A2M

Summary

A2M (alpha-2-macroglobulin, HGNC:7) is a protein-coding gene on chromosome 12p13.31, encoding Alpha-2-macroglobulin (P01023). Is able to inhibit all four classes of proteinases by a unique ’trapping’ mechanism.

The protein encoded by this gene is a protease inhibitor and cytokine transporter. It uses a bait-and-trap mechanism to inhibit a broad spectrum of proteases, including trypsin, thrombin and collagenase. It can also inhibit inflammatory cytokines, and it thus disrupts inflammatory cascades. Mutations in this gene are a cause of alpha-2-macroglobulin deficiency. This gene is implicated in Alzheimer’s disease (AD) due to its ability to mediate the clearance and degradation of A-beta, the major component of beta-amyloid deposits. A related pseudogene, which is also located on the p arm of chromosome 12, has been identified.

Source: NCBI Gene 2 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Alzheimer disease type 1 (No Known Disease Relationship, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 249 total — 16 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_000014

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7
Approved symbol	A2M
Name	alpha-2-macroglobulin
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	FWP007, S863-7, CPAMD5
Ensembl gene	ENSG00000175899
Ensembl biotype	protein_coding
OMIM	103950
Entrez	2

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 19 protein_coding, 5 protein_coding_CDS_not_defined, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000318602, ENST00000404455, ENST00000462568, ENST00000467091, ENST00000472360, ENST00000495442, ENST00000495709, ENST00000497324, ENST00000539638, ENST00000542567, ENST00000543436, ENST00000545828, ENST00000546069, ENST00000891824, ENST00000891825, ENST00000891826, ENST00000891827, ENST00000891828, ENST00000891829, ENST00000891830, ENST00000891831, ENST00000891832, ENST00000891833, ENST00000891834, ENST00000891835, ENST00000956132, ENST00000956133, ENST00000956134, ENST00000956135, ENST00000956136

RefSeq mRNA: 4 — MANE Select: NM_000014 NM_000014, NM_001347423, NM_001347424, NM_001347425

CCDS: CCDS44827

Canonical transcript exons

ENST00000318602 — 36 exons

Exon	Start	End
ENSE00000717786	9070488	9070578
ENSE00000717788	9072653	9072871
ENSE00000717790	9076756	9076936
ENSE00000718059	9106491	9106605
ENSE00000718061	9109321	9109405
ENSE00000718064	9112377	9112536
ENSE00000897838	9098607	9098756
ENSE00000897852	9101447	9101674
ENSE00000897866	9106236	9106345
ENSE00000897873	9107524	9107644
ENSE00001607964	9091201	9091429
ENSE00001618214	9077346	9077420
ENSE00001710304	9068740	9068842
ENSE00001710972	9074560	9074783
ENSE00001721442	9077701	9077857
ENSE00001753977	9069745	9069813
ENSE00001787383	9072359	9072486
ENSE00001945404	9115764	9115919
ENSE00003475180	9109867	9110035
ENSE00003489943	9104239	9104400
ENSE00003526824	9101144	9101207
ENSE00003532084	9089200	9089251
ENSE00003536200	9093465	9093579
ENSE00003555109	9080094	9080177
ENSE00003565450	9089902	9090023
ENSE00003570578	9068183	9068224
ENSE00003594068	9095539	9095700
ENSE00003602796	9079639	9079815
ENSE00003602989	9113360	9113543
ENSE00003609675	9094973	9095084
ENSE00003629555	9067708	9067839
ENSE00003641971	9099381	9099523
ENSE00003645463	9112159	9112211
ENSE00003670186	9079244	9079331
ENSE00003713497	9090356	9090482
ENSE00003786652	9110314	9110334

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 99.95.

FANTOM5 (CAGE): breadth broad, TPM avg 53.3555 / max 1869.9890, expressed in 851 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129396	35.2642	720
129397	9.3646	639
129395	5.1490	435
129398	1.8932	379
129399	0.9099	270
129400	0.3495	117
129384	0.1341	75
129402	0.0762	38
129387	0.0737	46
129388	0.0733	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower lobe of lung	UBERON:0008949	99.95	gold quality
upper lobe of lung	UBERON:0008948	99.89	gold quality
upper lobe of left lung	UBERON:0008952	99.89	gold quality
lung	UBERON:0002048	99.88	gold quality
right lung	UBERON:0002167	99.87	gold quality
descending thoracic aorta	UBERON:0002345	99.75	gold quality
visceral pleura	UBERON:0002401	99.71	gold quality
pericardium	UBERON:0002407	99.71	gold quality
colonic epithelium	UBERON:0000397	99.69	gold quality
right coronary artery	UBERON:0001625	99.69	gold quality
tendon of biceps brachii	UBERON:0008188	99.69	gold quality
adult organism	UBERON:0007023	99.67	gold quality
thoracic aorta	UBERON:0001515	99.66	gold quality
mucosa of urinary bladder	UBERON:0001259	99.65	gold quality
ascending aorta	UBERON:0001496	99.65	gold quality
heart right ventricle	UBERON:0002080	99.62	gold quality
metanephros cortex	UBERON:0010533	99.62	gold quality
aorta	UBERON:0000947	99.61	gold quality
urinary bladder	UBERON:0001255	99.61	gold quality
gall bladder	UBERON:0002110	99.60	gold quality
coronary artery	UBERON:0001621	99.58	gold quality
left coronary artery	UBERON:0001626	99.57	gold quality
liver	UBERON:0002107	99.57	gold quality
popliteal artery	UBERON:0002250	99.57	gold quality
tibial artery	UBERON:0007610	99.57	gold quality
mucosa of stomach	UBERON:0001199	99.56	gold quality
blood vessel layer	UBERON:0004797	99.56	gold quality
superficial temporal artery	UBERON:0001614	99.49	gold quality
saphenous vein	UBERON:0007318	99.49	gold quality
mammary duct	UBERON:0001765	99.44	gold quality

Single-cell (SCXA)

Detected in 39 experiment(s), a significant marker in 38.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	8599.15
E-MTAB-6653	yes	7207.11
E-MTAB-10137	yes	7055.73
E-HCAD-15	yes	6209.37
E-GEOD-130473	yes	6199.65
E-CURD-126	yes	6105.09
E-GEOD-84465	yes	5146.32
E-GEOD-81547	yes	3339.15
E-MTAB-10662	yes	2828.81
E-GEOD-137537	yes	2194.23
E-MTAB-6308	yes	2033.50
E-GEOD-81383	yes	1857.99
E-GEOD-134144	yes	1840.86
E-CURD-46	yes	1764.92
E-GEOD-135922	yes	1592.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, CEBPD, FOS, JUN, KLF6, NFKB1, NFKB, NR5A1, SPI1, STAT1, STAT3, STAT5A, STAT5B, TFCP2

miRNA regulators (miRDB)

7 targeting A2M, 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-9902	99.89	69.15	2250
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-224-5P	98.33	70.12	1256

Literature-anchored findings (GeneRIF, showing 40)

• there are two distinct steps in the repression of engrailed by Runt (PMID:12145660)
• These proteins provide a paradigm for understanding DNA-binding-independent regulation by developmentally important transcription factors. (PMID:12732185)
• Contrasting responses of different downstream targets to Runt in the presence or absence of Ftz is thus central to the combinatorial logic of the pair-rule to segment-polarity transition. (PMID:15102703)
• Lilli plays an architectural role in facilitating transcriptional activation that depends both on the target gene and the developmental context (PMID:17137570)
• Runt-dependent regulation in the Drosophila blastoderm embryo relies on unique, target-gene-specific molecular interactions. (PMID:21325629)
• A dual role for DNA binding by Runt in activation and repression of sloppy paired transcription. (PMID:34432496)
• Data show that innexins, including shakB and ogre, are not functionally interchangeable in Drosophila during photoreceptor development. (PMID:12154069)
• Seizures caused by bang-sensitive (bas2) and bang-senseless (bss1, bss2 alleles) mutations are not suppressed by shakB2 (PMID:16192342)
• The escape response is impaired in ShakB2 mutants, but they displayed normal voluntary flight initiation. The escape mechanism is subject to developmental modulation following eclosion and the GF system does not underlie voluntary flight. (PMID:17851667)
• Tryptophan scanning was used to probe the first transmembrane domain (M1) of the Drosophila innexin Shaking-B(Lethal). (PMID:22098739)
• Overexpression of ShakB(N+16) in JONs caused the formation of ectopic dye coupling (PMID:27043822)
• Misexpression of ShakB did not increase these parameters. Immunostaining showed no association between presynaptic active zones and the new ShakB plaques. (PMID:30118493)
• results suggest a role for CHD1 in the assembly of active chromatin and a function of ACF in the assembly of repressive chromatin (PMID:15643425)
• findings establish CHD1 as a major factor in replacement histone metabolism in the nucleus and reveal a critical role for CHD1 in the earliest developmental instances of genome-scale, replication-independent nucleosome assembly. (PMID:17717186)
• These results clarify the roles of chromatin remodelers in transcription and provide novel insights into CHD1 function. (PMID:18202396)
• our results emphasize a role for Chd1 in histone replacement in both budding yeast and Drosophila melanogaster, and surprisingly they show that the major effects of Chd1 on turnover occur at the 3’ ends of genes. (PMID:22807688)
• Intestinal resistance against infection by P. aeruginosa is linked to maintaining proper balance of gut-microbe interactions and the chromatin remodeler CHD1 is involved in regulating this aspect. (PMID:22912810)
• The Drosophila melanogaster CHD1 chromatin remodeling factor modulates global chromosome structure and counteracts HP1a and H3K9me2. (PMID:23533627)
• An effect of Chd1 null mutation can be increased by deficiency of one of the genes, encoding variant histone H3.3, His 3.3 B, suggesting that the role of CHD1 in the control of male X chromosome organization can be mediated by CHD1 activity in H3.3 histone deposition and exchange. (PMID:30191695)
• CHD1 controls H3.3 incorporation in adult brain chromatin to maintain metabolic homeostasis and normal lifespan. (PMID:34610319)
• Wb laminin is an extracellular matrix ligand that is essential for integrin-dependent cellular migration in Drosophila. (PMID:17223100)
• Mesenchymal-to-epithelial transitions require tissue-specific interactions with distinct laminins. (PMID:34047771)
• results show that LK6 binds to ERK and is activated by ERK signalling and it is responsible for phosphorylating eIF4E in Drosophila (PMID:15487973)
• our results suggest that the level of eIF4E protein is regulated by Diap1, and that IAPs may play a role in cap-dependent translation by regulating the level of eIF4E protein. (PMID:18182863)
• These results suggest that the eIF4E-1,2 gene is regulated by Hfp through a mechanism linked to transcription control and 3’ splice site selection, which determines the pattern and translation efficiency of eIF4E-1,2 mRNAs. (PMID:18671938)
• data are consistent with the idea that Parkin and eIF4E act in a common pathway, likely modulating cap-dependent translation initiation events. (PMID:20869429)
• eIF4E regulates the sex-specific expression of the master switch gene Sxl. (PMID:21829374)
• Protein-protein interactions rather than interactions with the mRNA are essential for the recruitment of eIF4E and for a putative nucleation function. (PMID:22507384)
• Eukaryotic initiation factor 4E-3 is essential for meiotic chromosome segregation, cytokinesis and male fertility in Drosophila. (PMID:22833128)
• eIF4E-binding protein requires non-canonical 4E-binding motifs and a lateral surface of eIF4E to repress translation. (PMID:25179781)
• Phosphorylation of 4E-BP1 impairs the competition with eIF4G for eIF4E binding. (PMID:25702871)
• Both eIF4E-1 and eIF4E-3 are required in spermatocytes for chromosome condensation and cytokinesis during the meiotic stages. (PMID:25849588)
• The structures of eIF4E-eIF4G complexes reveal an extended interface to regulate translation initiation. (PMID:27773676)
• Drosophila Me31B is a Dual eIF4E-Interacting Protein. (PMID:36638908)
• At1g09780 and At3g08590 has critical roles in stomatal movement, vegetative growth, and pollen production. (PMID:21813794)
• At1g09780 and At3g08590 has critical roles in stomatal movement, vegetative growth, and pollen production. (PMID:21813794)
• MOS2 promotes pri-miRNA processing through facilitating the recruitment of pri-miRNAs by the Dicing complexes. (PMID:23399598)
• MOS2 contributes to proper splicing of SNC1 transcript, redundantly with MOS2H. (PMID:23803746)
• Data indicate that strains within the 793/B serotype have > or =96% nucleotide identity within the whole S1 part of the spike protein gene. (PMID:15763735)
• Mutations and recombination events could contribute to the genetic diversity of the Italian isolates. (PMID:17043759)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	A2m	ENSMUSG00000030111
rattus_norvegicus	A2m	ENSRNOG00000028896
drosophila_melanogaster	Tep4	FBGN0041180
drosophila_melanogaster	Tep3	FBGN0041181
drosophila_melanogaster	Tep2	FBGN0041182
drosophila_melanogaster	Tep1	FBGN0041183
caenorhabditis_elegans	tep-1	WBGENE00013969

Paralogs (8): C5 (ENSG00000106804), C3 (ENSG00000125730), PZP (ENSG00000126838), CD109 (ENSG00000156535), CPAMD8 (ENSG00000160111), A2ML1 (ENSG00000166535), C4B (ENSG00000224389), C4A (ENSG00000244731)

Protein

Protein identifiers

Alpha-2-macroglobulin — P01023 (reviewed: P01023)

Alternative names: C3 and PZP-like alpha-2-macroglobulin domain-containing protein 5

All UniProt accessions (4): P01023, F5H1E8, F8W7L3, H0YFH1

UniProt curated annotations — full annotation on UniProt →

Function. Is able to inhibit all four classes of proteinases by a unique ’trapping’ mechanism. This protein has a peptide stretch, called the ‘bait region’ which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein which traps the proteinase. The entrapped enzyme remains active against low molecular weight substrates (activity against high molecular weight substrates is greatly reduced). Following cleavage in the bait region, a thioester bond is hydrolyzed and mediates the covalent binding of the protein to the proteinase.

Subunit / interactions. Homotetramer; disulfide-linked.

Subcellular location. Secreted.

Tissue specificity. Secreted in plasma.

Similarity. Belongs to the protease inhibitor I39 (alpha-2-macroglobulin) family.

RefSeq proteins (4): NP_000005, NP_001334352, NP_001334353, NP_001334354 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001599	Macroglobln_a2	Domain
IPR002890	MG2	Domain
IPR008930	Terpenoid_cyclase/PrenylTrfase	Homologous_superfamily
IPR009048	A-macroglobulin_rcpt-bd	Domain
IPR010916	TonB_box_CS	Conserved_site
IPR011625	A2M_N_BRD	Domain
IPR011626	Alpha-macroglobulin_TED	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR019742	MacrogloblnA2_CS	Conserved_site
IPR036595	A-macroglobulin_rcpt-bd_sf	Homologous_superfamily
IPR040839	MG4	Domain
IPR041555	MG3	Domain
IPR041813	A2M_TED	Domain
IPR047565	Alpha-macroglob_thiol-ester_cl	Conserved_site
IPR050473	A2M/Complement_sys	Family

Pfam: PF00207, PF01835, PF07677, PF07678, PF07703, PF17789, PF17791

UniProt features (65 total): strand 18, disulfide bond 13, glycosylation site 8, sequence conflict 8, sequence variant 5, region of interest 4, cross-link 3, helix 3, signal peptide 1, chain 1, turn 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
2P9R	X-RAY DIFFRACTION	2.3
7O7Q	ELECTRON MICROSCOPY	3.6
7O7R	ELECTRON MICROSCOPY	3.9
7VOO	ELECTRON MICROSCOPY	3.9
6TAV	X-RAY DIFFRACTION	4.2
7O7S	ELECTRON MICROSCOPY	4.3
7O7L	ELECTRON MICROSCOPY	4.5
7O7P	ELECTRON MICROSCOPY	4.6
7O7O	ELECTRON MICROSCOPY	4.8
7VON	ELECTRON MICROSCOPY	5.2
7O7M	ELECTRON MICROSCOPY	6.6
7O7N	ELECTRON MICROSCOPY	7.3
1BV8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01023-F1	81.61	0.30

Functional residue map

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

Post-translational modifications (3): 693, 694, 972–975

Disulfide bonds (13): 48–86, 251–299, 269–287, 278, 431, 470–563, 595–771, 642–689, 821–849, 847–883, 921–1321, 1079–1127, 1352–1467

Glycosylation sites (8): 410, 869, 991, 1424, 55, 70, 247, 396

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-8963896	HDL assembly
R-HSA-9855719	Regulation of FXIIa and plasma kallikrein activity
R-HSA-140837
R-HSA-109582	Hemostasis
R-HSA-140877
R-HSA-1474244	Extracellular matrix organization
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-382551	Transport of small molecules
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76005	Response to elevated platelet cytosolic Ca2+
R-HSA-8963898	Plasma lipoprotein assembly

MSigDB gene sets: 253 (showing top): GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, MODULE_128, GGGTGGRR_PAX4_03, TANG_SENESCENCE_TP53_TARGETS_UP, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_DN, HERNANDEZ_MITOTIC_ARREST_BY_DOCETAXEL_2_DN, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, CHESLER_BRAIN_D6MIT150_QTL_CIS, SMITH_TERT_TARGETS_DN, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_COMPLEMENT_ACTIVATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (2): negative regulation of complement activation, lectin pathway (GO:0001869), stem cell differentiation (GO:0048863)

GO Molecular Function (12): protease binding (GO:0002020), endopeptidase inhibitor activity (GO:0004866), serine-type endopeptidase inhibitor activity (GO:0004867), signaling receptor binding (GO:0005102), growth factor binding (GO:0019838), enzyme binding (GO:0019899), interleukin-8 binding (GO:0019959), interleukin-1 binding (GO:0019966), tumor necrosis factor binding (GO:0043120), calcium-dependent protein binding (GO:0048306), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), platelet alpha granule lumen (GO:0031093), extracellular exosome (GO:0070062), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Extracellular matrix organization	1
Plasma lipoprotein assembly	1
FXIIa activates plasma kallikrein-kinin system	1
Transport of small molecules	1
Hemostasis	1
Platelet activation, signaling and aggregation	1
Plasma lipoprotein assembly, remodeling, and clearance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
cytokine binding	2
cellular anatomical structure	2
complement activation, lectin pathway	1
regulation of complement activation, lectin pathway	1
negative regulation of innate immune response	1
negative regulation of complement activation	1
cell differentiation	1
enzyme binding	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
C-X-C chemokine binding	1
growth factor binding	1
calcium ion binding	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
external encapsulating structure	1
platelet alpha granule	1
secretory granule lumen	1
extracellular vesicle	1
extracellular region	1

Protein interactions and networks

STRING

2534 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
A2M	LRP1	Q07954	997
A2M	HP	P00737	997
A2M	APOA1	P02647	994
A2M	KLK4	Q9Y5K2	993
A2M	ALB	P02768	977
A2M	SERPINA1	P01009	977
A2M	IL1B	P01584	975
A2M	SERPINF2	P08697	964
A2M	HSPA5	P11021	960
A2M	APOE	P02649	957
A2M	IL6	P05231	950
A2M	RAB3IL1	Q8TBN0	949
A2M	SERPINA3	P01011	917
A2M	KLK3	P07288	914
A2M	SERPINC1	P01008	912

IntAct

308 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
AP2B1	A2M	psi-mi:“MI:0915”(physical association)	0.560
PRDM1	A2M	psi-mi:“MI:0915”(physical association)	0.560
CSF2	A2M	psi-mi:“MI:0915”(physical association)	0.560
A2M	CTNNB1	psi-mi:“MI:0915”(physical association)	0.560
H2AZ1	A2M	psi-mi:“MI:0915”(physical association)	0.560
HOXC4	A2M	psi-mi:“MI:0915”(physical association)	0.560
LYN	A2M	psi-mi:“MI:0915”(physical association)	0.560
MNDA	A2M	psi-mi:“MI:0915”(physical association)	0.560
PIK3R1	A2M	psi-mi:“MI:0915”(physical association)	0.560
A2M	SMN1	psi-mi:“MI:0915”(physical association)	0.560
TEAD1	A2M	psi-mi:“MI:0915”(physical association)	0.560
A2M	TXN	psi-mi:“MI:0915”(physical association)	0.560
BRK1	A2M	psi-mi:“MI:0915”(physical association)	0.560
RNF112	A2M	psi-mi:“MI:0915”(physical association)	0.560
FZD4	A2M	psi-mi:“MI:0915”(physical association)	0.560
H3C1	A2M	psi-mi:“MI:0915”(physical association)	0.560
COPS3	A2M	psi-mi:“MI:0915”(physical association)	0.560
A2M	PIAS1	psi-mi:“MI:0915”(physical association)	0.560
STX11	A2M	psi-mi:“MI:0915”(physical association)	0.560
IQSEC1	A2M	psi-mi:“MI:0915”(physical association)	0.560
CLEC2B	A2M	psi-mi:“MI:0915”(physical association)	0.560
A2M	Ppif	psi-mi:“MI:0915”(physical association)	0.560
STUB1	A2M	psi-mi:“MI:0915”(physical association)	0.560
KAT5	A2M	psi-mi:“MI:0915”(physical association)	0.560
A2M	KAT5	psi-mi:“MI:0915”(physical association)	0.560
UTP14A	A2M	psi-mi:“MI:0915”(physical association)	0.560
DDX20	A2M	psi-mi:“MI:0915”(physical association)	0.560
PARK7	A2M	psi-mi:“MI:0915”(physical association)	0.560
CYFIP1	A2M	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (221): A2M (Affinity Capture-MS), A2M (Two-hybrid), A2M (Synthetic Lethality), A2M (Affinity Capture-MS), A2M (Co-localization), A2M (Co-localization), A2M (Co-localization), A2M (Co-localization), PZP (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), CRTAC1 (Affinity Capture-MS), METRN (Affinity Capture-MS), PTX3 (Affinity Capture-MS), PRADC1 (Affinity Capture-MS), A2M (Affinity Capture-MS)

ESM2 similar proteins: A0AAQ4VMX2, A0RZC6, A8K7I4, C9XI63, C9XI66, I2C090, J3S836, P01023, P01024, P01025, P01026, P01027, P01029, P01030, P01031, P06684, P06756, P08649, P08650, P0C0L4, P0C0L5, P12247, P12387, P19069, P20740, P26007, P26008, P56652, P80746, P97280, P98093, Q01833, Q06033, Q0ZZJ6, Q2UVX4, Q3UU35, Q5RB37, Q61704, Q61739, Q63041

Diamond homologs: A8K2U0, P01023, P06238, P14046, P20739, P20740, P20742, P28665, P28666, Q03626, Q3UU35, Q5R4N8, Q61838, Q63041, Q6GQT1, Q6IE52, Q6ZMU1, Q7SIH1, P20738, Q6IE37, C9XI63, P20737, Q6YHK3, Q8IZJ3, Q8R422, Q9GYW4, P23667, Q8YM40, A0AAQ4VMX2, A0RZC6, P01024, P01026, P01029, P01030, P08649, P0C0L4, P0C0L5, P19069, Q0ZZJ6

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
MMP2	“down-regulates quantity by destabilization”	A2M	cleavage
MMP9	“down-regulates quantity by destabilization”	A2M	cleavage
A2M	“down-regulates activity”	MMP9	binding
A2M	“down-regulates activity”	MMP2	binding
CTSE	“down-regulates quantity by destabilization”	A2M	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 93 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
Interleukin-3, Interleukin-5 and GM-CSF signaling	5	24.8×	5e-04
FCGR3A-mediated phagocytosis	6	17.6×	5e-04
Regulation of actin dynamics for phagocytic cup formation	5	14.4×	2e-03
Leishmania infection	5	12.8×	2e-03
Parasitic Infection Pathways	5	12.8×	2e-03
Infectious disease	10	3.9×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
DNA damage response	9	6.4×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	1
Uncertain significance	152
Likely benign	21
Benign	18

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
147419	GRCh38/hg38 12p13.33-11.1(chr12:121255-34603274)x3	Pathogenic
148626	GRCh38/hg38 12p13.33-12.3(chr12:2871741-14987348)x3	Pathogenic
151004	GRCh38/hg38 12p13.33-11.1(chr12:54427-34608071)x4	Pathogenic
153563	GRCh38/hg38 12p13.33-12.2(chr12:1258274-20657577)x3	Pathogenic
253493	GRCh37/hg19 12p13.33-11.1(chr12:89061-34178799)x3	Pathogenic
3063250	GRCh37/hg19 12p13.33-11.1(chr12:173786-34835641)x3	Pathogenic
3391851	GRCh37/hg19 12p13.33-11.1(chr12:173787-34835837)x4	Pathogenic
4279359	GRCh37/hg19 12p13.33-11.1(chr12:173787-34835837)x3	Pathogenic
443532	GRCh37/hg19 12p13.33-11.22(chr12:173786-28219229)x3	Pathogenic
563989	GRCh37/hg19 12p13.33-11.1(chr12:173786-34835837)x2,3	Pathogenic
563990	GRCh37/hg19 12p13.33-11.1(chr12:173786-34835837)x3	Pathogenic
563991	GRCh37/hg19 12p13.33-q11(chr12:173786-37869107)x3	Pathogenic
59795	GRCh38/hg38 12p13.33-12.1(chr12:80412-25470329)x3	Pathogenic
59799	GRCh38/hg38 12p13.33-11.1(chr12:212976-33926913)x4	Pathogenic
686501	GRCh37/hg19 12p13.33-11.1(chr12:173786-34496628)x3	Pathogenic
815493	GRCh37/hg19 12p13.33-q11(chr12:274676-37869301)x4	Pathogenic
4682804	GRCh37/hg19 12p13.33-13.2(chr12:173787-11553849)x3	Likely pathogenic

SpliceAI

4054 predictions. Top by Δscore:

Variant	Effect	Δscore
12:9067848:T:TC	acceptor_gain	1.0000
12:9068177:GCTTA:G	donor_loss	1.0000
12:9068179:TTACC:T	donor_loss	1.0000
12:9068180:TA:T	donor_loss	1.0000
12:9068181:A:T	donor_loss	1.0000
12:9068220:CTCAT:C	acceptor_gain	1.0000
12:9068222:CAT:C	acceptor_gain	1.0000
12:9068223:ATC:A	acceptor_loss	1.0000
12:9068224:TC:T	acceptor_loss	1.0000
12:9068225:C:CC	acceptor_gain	1.0000
12:9068226:T:A	acceptor_loss	1.0000
12:9068734:A:AC	donor_gain	1.0000
12:9068734:ACTC:A	donor_loss	1.0000
12:9068735:C:CC	donor_gain	1.0000
12:9068736:TCAC:T	donor_loss	1.0000
12:9068738:A:AC	donor_gain	1.0000
12:9068738:A:T	donor_loss	1.0000
12:9068738:AC:A	donor_gain	1.0000
12:9068738:ACC:A	donor_gain	1.0000
12:9068739:C:A	donor_loss	1.0000
12:9068739:C:CT	donor_gain	1.0000
12:9068739:CC:C	donor_gain	1.0000
12:9068739:CCC:C	donor_gain	1.0000
12:9068739:CCCGT:C	donor_gain	1.0000
12:9068838:GACAC:G	acceptor_gain	1.0000
12:9068840:CAC:C	acceptor_gain	1.0000
12:9068841:AC:A	acceptor_gain	1.0000
12:9068842:CC:C	acceptor_gain	1.0000
12:9068843:C:CC	acceptor_gain	1.0000
12:9068844:T:A	acceptor_loss	1.0000

AlphaMissense

9611 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:9091377:A:G	W765R	0.994
12:9091377:A:T	W765R	0.994
12:9074572:G:C	F1248L	0.993
12:9074572:G:T	F1248L	0.993
12:9074574:A:G	F1248L	0.993
12:9091375:C:A	W765C	0.993
12:9091375:C:G	W765C	0.993
12:9079279:A:C	F1028L	0.992
12:9079279:A:T	F1028L	0.992
12:9079281:A:G	F1028L	0.992
12:9093490:A:G	W739R	0.991
12:9093490:A:T	W739R	0.991
12:9072871:C:G	D1253H	0.987
12:9093482:C:A	W741C	0.987
12:9093482:C:G	W741C	0.987
12:9079745:C:A	Q975H	0.986
12:9079745:C:G	Q975H	0.986
12:9079749:T:A	E974V	0.985
12:9077855:A:G	L1041P	0.984
12:9079647:A:G	L1008P	0.984
12:9079742:A:C	N976K	0.984
12:9079742:A:T	N976K	0.984
12:9109392:A:C	F229L	0.984
12:9109392:A:T	F229L	0.984
12:9109394:A:G	F229L	0.984
12:9079285:G:C	S1026R	0.983
12:9079285:G:T	S1026R	0.983
12:9079287:T:G	S1026R	0.983
12:9091357:G:C	C771W	0.983
12:9093484:A:G	W741R	0.983

dbSNP variants (sampled 300 via entrez): RS1000046307 (12:9080657 A>G), RS1000078744 (12:9080338 G>A), RS1000174967 (12:9085195 C>T), RS1000227663 (12:9074912 C>A,G), RS1000251227 (12:9073445 C>T), RS1000299252 (12:9108034 C>T), RS1000327515 (12:9105793 A>G), RS1000477784 (12:9067648 TA>T), RS1000493616 (12:9089339 T>C), RS1000508048 (12:9099346 T>C), RS1000594659 (12:9106292 G>T), RS1000663081 (12:9093783 G>A), RS1000725848 (12:9073093 T>G), RS1000842523 (12:9081827 A>G), RS1000943286 (12:9098891 A>G)

Disease associations

OMIM: gene MIM:103950 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
Alzheimer disease type 1	No Known Disease Relationship	Unknown

Mondo (2): megacolon (MONDO:0001273), Alzheimer disease type 1 (MONDO:0007088)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_207	Refractive error	1.000000e-40

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008531	Megacolon	C06.405.469.158.701
C536594	Alzheimer disease type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295690 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs669	Efficacy	3	Enzymes	Stroke

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs669	A2M, KLRG1	3	4.00	1	Enzymes

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	4
Benzo(a)pyrene	increases expression, increases methylation, affects cotreatment, affects expression	3
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
Cyclosporine	decreases expression	3
bisphenol A	affects expression, affects cotreatment, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cadmium	affects binding, decreases expression, increases abundance	2
Dexamethasone	increases expression, affects cotreatment, decreases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Selenium	increases expression, decreases expression, decreases reaction, increases reaction	2
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
deoxynivalenol	decreases expression	1
fluoranthene	affects cotreatment, affects expression	1
glycidyl methacrylate	increases expression	1
potassium persulfate	increases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression	1
potassium bromate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	decreases expression	1
1,2,5,6-dibenzanthracene	affects cotreatment, affects expression	1
perfluorobutyric acid	decreases expression	1
nivalenol	decreases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
1-methylphenanthrene	affects cotreatment, affects expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4150990	Binding	Inhibition of alpha-2 macroglobulin (unknown origin)	Biosynthetic Baeyer-Villiger Chemistry Enables Access to Two Anthracene Scaffolds from a Single Gene Cluster in Deep-Sea-Derived Streptomyces olivaceus SCSIO T05. — J Nat Prod

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04520308	PHASE4	UNKNOWN	An Open-label, Single-arm Longitudinal Study With Dupilumab for Patients With Atopic Dermatitis
NCT02380573	PHASE2	COMPLETED	Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer’s Disease
NCT03806478	PHASE2	UNKNOWN	Study of APH-1105 in Patients With Mild to Moderate Alzheimer’s Disease
NCT07011706	PHASE2	ACTIVE_NOT_RECRUITING	ATI-045 Versus Placebo in Patients With Moderate-to-Severe Atopic Dermatitis
NCT07252440	PHASE2	RECRUITING	A Study to Evaluate the Efficacy and Safety of TTYP01 Tablets in Early Symptomatic Alzheimer’s Disease
NCT03932916	PHASE1	COMPLETED	Safety and Pharmacokinetic of Donepezil Pamoate in Healthy Subjects
NCT06593626	PHASE1	COMPLETED	A Phase I Clinical Study on the Safety and Pharmacokinetics of [18F]Florbetazine Injection
NCT05984784	PHASE1/PHASE2	TERMINATED	A Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of IMG-007 in Adults With Atopic Dermatitis (AD)
NCT01733355	EARLY_PHASE1	TERMINATED	A Phase 0, Open Label, Multi-center Exploratory and Safety Study of [F-18]T807
NCT05469009	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Safety and Feasibility of Exablate Blood-Brain Barrier Disruption for Mild Cognitive Impairment or Mild Alzheimer’s Disease Undergoing Standard of Care Monoclonal Antibody (mAb) Therapy
NCT01190904	Not specified	COMPLETED	Hormones and Sexual Function Predict Outcomes in Revascularized Men With Diabetes
NCT02273895	Not specified	COMPLETED	The Use of EEG in Alzheimer’s Disease, With and Without Scopolamine - A Pilot Study
NCT04100889	Not specified	WITHDRAWN	A Non-Interventional Pilot Study to Explore the Role of Gut Flora in Alzheimer’s Disease
NCT05078944	Not specified	COMPLETED	Progress of Mild Alzheimer’s Disease in Participants on Acupuncture Versus Sham Acupuncture
NCT05372458	Not specified	UNKNOWN	The Mechanism Study of Diabetic Pancreatic Amyloid Deposition on Cognitive Dysfunction in Alzheimer’s Disease
NCT05637801	Not specified	ACTIVE_NOT_RECRUITING	A Pivotal Study of Sensory Stimulation in Alzheimer’s Disease (HOPE Study)
NCT06039267	Not specified	COMPLETED	Brain Health & the Microbiome
NCT06155201	Not specified	UNKNOWN	Development and Application of Intelligent Diagnosis and Treatment Norms for Children and Adolescents With Mental Disorders
NCT06245031	Not specified	ENROLLING_BY_INVITATION	Extension to a Pivotal Study of Sensory Stimulation in Alzheimer’s Disease (OLE Hope Study, CA-0015)
NCT06335836	Not specified	RECRUITING	The Effects of Social Isolation and Social Interaction on the Risk of Dementia Progression and Brain Function in SCD (Subjective Cognitive Decline, SCD)
NCT07100470	Not specified	NOT_YET_RECRUITING	Metabolic Characterization of Alzheimer’s Disease and Frontotemporal Dementia by 23Na-MRI and FDG-PET
NCT04340856	Not specified	COMPLETED	Retrospective, Uncontrolled Cohort Study on the Therapy of Chronic Megalon
NCT07470892	Not specified	NOT_YET_RECRUITING	Preoperative Fish Oil PN and Prognosis After Constipation Surgery