SERPINA1

Chr 14AR

serpin family A member 1

Also known as: A1A, A1AT, AAT, PI, PI1, PRO2275, alpha1AT, nNIF

NCBI Gene: 5265ENSG00000197249UniProt: P01009

The protein encoded by this gene is a serine protease inhibitor belonging to the serpin superfamily whose targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. This protein is produced in the liver, the bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut. Defects in this gene are associated with chronic obstructive pulmonary disease, emphysema, and chronic liver disease. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

Primary Disease Associations & Inheritance

Emphysema due to AAT deficiencyMIM #613490
AR
Emphysema-cirrhosis, due to AAT deficiencyMIM #613490
AR
Hemorrhagic diathesis due to antithrombin PittsburghMIM #613490
AR
UniProtAlpha-1-antitrypsin deficiency
12
Active trials
66
Pathogenic / LP
345
ClinVar variants
10
Pubs (1 yr)
-0.4
Missense Z
1.63
LOEUF
Clinical Summary— SERPINA1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
66 Pathogenic / Likely Pathogenic· 77 VUS of 345 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available
📖
GeneReview available — SERPINA1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.63LOEUF
pLI 0.000
Z-score 0.00
OE 1.00 (0.63–1.63)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.37Z-score
OE missense 1.07 (0.96–1.19)
242 obs / 226.2 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.00 (0.63–1.63)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.07 (0.96–1.19)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 11 / 11.0Missense obs/exp: 242 / 226.2Syn Z: -0.07
DN
0.5081th %ile
GOF
0.7126th %ile
LOF
0.1796th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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

345 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic28
VUS77
Likely Benign176
Benign17
Conflicting9
38
Pathogenic
28
Likely Pathogenic
77
VUS
176
Likely Benign
17
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
3
25
0
38
Likely Pathogenic
14
9
5
0
28
VUS
0
55
22
0
77
Likely Benign
0
19
34
123
176
Benign
2
6
6
3
17
Conflicting
—9
Total269292126345

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

View in ClinVar →

Protein Context — Lollipop Plot

SERPINA1 · 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
Idiopathic Interstitial Pneumopathy/Pneumopathy Interstitial DiffusePaediatric and Adult Patients

RaDiCo PID Cohort (RaDiCo-ILD Cohort in English)

RECRUITING
NCT04238871Institut National de la Santé Et de la Recherche Médicale, FranceStarted 2017-06-21
Alpha 1-Antitrypsin Deficiency

Gene Therapy for Alpha-1 Antitrypsin Deficiency

RECRUITING
NCT06996756Phase PHASE1Weill Medical College of Cornell UniversityStarted 2025-02-26
AAV8hAAT(AVL)
Cystic FibrosisPulmonary FibrosisTuberous Sclerosis

Role of Genetic Factors in the Development of Lung Disease

RECRUITING
NCT00001532National Heart, Lung, and Blood Institute (NHLBI)Started 1996-09-13
Malnutrition PregnancyMalnutrition in ChildrenMalnutrition (Calorie)

Early Life Malnutrition, Environmental Enteric Dysfunction and Microbiome Trajectories

RECRUITING
NCT07195006University of ZimbabweStarted 2025-01-27
Malnutrition in pregnancy as exposurePoor WASH living conditions as exposure
Alpha 1-Antitrypsin Deficiency

Study of BMN 349 Single Dose in PiZZ and PiMZ/MASH Adult Participants

RECRUITING
NCT06738017Phase PHASE1BioMarin PharmaceuticalStarted 2025-02-21
BMN 349Placebo
Alpha1-antitrypsin Deficiency

Preparation of IPSC for Cell Gene Editing for the Treatment of AATD

ENROLLING BY INVITATION
NCT06892236Phase NAFondazione IRCCS Policlinico San Matteo di PaviaStarted 2025-01-15
iPSC generation
Crohn's Disease

Impact of Diet and Lifestyle Modification on the Intestinal Barrier Integrity in Crohn's Disease

RECRUITING
NCT06719778Phase NAUniversität Duisburg-EssenStarted 2024-08-01
Two-stage nutritional therapy concept
Weight GainAnemia, Iron DeficiencyBirth Weight

Egg Intervention During Pregnancy in Indonesia

ACTIVE NOT RECRUITING
NCT04694235Phase NASEAMEO Regional Centre for Food and NutritionStarted 2021-02-12
Egg intervention
Ulcerative Colitis (UC)Crohn Disease (CD)

Wild Blueberries in Colitis

RECRUITING
NCT06698601Phase NAUniversität Duisburg-EssenStarted 2024-09-24
blueberry-rich dietControl diet
Alpha 1-Antitrypsin Deficiency

A Study of KB408 for the Treatment of Alpha-1 Antitrypsin Deficiency

RECRUITING
NCT06049082Phase PHASE1Krystal Biotech, Inc.Started 2024-02-15
KB408 (Nebulization)
Alpha 1-AntitrypsinCOPDAntibody Deficiency

Genetic Variation in IgG in Alpha 1 Antitrypsin Deficiency

RECRUITING
NCT07135427Phase PHASE4University of Alabama at BirminghamStarted 2025-09-03
20-valent pneumococcal conjugate vaccine
Alpha 1-antitrypsin Deficiency (AATD)

Screening for Alpha-1 Antitrypsin Deficiency in Patients With Airway Obstruction

RECRUITING
NCT07152834Muğla Sıtkı Koçman UniversityStarted 2025-08-06
Blood Sampling
Clinical Literature
Landmark / reviewRecent case evidence
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
Clinical implications of a novel SERPINA1 variant c.236 T > A: Challenges in characterizing new rare alpha-1 antitrypsin mutations.
Olivares-Rivera A et al.·Mol Genet Metab Rep
2026Open Access
Do LRG1-SERPINA1 Interactions Modulate Fibrotic and Inflammatory Signatures in Rheumatoid Arthritis? A Proteomic and In Silico Investigation.
Hussain T et al.·Pathophysiology
2026Open Access
Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency.
Matamala N et al.·Respir Res
2026Open AccessFunctional
SERPINA1 as a Shared Biomarker in Periodontitis and Oral Squamous Cell Carcinoma.
Zhang J et al.·Int Dent J
2026Open Access
SERPINA1 activation by RUNX1 drives microglial M2 polarization and reduces neuronal injury in a Parkinson's disease mouse model.
Zhang K et al.·Cytotechnology
2026Functional
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