rs28929474

badMag 9.0

This is a variant in the SERPINA1 gene that changes a glutamate to an lysine.

Key Literature Trait Associations

Alpha-1 Antitrypsin Deficiency

The Pi*Z allele (rs28929474-T, p.Glu342Lys) is the defining molecular basis of classical alpha-1 antitrypsin deficiency. Homozygous Pi*ZZ individuals produce only ~10–15% of normal circulating A1AT, meeting clinical diagnostic criteria for deficiency and facing high lifetime risks of emphysema and liver disease. Pi*MZ heterozygotes retain ~60% of normal A1AT levels, conferring intermediate risk. ClinVar classifies the T allele as pathogenic for A1AT deficiency, and the mutation is the most prevalent serious Mendelian allele in European-ancestry populations (~1.5–2% allele frequency). Penetrance for symptomatic lung disease is strongly modified by smoking.

North TL et al. “A study of common Mendelian disease carriers across ageing British cohorts: meta-analyses reveal heterozygosity for alpha 1-antitrypsin deficiency increases respiratory capacity and height.” Journal of Medical Genetics (2016)
Allele T
OR —
p 1.7e-5
N 19,000
Preliminary work
European (British)

Liver disease

Homozygous Pi*ZZ individuals face dramatically elevated risks of liver disease due to intrahepatic accumulation of misfolded A1AT polymer. A 2025 meta-analysis of 45 studies (n=8,638 ZZ patients) found crude ORs of 10.43 for cirrhosis, 9.85 for liver fibrosis, and 14.12 for hepatocellular carcinoma compared to Pi*MM controls; 5% of adult ZZ patients required liver transplantation. Pi*MZ heterozygotes have a more modest but measurable increased risk, including higher odds of portal hypertension (OR ~2.5) in some cohorts. A1AT deficiency is the leading genetic cause of liver disease and liver transplantation in children.

Syanda AM et al. “Liver Disease and Prevalence of Liver Transplantation in Adults With ZZ Alpha-1 Antitrypsin Deficiency-A Meta-Analysis.” Liver International Communications (2025)
Allele T
OR 10.43
p —
N 8,638
Meta-analysis
multi-ancestry (predominantly European)

Chronic obstructive pulmonary disease

The Pi*Z allele (rs28929474-T) is a well-established genetic risk factor for COPD, acting through severe reduction in circulating A1AT and consequent unopposed neutrophil elastase activity in the lung. Large meta-analyses confirm the Z allele confers an approximately 1.4- to 2.3-fold increased odds of COPD, with stronger effects in smokers and for the Pi*ZZ genotype. Pi*MZ heterozygotes with COPD exhibit 3.9% lower FEV1% predicted and 4.14% greater emphysema extent compared to MM individuals. Z-allele carriers also face ~25% higher odds of COPD exacerbations (OR 1.25, 95% CI 1.05–1.48). The association is genome-wide significant across multiple large cohorts.

Moll M et al. “A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease.” American Journal of Physiology. Lung Cellular and Molecular Physiology 321(1):L130-L143 (2021)
Allele T
OR 1.43
p 4.3e-3
N 252,250
Preliminary work
multi-ancestry (predominantly European)
Ingebrigtsen TS et al. “Fibrinogen and α1-antitrypsin in COPD exacerbations.” Thorax (2015)
Allele T
OR 1.25
p 1.0e-2
N 13,405
Preliminary work
European (Danish general population)
Dahl M et al. “Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin MZ heterozygotes: A longitudinal study of the general population.” Annals of Internal Medicine (2002)
Allele T
OR 1.30
p 2.3e-2
N 9,187
Preliminary work
European (Danish general population)
Ghosh AJ et al. “Alpha-1 Antitrypsin MZ Heterozygosity Is an Endotype of Chronic Obstructive Pulmonary Disease.” American Journal of Respiratory and Critical Care Medicine (2022)
Allele T
OR —
β -3.900
p —
N 6,474
Preliminary work
European (US cohorts: LTRC, ECLIPSE, COPDGene)
Li X et al. “Genome-wide association study of lung function and clinical implication in heavy smokers.” Bmc Medical Genetics 19(1):134 (2018)
Allele T
OR 2.30
p 1.2e-8
N 1,645
Large GWAS
European (non-Hispanic White US smokers)

Venous thromboembolism

The Pi*Z allele is associated with elevated venous thromboembolism (VTE) risk, confirmed in a large population-based study with UK Biobank replication. Homozygous Pi*ZZ individuals face a hazard ratio of 2.2 for VTE (95% CI 1.3–3.7) with an absolute risk of 7.8%, comparable to the prothrombin G20210A variant. Pi*MZ heterozygotes have a more modest hazard ratio of 1.1 (95% CI 1.0–1.2). The population attributable fraction is small (~0.7%), but the finding has implications for thromboprophylaxis in ZZ individuals facing surgical or immobilization risk.

Riis J et al. “α(1) -Antitrypsin Z allele and risk of venous thromboembolism in the general population.” Journal of Thrombosis and Haemostasis : Jth (2022)
Allele T
OR 2.20
p —
N 107,075
Preliminary work
European (Copenhagen General Population Study + UK Biobank)
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GWAS Catalog Trait Associations (283)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

39S ribosomal protein L33, mitochondrial measurement

Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele T
OR 1.73
p —
N 10,708
Large GWAS
European
Sun BB et al. “Genomic atlas of the human plasma proteome.” Nature 558(7708):73-79 (2018)
Allele T
OR 1.74
p 4.0e-109
N 3,301
Large GWAS
European

alpha-1-antitrypsin measurement

Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele T
OR 1.90
p —
N 10,708
Large GWAS
European
Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)
Allele T
OR 0.42
p 2.0e-84
N 47,745
Large GWAS
European

glypican-6 measurement

Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele T
OR 1.66
p 7.0e-319
N 10,708
Large GWAS
European
Sun BB et al. “Genomic atlas of the human plasma proteome.” Nature 558(7708):73-79 (2018)
Allele T
OR 0.62
p 9.0e-14
N 3,301
Large GWAS
European

serum albumin amount

Jee YH et al. “Genome-wide association studies in a large Korean cohort identify quantitative trait loci for 36 traits and illuminate their genetic architectures.” Nature Communications 16(1):4935 (2025)
Allele T
OR 0.32
p 3.0e-279
N 928,679
Large GWAS
multi-ancestry
Sakaue S et al. “A cross-population atlas of genetic associations for 220 human phenotypes.” Nature Genetics 53(10):1415-1424 (2021)
Allele T
OR 0.27
p 2.0e-202
N 435,807
Large GWAS
multi-ancestry
Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)
Allele T
OR 0.13
p 1.0e-49
N 372,982
Major Consortium StudyLarge GWAS
European
Sinnott-Armstrong N et al. “Genetics of 35 blood and urine biomarkers in the UK Biobank.” Nature Genetics 53(2):185-194 (2021)
Allele T
OR 0.28
p 8.0e-205
N 325,292
Major Consortium StudyLarge GWAS
multi-ancestry
Richardson TG et al. “Characterising metabolomic signatures of lipid-modifying therapies through drug target mendelian randomisation.” Plos Biology 20(2):e3001547 (2022)
Allele T
OR 0.43
p 3.0e-187
N 115,064
Large GWAS
European
Harrison S et al. “Testosterone and socioeconomic position: Mendelian randomization in 306,248 men and women in UK Biobank.” Science Advances 7(31) (2021)
Allele T
OR 0.69
p 2.0e-40
N 104,632
Major Consortium StudyLarge GWAS
European
Davyson E et al. “Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids.” Biological Psychiatry 94(8):630-639 (2023)
Allele T
OR 0.43
p 4.0e-146
N 88,315
Large GWAS
European

neutrophil cytosol factor 2 measurement

Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele T
OR 1.54
p 2.0e-259
N 10,708
Large GWAS
European
Sun BB et al. “Genomic atlas of the human plasma proteome.” Nature 558(7708):73-79 (2018)
Allele T
OR 1.05
p 3.0e-37
N 3,301
Large GWAS
European

asialoglycoprotein receptor 2 measurement

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)
Allele T
OR 0.64
p 3.0e-246
N 47,745
Large GWAS
European

lysosomal acid phosphatase measurement

Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele T
OR 1.49
p 1.0e-242
N 10,708
Large GWAS
European
Sun BB et al. “Genomic atlas of the human plasma proteome.” Nature 558(7708):73-79 (2018)
Allele T
OR 1.20
p 6.0e-49
N 3,301
Large GWAS
European

level of 11-beta-hydroxysteroid dehydrogenase 1 in blood

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)
Allele T
OR 0.59
p 2.0e-213
N 47,745
Large GWAS
European

protein amnionless measurement

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)
Allele T
OR 0.61
p 1.0e-204
N 47,745
Large GWAS
European

chymotrypsin-like elastase family member 2A measurement

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)
Allele T
OR 0.52
p 7.0e-170
N 47,745
Large GWAS
European
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ClinVar annotation

Pathogenic★★★☆
1 submitter106 publications

Alpha-1-antitrypsin deficiency (A1ATD); COPD, severe early onset; Chronic obstructive pulmonary disease; FRAXE; Inborn genetic diseases; Neurodevelopmental disorder; PI Z; PI Z(AUGSBURG); PI Z(TUN); SERPINA1-related disorder; See cases; Susceptibility to severe coronavirus disease (COVID-19); not specified

View on ClinVar →
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Research that mentions this SNP (3)

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Association between catechol‐O‐methyl transferase gene polymorphisms and fibromyalgia in a Korean population: A case–control study
AssociationN=426Park DJ et al.(2016)· European Journal of Pain

This international doctoral thesis examined gene-physical activity interactions in fibromyalgia through six studies analyzing 64 SNPs across 34 candidate genes in Spanish women. The case-control study (314 fibromyalgia cases vs. 112 controls) identified associations of rs841 (GCH1), rs1799971 (OPRM1), and rs2097903 (COMT) with fibromyalgia susceptibility (p=0.04, p=0.02, and p=0.04 respectively). Cross-sectional studies (n=274-276 fibromyalgia patients) found that SCN9A rs4453709 and other genetic polymorphisms interacted with physical activity to influence pain, fatigue, and resilience outcomes.

Traits studied:Fatigue (reduced motivation, reduced activity)Fibromyalgia susceptibilityPain (algometry, bodily pain)Resilience (optimism, satisfaction with life)
PubMedDOIMetascience Observatory
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A Linkage Disequilibrium between Genes at the Serine Protease Inhibitor Gene Cluster on Chromosome 14q32.1 Is Associated with Wegener's Granulomatosis
AssociationN=350Stefan Borgmann et al.(2001)· Clinical Immunology

This doctoral thesis conducted multiple candidate gene association studies in 274-426 southern Spanish women with fibromyalgia to investigate gene-physical activity/sedentary behavior interactions with pain, fatigue, and resilience. Study III identified rs841 (GCH1) GG genotype (OR=0.61, p=0.04) and rs2097903 (COMT) AT/TT genotypes (OR=1.66, p=0.04) associated with fibromyalgia susceptibility, and confirmed rs1799971 (OPRM1) GG genotype (OR=0.58, p=0.02) confers genetic risk. Study IV found rs6311/rs6313 (HTR2A) polymorphisms individually associated with algometer pain score, and gene-sedentary behavior interactions involving rs4680/rs165599 (COMT), rs1383914 (ADRA1A), rs12994338/rs4453709 (SCN9A), and rs6860 (CHMP1A) significantly associated with pain outcomes. SCN9A emerged as most robust gene for fibromyalgia phenotype.

Traits studied:FatigueFibromyalgia susceptibilityPain (algometer pain threshold, bodily pain, pain catastrophizing, acute pain/VAS)Physical activity levelResilienceSedentary behavior
PubMedDOIMetascience Observatory
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Genetic diversity from a limited repertoire of mutations on different common allelic backgrounds: α1-antitrypsin deficiency variant Pduarte
ReviewHildesheim J. et al.(1993)· Human Mutation

Alpha-1 Antitrypsin Deficiency (AATD) is caused by over 120 mutations in SERPINA1, with the Z allele (p.Glu342Lys) and S allele (p.Glu264Val) being major pathogenic variants. Large-scale genomic sequencing has revealed >500 rare SERPINA1 variants, many with loss-of-function or gain-of-function effects causing varied clinical manifestations including pulmonary emphysema and hepatic disease. This review synthesizes the SERPINA1 mutation spectrum, their geographic distribution, population history, and pathophysiological mechanisms to guide comprehensive AATD diagnosis beyond common variants.

Traits studied:ANCA-associated vasculitisAlpha-1 Antitrypsin DeficiencyBronchiectasisChronic Obstructive Pulmonary DiseaseEmphysemaHepatic diseaseLiver diseasePanniculitis
PubMedDOIMetascience Observatory

Gene information from NCBI Gene. Variant classifications from ClinVar.

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