The packet lists SERPINA1 as the associated gene and supplies no ClinGen validity classification for it. The packet's inheritance field lists an autosomal recessive pattern, while GeneReviews states that AATD is inherited in an autosomal codominant manner and refers to biallelic pathogenic variants in SERPINA1.

GeneReviews summarizes genotype-phenotype correlations. PI*MM is associated with normal serum AAT and no increased risk of liver or lung disease. PI*MZ nonsmokers are in general not considered at increased risk for lung disease, whereas PI*MZ smokers have increased risk of COPD. PI*SZ is not usually associated with high risk, although about 11% of individuals have serum AAT below the protective threshold. PI*ZZ is associated with serum AAT of approximately 10%-20% of normal, high risk for both liver and lung disease, and is present in 95% of affected individuals with clinical manifestations. PI*null-null individuals have no measurable serum AAT; because protein does not accumulate in the liver they are not at increased risk of liver disease, but are at high risk of lung disease. Alleles associated with intrahepatic inclusions (for example Z, Mmalton, Siiyama) carry increased risk of liver disease. GeneReviews notes variable expressivity among PI*ZZ individuals not explained by known risk factors, and names smoking as the major factor accelerating COPD development in adults.

GeneReviews describes AATD as suspected with evidence of COPD (emphysema, persistent airflow obstruction, chronic bronchitis, and/or bronchiectasis) and/or liver disease at any age, C-ANCA positive vasculitis, or necrotizing panniculitis. It reports a diagnostic delay of 5-7 years between first symptoms and diagnosis, associated with worsened clinical status at diagnosis.

According to GeneReviews, the diagnosis relies on either demonstration of a low serum AAT concentration, most commonly measured by nephelometry (normal levels described as approximately 100-220 mg/dL), or identification of biallelic pathogenic variants in SERPINA1. Described molecular approaches include single-gene testing, with targeted analysis for the common PI*Z, PI*S, PI*I, and PI*F alleles and sequence analysis of SERPINA1, followed by deletion/duplication analysis when only one or no variant is found; multigene panels; and comprehensive genomic testing when the diagnosis was not considered because of atypical features. GeneReviews lists differential diagnoses including other causes of COPD, and, for liver disease, neonatal cholestasis from metabolic and non-hereditary causes, chronic viral hepatitis, steatohepatitis, sclerosing cholangitis, and primary biliary cholangitis.

The packet certifies no FDA-approved treatment record and no foundational therapy entries for AATD; the descriptions below come from the GeneReviews management section. For COPD, GeneReviews lists standard therapy including inhaled corticosteroids, long-acting beta agonists, long-acting muscarinic antagonists, pulmonary rehabilitation, supplemental oxygen, and vaccinations. For emphysema, it lists augmentation therapy with intravenous pooled human serum AAT in those with established emphysema, with greatest benefit observed in moderate airflow obstruction (FEV1 35%-60% predicted). For end-stage lung disease it lists lung transplantation, and for severe liver disease liver transplantation, which restores AAT levels, with vaccinations against hepatitis A and B. For panniculitis it lists dapsone or doxycycline and, if refractory, high-dose intravenous AAT augmentation. GeneReviews also describes evaluations after diagnosis (pulmonary function tests, chest CT, liver biopsy where clinically indicated, skin examination, genetic counseling) and a surveillance table covering pulmonary function and liver tests.

Orphan drug entries in the packet are designations only and do not indicate approval; sponsors include Mereo Biopharma (alvelestat), Sanofi, Beam Therapeutics, Tessera Therapeutics, and BioMarin, and three entries carry a WITHDRAWN status.

A dedicated prognosis source is not certified in this packet, and no survival figures are supplied. The GeneReviews clinical description states that the natural history varies, depending in part on what brought the individual to medical attention, and that nonsmokers may have a normal life span but can also develop lung and/or liver disease. It also reports that about 65% of those with neonatal cholestasis go on to severe liver disease.

The packet certifies 26 active clinical trial records, and active clinical trials for this condition are listed on ClinicalTrials.gov. Examples: NCT06996756, Gene Therapy for Alpha 1-Antitrypsin Deficiency, Phase 1, Weill Medical College of Cornell University, RECRUITING, 2025-02-26 to 2032-08-01; NCT07227207, TSRA-196 in adults with PiZZ AATD, Phase 1, Tessera Therapeutics, RECRUITING, 2026-04-21 to 2029-03-01; NCT07431112, AIR-001 in adults with AATD, Phase 1, AIRNA Corporation, RECRUITING, 2026-03-17 to 2029-01-01; NCT07555483, weekly subcutaneous Alpha1-PI 15% versus intravenous Alpha1-PI, Phase 3, Grifols Therapeutics, RECRUITING, 2026-05-05 to 2027-09-30; NCT04157049, Alpha-1 Research Registry, Alpha-1 Foundation, RECRUITING, 2019-06-20 to 2029-06-20.

GeneReviews describes therapies under investigation including inhaled, liquid, and recombinant AAT, alternate dosing regimens of augmentation therapy, an oral neutrophil elastase inhibitor, molecules to block polymer formation, and gene therapy with viral vectors; for liver disease it lists carbamazepine or sirolimus to increase autophagy and small interfering RNA. The packet's digest classifies 504 publications, with Basic Science / Preclinical dominant.