
neocortex	UBERON:0001950	48.87	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac atrium	UBERON:0002081	48.82	gold quality
right atrium auricular region	UBERON:0006631	48.70	gold quality
muscle of leg	UBERON:0001383	48.67	gold quality
thymus	UBERON:0002370	48.63	gold quality
descending thoracic aorta	UBERON:0002345	48.59	gold quality
corpus callosum	UBERON:0002336	48.55	silver quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
kidney epithelium	UBERON:0004819	48.51	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	47.98	gold quality
right hemisphere of cerebellum	UBERON:0014890	47.97	silver quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
heart	UBERON:0000948	47.78	gold quality
heart left ventricle	UBERON:0002084	47.73	gold quality
cerebellar cortex	UBERON:0002129	47.70	silver quality
uterine cervix	UBERON:0000002	47.61	silver quality
cerebellar hemisphere	UBERON:0002245	47.59	silver quality
cerebellum	UBERON:0002037	47.56	silver quality
cardiac ventricle	UBERON:0002082	47.47	gold quality
nephron tubule	UBERON:0001231	47.30	gold quality
smooth muscle tissue	UBERON:0001135	47.25	gold quality
diaphragm	UBERON:0001103	47.05	gold quality
gluteal muscle	UBERON:0002000	47.03	gold quality
triceps brachii	UBERON:0001509	47.01	gold quality
hypothalamus	UBERON:0001898	46.95	gold quality
thoracic aorta	UBERON:0001515	46.89	gold quality
endometrium epithelium	UBERON:0004811	46.85	gold quality
middle temporal gyrus	UBERON:0002771	46.83	gold quality
cerebral cortex	UBERON:0000956	46.66	gold quality
ascending aorta	UBERON:0001496	46.64	gold quality
colonic epithelium	UBERON:0000397	46.60	gold quality
aorta	UBERON:0000947	45.87	gold quality
layer of synovial tissue	UBERON:0007616	45.76	gold quality
right coronary artery	UBERON:0001625	45.75	gold quality
nasal cavity epithelium	UBERON:0005384	45.61	gold quality
left coronary artery	UBERON:0001626	45.58	gold quality
sural nerve	UBERON:0015488	45.50	gold quality
vermiform appendix	UBERON:0001154	45.49	silver quality
cingulate cortex	UBERON:0003027	45.49	gold quality
dorsal root ganglion	UBERON:0000044	45.34	gold quality
right frontal lobe	UBERON:0002810	45.33	gold quality
coronary artery	UBERON:0001621	45.28	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.45

HPA expression

RNA tissue specificity: Tissue enriched

44 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Testis	tissue	8.1	medium
Postcentral gyrus	tissue	5.8
Choroid plexus	tissue	4.1
Nucleus accumbens	tissue	3.9
Hippocampus	tissue	3.7	not detected
Locus coeruleus	tissue	3.5
Retina	tissue	1.2
Cerebral cortex	tissue	0.3	not detected
Basal ganglia	tissue	0.3	not detected
Putamen	tissue	0.3
Amygdala	tissue	0.3
Ventral forebrain	tissue	0.3
Retrosplenial and cingulate cortex	tissue	0.3
Insular cortex	tissue	0.3
Pituitary gland	tissue	0.2
Prefrontal cortex	tissue	0.2
Heart muscle	tissue	0.2	not detected
Hypothalamus	tissue	0.2
Spinal cord	tissue	0.2
Hippocampal formation	tissue	0.2
Entorhinal cortex	tissue	0.2
Septum	tissue	0.2
Retrosplenial cortex	tissue	0.2
Temporal cortex	tissue	0.2
Lymph node	tissue	0.1	not detected
Pons	tissue	0.1
Ovary	tissue	0.1	not detected
Vagina	tissue	0.1	not detected
Skeletal muscle	tissue	0.1	not detected
Motor cortex	tissue	0.1
Tongue	tissue	0.1
Frontal cortex	tissue	0.1
Midbrain	tissue	0.1
Medulla oblongata	tissue	0.1
Thalamus	tissue	0.1
Superior colliculi	tissue	0.1
Substantia nigra	tissue	0.1
Corpus callosum	tissue	0.1
Adrenal gland	tissue	0.1	not detected
Periaqueductal gray	tissue	0.1
Olfactory bulb	tissue	0.1
Somatosensory cortex	tissue	0.1
Appendix	tissue	0.1	not detected
Occipital cortex	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Parietal operculum (5.2), Postcentral gyrus, middle (5.1), Precentral gyrus (5.1), Frontal eye field (4.9), Posterior cingulate cortex (4.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ADAM21 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

22 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-1301-3P	98.64	68.27	1071
HSA-MIR-5047	98.64	68.62	1035
HSA-MIR-5011-3P	98.63	64.81	638
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-4536-5P	98.47	64.39	657
HSA-MIR-12128	96.67	66.98	1471

Functional genomics

gnomAD constraint: pLI 0.141, LOEUF 1.91, missense Z 2.33 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000603540 splits into 4 regions with different missense tolerance; 1 is missense-constrained (≈5% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
14:70,457,500–70,457,651	51 / 59.5	0.86	no
14:70,457,652–70,457,764	15 / 47.3	0.32	yes (p 2.6e-06)
14:70,457,765–70,459,276	448 / 611.2	0.73	no
14:70,459,277–70,459,665	164 / 156.4	1.05	no

Literature-anchored findings (GeneRIF, showing 1)

• ADAM21 was overexpressed in KYN-2 hepatocellular carcinoma (HCC) cell line, and its knockdown reduced invasion, migration, proliferation, and metastasis relative to controls. In HCC clinical specimens, ADAM21 positivity was associated with vascular invasion, large tumor size, high histological grade, and lower overall and recurrence-free survival as compared to cases that were negative for ADAM21 expression. (PMID:29138461)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	adam10b	ENSDARG00000015502
danio_rerio	adam10a	ENSDARG00000053468
danio_rerio	adam9b	ENSDARG00000057138
danio_rerio	si:ch1073-396h14.1	ENSDARG00000057590
mus_musculus	Adam21	ENSMUSG00000008438
rattus_norvegicus	LOC103690152	ENSRNOG00000047682
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), ADAM15 (ENSG00000143537), ADAM12 (ENSG00000148848), ADAM33 (ENSG00000149451), ADAM8 (ENSG00000151651), ADAM17 (ENSG00000151694), ADAM29 (ENSG00000168594), ADAM9 (ENSG00000168615), ADAM18 (ENSG00000168619), ADAM32 (ENSG00000197140)

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Trichophyton verrucosum HKI 0517	D4DCV9	97.9%	Diamond
Macaca fascicularis	Q28478	91.4%	Diamond
Xenopus laevis	Q9PSZ3	77.8%	Diamond
Bos taurus	O77780	65.0%	Diamond
Oryctolagus cuniculus	Q28660	64.6%	Diamond
Cavia porcellus	Q60411	56.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
COX16	protein-coding	51241
SYNJ2BP	protein-coding	55333
SYNJ2BP-COX16	protein-coding	100529257
ADAM20	protein-coding	8748

Protein

Protein identifiers

Disintegrin and metalloproteinase domain-containing protein 21 — Q9UKJ8 (reviewed: Q9UKJ8)

All UniProt accessions (1): Q9UKJ8

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in sperm maturation and/or fertilization. May also be involved in epithelia functions associated with establishing and maintaining gradients of ions or nutrients.

Subcellular location. Membrane.

Post-translational modifications. Has no obvious cleavage site for furin endopeptidase, suggesting that the proteolytic processing is regulated.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. A tripeptide motif (VGE) within disintegrin-like domain could be involved in the binding to egg integrin receptor and thus could mediate sperm/egg binding. The cysteine-rich domain encodes putative cell-fusion peptides, which could be involved in sperm-egg fusion. 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. May be the functional equivalent of ADAM 1/fertilin alpha which is a pseudogene in human.

RefSeq proteins (1): NP_003804* (*=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 (35 total): glycosylation site 7, disulfide bond 7, sequence conflict 6, binding site 4, domain 3, topological domain 2, signal peptide 1, propeptide 1, active site 1, chain 1, transmembrane region 1, short sequence motif 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKJ8-F1	83.17	0.48

Human Protein Atlas

Protein class: Predicted membrane proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH uncertain

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)

Position	Role
342

Ligand- & substrate-binding residues (4)

Position	Role
173	Zn(2+)
341	Zn(2+)
345	Zn(2+)
351	Zn(2+)

Disulfide bonds (7)

Type	Positions
Disulfide bond	316–393, 356–378, 358–363, 464–484, 634–645, 639–651, 653–662

Glycosylation sites (7)

Type	Positions
N-linked (glcnac…) asparagine	164, 227, 377, 437, 478, 546, 600

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-2534343	Interaction With Cumulus Cells And The Zona Pellucida	curated
R-HSA-1187000	Fertilization	—
R-HSA-1474165	Reproduction	—

MSigDB gene sets: 60 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_SINGLE_FERTILIZATION, GOMF_METALLOPEPTIDASE_ACTIVITY, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, GOCC_CELL_SURFACE, chr14q24, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_SEX_DIFFERENTIATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOCC_NEURON_PROJECTION, GOBP_FERTILIZATION, GOBP_MALE_SEX_DIFFERENTIATION, GOBP_DEVELOPMENT_OF_PRIMARY_SEXUAL_CHARACTERISTICS, GOCC_SIDE_OF_MEMBRANE

GO Biological Process (3): proteolysis (GO:0006508), single fertilization (GO:0007338), male gonad development (GO:0008584)

GO Molecular Function (6): metalloendopeptidase activity (GO:0004222), metallopeptidase activity (GO:0008237), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (7): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), axon (GO:0030424), neuronal cell body (GO:0043025), sperm head plasma membrane (GO:1990913), membrane (GO:0016020), neuron projection (GO:0043005)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Fertilization	1
Reproduction	1

GO top-level categories

25 GO namespaces:

Category	Terms
protein metabolic process	1
fertilization	1
gonad development	1
development of primary male sexual characteristics	1
endopeptidase activity	1
metallopeptidase activity	1
peptidase activity	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
neuron projection	1
somatodendritic compartment	1
cell body	1
sperm head	1
sperm plasma membrane	1
plasma membrane region	1
cellular anatomical structure	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

showing 15 of 542 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM21	OR2T27	Q8NH04	387
ADAM21	MAGEB6B	A0A0J9YX57	380
ADAM21	TEKTIP1	A6NCJ1	360
ADAM21	TEX55	Q96M34	359
ADAM21	ADAMTSL5	Q6ZMM2	345
ADAM21	COX16	Q9P0S2	344
ADAM21	FAM228A	Q86W67	323
ADAM21	A0A087WYV9	A0A087WYV9	322
ADAM21	SYNJ2BP	P57105	307
ADAM21	WDR48	Q8TAF3	307
ADAM21	SUSD6	Q92537	300
ADAM21	DCAF5	Q96JK2	295
ADAM21	ADAMTSL2	Q86TH1	292
ADAM21	CNBD2	Q96M20	289
ADAM21	SIAH1	Q8IUQ4	288

IntAct

Human interaction partners of ADAM21 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
CNR2	physical association	0.560	3
SGTA	physical association	0.560	3
PLXNA2	association	0.530	2
FGA	physical association	0.400	1
PLXNB2	association	0.350	1

BioGRID (83 interactions; top human partners by supporting records): VEGFB (Affinity Capture-MS; 3 records), ACTA2 (Affinity Capture-MS; 2 records), CANX (Affinity Capture-MS; 2 records), CCPG1 (Affinity Capture-MS; 2 records), CHSY3 (Affinity Capture-MS; 2 records), DHFRL1 (Affinity Capture-MS; 2 records), EGFL7 (Affinity Capture-MS; 2 records), HLA-B (Affinity Capture-MS; 2 records), ITGB5 (Affinity Capture-MS; 2 records), LCLAT1 (Affinity Capture-MS; 2 records), LRFN3 (Affinity Capture-MS; 2 records), LRP10 (Affinity Capture-MS; 2 records), LRRC3 (Affinity Capture-MS; 2 records), MANF (Affinity Capture-MS; 2 records), PCSK1N (Affinity Capture-MS; 2 records)

Disease & clinical

Genetic variants

Variant evidence for ADAM21: 114 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	99
Likely benign	9
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 19 predictions of 36):

Position(s)	Effect	Δscore	Sites
14:70452264–70452265	donor_loss	0.9900	5
14:70457347–70457348	acceptor_loss	0.9400	6
14:70455260	donor_gain	0.9100
14:70457336	acceptor_loss	0.9100
14:70457342	acceptor_loss	0.9000
14:70457351	acceptor_gain	0.7600
14:70455256	donor_gain	0.6500
14:70457346	acceptor_loss	0.6500
14:70457352	acceptor_gain	0.5200
14:70457469	acceptor_gain	0.4500

AlphaMissense

760 missense substitutions predicted likely pathogenic (of 4,811 scored), across 202 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M365	9	0.788	0.961
H341	8	0.797	0.907
H345	8	0.762	0.893
D472	8	0.758	0.817
C662	7	0.913	0.958
C653	7	0.905	0.950
C651	7	0.899	0.948
C639	7	0.892	0.943
F375	7	0.877	0.964
C471	7	0.871	0.939
C560	7	0.861	0.920
C477	7	0.860	0.939
C645	7	0.859	0.933
C613	7	0.857	0.927
C502	7	0.848	0.910
C619	7	0.848	0.913
C451	7	0.847	0.917
C446	7	0.841	0.898
C553	7	0.839	0.932
C452	7	0.837	0.899

HPA cancer prognostics

RNA cancer specificity: Not detected

Disease associations

OMIM: gene MIM:603713 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST004362_1	Plasma estrone levels in resected estrogen-receptor positive breast cancer	1e-6
GCST012137_5	Motor coordination	2e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0007970	estrone measurement
EFO:0010749	motor function measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M12: Astacin/Adamalysin

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
testosterone enanthate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases methylation	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
sulforaphane	increases expression	1
butyraldehyde	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
Cadmium	decreases expression, increases abundance	1
Lipopolysaccharides	affects response to substance, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.