rs17580

badMag 6.5

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

Key Literature Trait Associations

Alpha-1 Antitrypsin Deficiency

The rs17580 A allele defines the PI*S variant (p.Glu288Val) in SERPINA1, one of two major deficiency alleles underlying alpha-1 antitrypsin deficiency (AATD). PI*SS homozygotes retain ~60% of normal AAT serum levels and face moderately elevated lung disease risk, while PI*SZ compound heterozygotes retain only ~37% of normal levels and carry substantially increased COPD risk (OR ~3.3 by meta-analysis). ClinVar classifies this variant as pathogenic/pathogenic-low penetrance with multiple-submitter criteria. The PI*S allele is common in Europeans (~3–5%) and is causally associated with reduced circulating AAT protein concentrations in large-scale proteomics GWAS involving thousands of participants.

Dahl M et al. “The protease inhibitor PI*S allele and COPD: a meta-analysis.” The European Respiratory Journal (2005)
Allele A
OR 3.26
p —
Meta-analysis
European
Thun GA et al. “Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels.” Plos Genetics (2013)
Allele A
OR —
p —
N 9,665
Preliminary work
European
de Serres FJ et al. “Estimating the risk for alpha-1 antitrypsin deficiency among COPD patients: evidence supporting targeted screening.” Copd (2006)
Allele A
OR —
p —
Candidate gene study
European

Serum alpha-1 antitrypsin levels

The rs17580-A (PI*S) allele is a causal determinant of reduced serum alpha-1 antitrypsin concentrations. Large proteomics GWAS reaching p-values as extreme as 4×10⁻²²⁹ (GWAS Catalog, beta=0.966 units increase for AAT-related proteins in A allele carriers) confirm this locus as among the strongest genetic regulators of circulating AAT. A multi-cohort GWAS (n~9,665) demonstrated that common variants at the SERPINA1 locus show only synthetic associations with AAT, whereas the PI*S and PI*Z coding variants are the true causal drivers of reduced serum protein levels.

Thun GA et al. “Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels.” Plos Genetics (2013)
Allele A
OR —
p 1.0e-30
N 9,665
Large GWAS
European
Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele A
OR —
β 0.966
p 4.0e-229
N 10,708
Large GWAS
European

Chronic obstructive pulmonary disease

The PI*S allele (rs17580-A) is a risk factor for COPD primarily in the context of compound PI*SZ heterozygosity, with a meta-analysis-confirmed OR of ~3.3. Heterozygous PI*MS individuals show minimal independent COPD risk after adjusting for smoking. A 2012 SAPALDIA cohort study (n>4,600, 11-year follow-up) found no significant lung function decline attributable to the S allele alone, in contrast to the Z allele. A case-control study in Mexican mestizos found the rs17580 AT genotype associated with COPD in both tobacco smokers (OR 2.16) and biomass-exposed individuals (OR 11.50), suggesting gene-environment interactions.

Dahl M et al. “The protease inhibitor PI*S allele and COPD: a meta-analysis.” The European Respiratory Journal (2005)
Allele A
OR 3.26
p —
Meta-analysis
European
Thun GA et al. “SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort.” Plos One (2012)
Allele A
OR —
p —
N 4,600
Preliminary work
European
Pérez-Rubio G et al. “Heterozygous Genotype rs17580 AT (PiS) in SERPINA1 is Associated with COPD Secondary to Biomass-Burning and Tobacco Smoking: A Case-Control and Populational Study.” International Journal of Chronic Obstructive Pulmonary Disease (2020)
Allele A
OR 2.16
p 1.0e-3
N 1,878
Preliminary work
Mexican Mestizo

Asthma

A 2024/2025 multi-cohort study incorporating discovery (n=369), replication (n=525 Spanish), and validation in UK Biobank and FinnGen found that the PI*S allele (rs17580-A) was associated with a 2.38-fold increased risk of asthma exacerbations (p=0.001). The PI*Z allele showed an even stronger effect (OR 3.49). Lower circulating AAT protein levels correlated with higher exacerbation frequency, suggesting a mechanistic link through reduced protease inhibition in the airway. Evidence is strongest for exacerbation risk rather than asthma prevalence per se.

Martín-González E et al. “Alpha-1 antitrypsin deficiency and Pi*S and Pi*Z SERPINA1 variants are associated with asthma exacerbations.” Pulmonology (2025)
Allele A
OR 2.38
p 1.0e-3
N 1,219
Preliminary work
European
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GWAS Catalog Trait Associations (75)

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

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 A
OR 1.35
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 A
OR 0.66
p 1.0e-32
N 3,301
Large GWAS
European

syntaxin-2 measurement

Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele A
OR 1.25
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 A
OR 1.00
p 2.0e-75
N 3,301
Large GWAS
European

urea transporter 2 measurement

Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele A
OR 0.97
p 4.0e-229
N 10,708
Large GWAS
European
Sun BB et al. “Genomic atlas of the human plasma proteome.” Nature 558(7708):73-79 (2018)
Allele A
OR 1.08
p 1.0e-89
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 A
OR 0.88
p 4.0e-194
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 A
OR 0.34
p 5.0e-126
N 47,745
Large GWAS
European

ubiquitin carboxyl-terminal hydrolase isozyme L1 measurement

Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele A
OR 0.73
p 1.0e-140
N 10,708
Large GWAS
European

serine/threonine-protein kinase MRCK alpha measurement

Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele A
OR 0.74
p 2.0e-127
N 10,708
Large GWAS
European
Sun BB et al. “Genomic atlas of the human plasma proteome.” Nature 558(7708):73-79 (2018)
Allele A
OR 0.56
p 3.0e-23
N 3,301
Large GWAS
European

synaptosomal-associated protein 25 measurement

Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele A
OR 0.71
p 1.0e-114
N 10,708
Large GWAS
European
Sun BB et al. “Genomic atlas of the human plasma proteome.” Nature 558(7708):73-79 (2018)
Allele A
OR 1.01
p 1.0e-76
N 3,301
Large GWAS
European

melanoma-associated antigen 3 measurement

Pietzner M et al. “Mapping the proteo-genomic convergence of human diseases.” Science (new York, N.y.) 374(6569):eabj1541 (2021)
Allele A
OR 0.65
p 7.0e-97
N 10,708
Large GWAS
European

level of integrin alpha-2 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 A
OR 0.21
p 3.0e-87
N 47,745
Large GWAS
European

neurogenic locus notch homolog protein 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 A
OR 0.25
p 1.0e-86
N 47,745
Large GWAS
European
▶

ClinVar annotation

Pathogenic★★★☆
37 submitters43 publications

Alpha-1-antitrypsin deficiency (A1ATD); Chronic obstructive pulmonary disease; Cystic fibrosis (CF); Inborn genetic diseases; PI S; SERPINA1-related disorder; Susceptibility to severe coronavirus disease (COVID-19); not specified

View on ClinVar →
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Research that mentions this SNP (1)

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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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