The SERPINA1 gene encodes the alpha-1 antitrypsin (AAT) protein, also known as protease inhibitor (PI). Over 75 alleles (variants) are known for AAT/Pi, however with few exceptions, most are considered relatively benign. The variants that are considered pathologic predispose individuals (especially smokers) to early onset lung disease, specifically chronic obstructive pulmonary disease, but also, potentially, emphysema and liver cirrhosis.
There are four common variants of AAT, which were originally named based on how quickly the corresponding proteins moved in an electrophoretic field (F = fast, M = medium, S = slow, Z = very slow). The PiM allele is the normal/wild-type, and is the most common. The PiZ allele is a deficiency variant found primarily in Northern Europeans, while the PiS deficiency variant is more common in South-West Europe. Discovered over 50 years ago, the PiZ variant is the most common of the medically significant null variants, and it associated with significant AAT deficiency, lung and liver disease, though there is considerable disparity in clinical phenotype.[PMID 15115878]
These SERPINA1 variants are determined by the following SNPs:
According to the Alpha-1 Foundation, 95% of people clinically identified with Alpha-1 deficiency have two Z alleles (ZZ). Current evidence suggests that there are at least 100,000 people with Alpha-1 (ZZ) in the United States. Another deficient SNP combination is SZ, although people with this combination are less likely to get lung or liver problems than those with two Z alleles.
ClinGen has issued an Actionability recommendation for carriers of PiS and PiZ alleles which can be found here.
Much rarer A1AT SERPINA1 null variants include: