A2M

Chr 12

alpha-2-macroglobulin

Also known as: A2MD, CPAMD5, FWP007, S863-7

NCBI Gene: 2ENSG00000175899UniProt: P01023

Alpha-2-macroglobulin functions as a protease inhibitor that uses a unique "bait-and-trap" mechanism to inhibit multiple classes of proteinases and also serves as a cytokine transporter to disrupt inflammatory cascades. Mutations cause alpha-2-macroglobulin deficiency with autosomal recessive inheritance. This gene is extremely intolerant to loss-of-function variation (pLI near 1.0, LOEUF 0.544), indicating that heterozygous loss-of-function mutations are likely pathogenic.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
69
Pubs (1 yr)
36
P/LP submissions
0%
P/LP missense
0.54
LOEUF
DN
Mechanism· predicted
Clinical Summary— A2M
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
36 unique Pathogenic / Likely Pathogenic· 152 VUS of 273 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.54LOEUF
pLI 0.000
Z-score 4.90
OE 0.41 (0.30–0.54)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.87Z-score
OE missense 0.81 (0.76–0.87)
627 obs / 773.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.41 (0.30–0.54)
0≤0.351.4
Missense OE0.81 (0.76–0.87)
0≤0.61.4
Synonymous OE0.88
0≤1.21.6
LoF obs/exp: 32 / 79.0Missense obs/exp: 627 / 773.5Syn Z: 1.65
DN
0.6842th %ile
GOF
0.6053th %ile
LOF
0.2484th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

273 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic2
VUS152
Likely Benign22
Benign18
34
Pathogenic
2
Likely Pathogenic
152
VUS
22
Likely Benign
18
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
34
0
34
Likely Pathogenic
0
0
2
0
2
VUS
0
144
8
0
152
Likely Benign
0
12
2
8
22
Benign
2
7
2
7
18
Total21634815228

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

A2M · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients