A2M

alpha-2-macroglobulin, the group of Alpha-2-macroglobulin family

Basic information

Region (hg38): 12:9067664-9116229

Links

ENSG00000175899 ∙ NCBI:2 ∙ OMIM:103950 ∙ HGNC:7 ∙ Uniprot:P01023 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Alzheimer disease type 1 (No Known Disease Relationship), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Alpha-2-macroglobulin deficiency	AD	General	The clinical consequences of variants are unclear	General	94459; 2475424; 1370808
Variants have been implicated in pulmonary disease, but the evidence appears mixed

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the A2M gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the A2M gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				8	7	15
missense			58	9	5	72
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)					1	1
splice region					2	2
non coding				2		2
Total	0	0	58	19	13

Variants in A2M

This is a list of pathogenic ClinVar variants found in the A2M region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-9068192-A-C		not specified	Uncertain significance (Aug 30, 2021)
12-9068742-G-A		not specified	Uncertain significance (Dec 05, 2022)
12-9068842-C-T		not specified	Uncertain significance (Dec 06, 2021)
12-9069776-C-T		not specified	Uncertain significance (Jun 22, 2024)
12-9069803-G-C		not specified	Uncertain significance (Dec 17, 2023)
12-9069804-A-C		not specified	Uncertain significance (Aug 22, 2023)
12-9070564-C-T		not specified	Uncertain significance (Dec 30, 2023)
12-9072396-T-C		not specified	Uncertain significance (Jul 26, 2022)
12-9072405-C-G		not specified	Uncertain significance (Sep 30, 2021)
12-9072429-C-T		not specified	Uncertain significance (Oct 18, 2021)
12-9072799-G-T		not specified	Uncertain significance (Nov 10, 2022)
12-9074556-C-T			Benign (Oct 17, 2017)
12-9074642-G-A		not specified	Uncertain significance (May 30, 2023)
12-9074660-G-T		not specified	Uncertain significance (Dec 30, 2023)
12-9074663-G-A		not specified	Uncertain significance (Nov 07, 2023)
12-9074723-T-A		not specified	Uncertain significance (Dec 21, 2021)
12-9076794-T-C		A2M-related disorder	Likely benign (Feb 15, 2022)
12-9076800-C-G		not specified	Uncertain significance (Feb 28, 2024)
12-9076803-T-C		A2M-related disorder	Likely benign (Oct 08, 2019)
12-9076832-A-G			Benign (Dec 04, 2017)
12-9076903-C-T		not specified	Uncertain significance (Jan 06, 2023)
12-9077348-T-G		not specified	Uncertain significance (Apr 17, 2024)
12-9077398-G-T		not specified	Uncertain significance (Dec 05, 2022)
12-9077429-A-C		A2M-related disorder	Likely benign (May 25, 2023)
12-9079271-C-T		A2M-related disorder	Likely benign (Jul 10, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
A2M	protein_coding	protein_coding	ENST00000318602	36	48566

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.52e-11	1.00	125656	1	91	125748	0.000366

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.87	627	773	0.811	0.0000404	9524
Missense in Polyphen		109	167.8	0.6496		2089
Synonymous	1.65	269	306	0.880	0.0000170	2896
Loss of Function	4.90	32	79.0	0.405	0.00000403	963

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00112	0.00109
Ashkenazi Jewish	0.000108	0.0000992
East Asian	0.000109	0.000109
Finnish	0.0000928	0.0000924
European (Non-Finnish)	0.000475	0.000457
Middle Eastern	0.000109	0.000109
South Asian	0.000297	0.000294
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: 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.
• Pathway: Complement and coagulation cascades - Homo sapiens (human);Human Complement System;Dengue-2 Interactions with Complement and Coagulation Cascades;Complement and Coagulation Cascades;Signal Transduction;HDL assembly;Plasma lipoprotein assembly;Extracellular matrix organization;Rho GTPase cycle;Transport of small molecules;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;Signaling by Rho GTPases;Intrinsic Pathway of Fibrin Clot Formation;Hemostasis;Degradation of the extracellular matrix;Formation of Fibrin Clot (Clotting Cascade);Plasma lipoprotein assembly, remodeling, and clearance;IL6-mediated signaling events (Consensus)

Recessive Scores

• pRec: 0.796

Intolerance Scores

• loftool: 0.944
• rvis_EVS: 0.1
• rvis_percentile_EVS: 60.76

Haploinsufficiency Scores

• pHI: 0.270
• hipred: N
• hipred_score: 0.319
• ghis: 0.515

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.930

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: A2m

Gene ontology

• Biological process: negative regulation of complement activation, lectin pathway;platelet degranulation;blood coagulation, intrinsic pathway;negative regulation of endopeptidase activity;extracellular matrix disassembly;positive regulation of GTPase activity;stem cell differentiation;regulation of small GTPase mediated signal transduction
• Cellular component: extracellular region;cytosol;platelet alpha granule lumen;collagen-containing extracellular matrix;extracellular exosome;blood microparticle
• Molecular function: protease binding;serine-type endopeptidase inhibitor activity;GTPase activator activity;signaling receptor binding;protein binding;growth factor binding;enzyme binding;interleukin-8 binding;interleukin-1 binding;tumor necrosis factor binding;calcium-dependent protein binding