SERPINA1

serpin family A member 1, the group of Serpin peptidase inhibitors

Basic information

Region (hg38): 14:94376746-94390693

Previous symbols: [ "PI" ]

Links

ENSG00000197249 ∙ NCBI:5265 ∙ OMIM:107400 ∙ HGNC:8941 ∙ Uniprot:P01009 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• alpha 1-antitrypsin deficiency (Limited), mode of inheritance: AR
• alpha 1-antitrypsin deficiency (Strong), mode of inheritance: AR
• alpha 1-antitrypsin deficiency (Strong), mode of inheritance: AR
• alpha 1-antitrypsin deficiency (Supportive), mode of inheritance: AR
• hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation (Supportive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Alpha-1-Antitrypsin deficiency	AR	Gastrointestinal; Pulmonary	Medical treatment (augmentation therapy with purified alpha-1-antitrypsin, Vitamin E supplementation) can be helpful for pulmonary and hepatic manifestations; Exacerbating factors (eg, smoking) should be avoided; Liver transplantation may be necessary in individuals with severe liver manifestations	Gastrointestinal; Pulmonary	4240153; 4117022; 3494198; 2185272; 2035327; 7875269; 8066566; 10898319; 12740257; 11320399; 12452881; 12574076; 14522813; 15282394; 15214923; 20301692; 21457231; 21752289; 22016686; 22215832; 22330941; 22500781; 22536580; 22933512; 23055718; 23251618; 23766346

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SERPINA1 gene.

• Alpha-1-antitrypsin deficiency (321 variants)
• not provided (96 variants)
• Inborn genetic diseases (42 variants)
• not specified (17 variants)
• SERPINA1-related condition (12 variants)
• - (3 variants)
• Hereditary angioedema with normal C1Inh (2 variants)
• Susceptibility to severe coronavirus disease (COVID-19) (2 variants)
• PI M1-ALA213 (2 variants)
• PI M(HEERLEN) (1 variants)
• PI P(ST. ALBANS) (1 variants)
• PI M3 (1 variants)
• PI M2 (1 variants)
• PI Q0(GRANITE FALLS) (1 variants)
• PI, M1V (1 variants)
• PI M4 (1 variants)
• PI M(PROCIDA) (1 variants)
• See cases (1 variants)
• PI NULL(BOLTON) (1 variants)
• PI Q0(CARDIFF) (1 variants)
• Chronic obstructive pulmonary disease (1 variants)
• Squamous cell carcinoma (1 variants)
• FRAXE (1 variants)
• PI Q0(BOLTON) (1 variants)
• PI Q0(BELLINGHAM) (1 variants)
• PI Z(WREXHAM) (1 variants)
• PI NULL(WEST) (1 variants)
• PI NULL(BELLINGHAM) (1 variants)
• PI S(IIYAMA) (1 variants)
• PI P(LOWELL) (1 variants)
• PI Z(TUN) (1 variants)
• PI P(DUARTE) (1 variants)
• PI KALSHEKER-POLLER (1 variants)
• COPD, severe early onset;Alpha-1-antitrypsin deficiency (1 variants)
• PI I (1 variants)
• PI S (1 variants)
• PI W(BETHESDA) (1 variants)
• Neurodevelopmental disorder (1 variants)
• PI X (1 variants)
• PI Z (1 variants)
• PI CHRISTCHURCH (1 variants)
• PI M(MALTON) (1 variants)
• PI Z(AUGSBURG) (1 variants)
• Cystic fibrosis (1 variants)
• PI Z(BRISTOL) (1 variants)
• PI, M1A (1 variants)
• Reduced circulating alpha-1-antitrypsin concentration (1 variants)
• Chronic obstructive pulmonary disease;Alpha-1-antitrypsin deficiency (1 variants)
• PI NULL(CARDIFF) (1 variants)
• PI F (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SERPINA1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	104	2	111
missense	4	10	50	39	1	104
nonsense	4	8				12
start loss		1				1
frameshift	8	13				21
inframe indel	1					1
splice donor/acceptor (+/-2bp)	1	4				5
splice region			3	8		11
non coding			47	13	13	73
Total	18	36	102	156	16

Highest pathogenic variant AF is 0.000177

Variants in SERPINA1

This is a list of pathogenic ClinVar variants found in the SERPINA1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
14-94376821-C-T		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 12, 2018)
14-94376873-C-T		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 12, 2018)
14-94376882-G-C		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94376894-G-A		Alpha-1-antitrypsin deficiency	Likely benign (Jan 12, 2018)
14-94376955-T-A		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377035-C-T		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377118-C-T		PI KALSHEKER-POLLER • Alpha-1-antitrypsin deficiency	Benign/Likely benign (Jan 15, 2024)
14-94377155-A-G		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377157-G-A		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377162-C-T		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377214-G-A		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377228-T-C		Alpha-1-antitrypsin deficiency	Benign (Jan 13, 2018)
14-94377254-C-T		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 12, 2018)
14-94377276-A-G		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377308-T-C		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377382-C-T		Alpha-1-antitrypsin deficiency	Benign (Jan 13, 2018)
14-94377383-C-G		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 12, 2018)
14-94377388-G-A		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377481-A-G		Alpha-1-antitrypsin deficiency	Benign (Jan 12, 2018)
14-94377503-G-A		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377595-A-G		Alpha-1-antitrypsin deficiency	Benign (Jan 13, 2018)
14-94377596-G-A		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377657-G-A		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)
14-94377708-G-A		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 12, 2018)
14-94377724-C-T		Alpha-1-antitrypsin deficiency	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SERPINA1	protein_coding	protein_coding	ENST00000448921	4	13947

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.85e-8	0.150	125725	0	23	125748	0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.373	242	226	1.07	0.0000121	2771
Missense in Polyphen		54	58.882	0.91708		778
Synonymous	-0.0692	103	102	1.01	0.00000647	825
Loss of Function	0.00374	11	11.0	0.999	4.78e-7	140

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000300	0.000300
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000968	0.0000967
Middle Eastern	0.0000544	0.0000544
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin. Irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. The aberrant form inhibits insulin-induced NO synthesis in platelets, decreases coagulation time and has proteolytic activity against insulin and plasmin.
• Disease: DISEASE: Alpha-1-antitrypsin deficiency (A1ATD) [MIM:613490]: A disorder whose most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age. {ECO:0000269|PubMed:1905728, ECO:0000269|PubMed:2227940, ECO:0000269|PubMed:2390072}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Complement and coagulation cascades - Homo sapiens (human);Nuclear Receptors Meta-Pathway;NRF2 pathway;Lung fibrosis;Dengue-2 Interactions with Complement and Coagulation Cascades;Complement and Coagulation Cascades;Neutrophil degranulation;Vesicle-mediated transport;Membrane Trafficking;Post-translational protein phosphorylation;Post-translational protein modification;Metabolism of proteins;Innate Immune System;Immune System;p73 transcription factor network;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;Cargo concentration in the ER;Transport to the Golgi and subsequent modification;Asparagine N-linked glycosylation;Hemostasis;FOXA1 transcription factor network;COPII-mediated vesicle transport;ER to Golgi Anterograde Transport (Consensus)

Recessive Scores

• pRec: 0.798

Intolerance Scores

• loftool: 0.00462
• rvis_EVS: 0.53
• rvis_percentile_EVS: 81.01

Haploinsufficiency Scores

• pHI: 0.195
• hipred: N
• hipred_score: 0.428
• ghis: 0.850

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.975

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Serpina1e

Gene ontology

• Biological process: platelet degranulation;endoplasmic reticulum to Golgi vesicle-mediated transport;acute-phase response;blood coagulation;negative regulation of endopeptidase activity;neutrophil degranulation;post-translational protein modification;cellular protein metabolic process;COPII vesicle coating
• Cellular component: Golgi membrane;extracellular region;extracellular space;endoplasmic reticulum;endoplasmic reticulum lumen;Golgi apparatus;COPII-coated ER to Golgi transport vesicle;platelet alpha granule lumen;endoplasmic reticulum-Golgi intermediate compartment membrane;intracellular membrane-bounded organelle;collagen-containing extracellular matrix;extracellular exosome;ficolin-1-rich granule lumen
• Molecular function: protease binding;serine-type endopeptidase inhibitor activity;protein binding;identical protein binding