NM_000295.5(SERPINA1):c.1177C>T (p.Pro393Ser) AND Alpha-1-antitrypsin deficiency

Germline classification:: Pathogenic/Likely pathogenic (11 submissions)
Last evaluated:: May 23, 2026
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000336993.44

Allele description [Variation Report for NM_000295.5(SERPINA1):c.1177C>T (p.Pro393Ser)]

NM_000295.5(SERPINA1):c.1177C>T (p.Pro393Ser)

Gene:

SERPINA1:serpin family A member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q32.13

Genomic location:

Preferred name:

NM_000295.5(SERPINA1):c.1177C>T (p.Pro393Ser)

HGVS:

NC_000014.9:g.94378529G>A
NG_008290.1:g.17164C>T
NM_000295.5:c.1177C>TMANE SELECT
NM_001002235.3:c.1177C>T
NM_001002236.3:c.1177C>T
NM_001127700.2:c.1177C>T
NM_001127701.2:c.1177C>T
NM_001127702.2:c.1177C>T
NM_001127703.2:c.1177C>T
NM_001127704.2:c.1177C>T
NM_001127705.2:c.1177C>T
NM_001127706.2:c.1177C>T
NM_001127707.2:c.1177C>T
NP_000286.3:p.Pro393Ser
NP_001002235.1:p.Pro393Ser
NP_001002236.1:p.Pro393Ser
NP_001121172.1:p.Pro393Ser
NP_001121173.1:p.Pro393Ser
NP_001121173.1:p.Pro393Ser
NP_001121174.1:p.Pro393Ser
NP_001121175.1:p.Pro393Ser
NP_001121176.1:p.Pro393Ser
NP_001121177.1:p.Pro393Ser
NP_001121178.1:p.Pro393Ser
NP_001121179.1:p.Pro393Ser
LRG_575t1:c.1177C>T
LRG_575:g.17164C>T
LRG_575p1:p.Pro393Ser
NC_000014.8:g.94844866G>A
NM_000295.4:c.1177C>T
NM_001127701.1:c.1177C>T
NM_001127707.1:c.1177C>T

Protein change:

P393S

Links:

dbSNP: rs61761869

Molecular consequence:

NM_000295.5:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001002235.3:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001002236.3:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127700.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127701.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127702.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127703.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127704.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127705.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127706.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127707.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Alpha-1-antitrypsin deficiency (A1ATD)
Synonyms:: AAT deficiency; A1AT deficiency; Alpha1-Antitrypsin Deficiency
Identifiers:: MONDO: MONDO:0013282; MedGen: C0221757; Orphanet: 60; OMIM: 613490

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000630387	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2026)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18024524, 2784123, 10234508, 27296815, 28492532
SCV000711354	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (May 13, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 19437508, 22723858, 21228398, 19654085, 11214903, 27296815, 10234508, 21474916, 24033266
SCV000915659	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Aug 17, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10234508, 18515255, 11474657, 19437508, 27296815 Citation Link,
SCV002020069	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060278	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Jan 6, 2025)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10234508, 10878477, 18515255, 19437508, 19654085, 21474916, 22723858, 23222880, 27296815 Citation Link,
SCV002519713	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV002768009	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 30, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10234508, 26321041, 27296815, 31307431, 25741868
SCV004203113	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 23, 2026)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005884918	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 23, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10234508, 27296815, 10878477, 18024524, 38876920 Citation Link,
SCV006055528	Department of Pathology and Laboratory Medicine, Sinai Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 4, 2022)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV007592995	Variantyx, Inc.	criteria provided, single submitter (Variantyx Assertion Criteria 2022)	Pathogenic (Oct 13, 2025)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10234508, 27296815, 2784123, 19437508, 18515255, 18024524 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Carrier testing for severe childhood recessive diseases by next-generation sequencing.

Bell CJ, Dinwiddie DL, Miller NA, Hateley SL, Ganusova EE, Mudge J, Langley RJ, Zhang L, Lee CC, Schilkey FD, Sheth V, Woodward JE, Peckham HE, Schroth GP, Kim RW, Kingsmore SF.

Sci Transl Med. 2011 Jan 12;3(65):65ra4. doi: 10.1126/scitranslmed.3001756.

PubMed [citation]

PMID:: 21228398
PMCID:: PMC3740116

See all PubMed Citations (20)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000630387.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 393 of the SERPINA1 protein (p.Pro393Ser). This variant is present in population databases (rs61761869, gnomAD 0.05%). This missense change has been observed in individuals with alpha-1-antitrypsin deficiency (AATD) (PMID: 18024524, 27296815). ClinVar contains an entry for this variant (Variation ID: 289135). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SERPINA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 10234508, 27296815). This variant disrupts the p.Pro393 amino acid residue in SERPINA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2784123, 10234508, 27296815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711354.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

The p.Pro393Ser variant in SERPINA1 (MWurzburg allele) has been reported in at l east 5 individuals with SERPINA1-related phenotypes, including alpha-1-antitryps in deficiency (AATD), asthma, elevated transaminases, and intrahepatic inclusion s (Poller 1999, Sexias 2001, Medicina 2009, Silva 2016, and Denden 2009). Three of these individuals were heterozygous, while 2 individuals with liver phenotype s were compound heterozygous. The variant segregated in at least 1 family member with low levels of alpha-1-antritrypsin and 2 members of 1 family with asthma ( Poller 1999, Denden 2009). In vitro and in vivo functional studies provide some evidence that the p.Pro393Ser variant may impact protein function; however, thes e types of assays may not accurately represent biological function (Poller 1999, Fra 2012). This variant has also been identified in 29/66728 European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs61761869); however, this frequency is low enough to be consistent with a r ecessive carrier frequency. Furthermore, a different variant at the same positio n (p.Pro393Leu) has been classified as pathogenic by our laboratory, supporting that a change at this position may not be tolerated. In summary, although additi onal studies are required to fully establish its clinical significance, the p.Pr o393Ser variant is likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Illumina Laboratory Services, Illumina, SCV000915659.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The SERPINA1 c.1177C>T (p.Pro393Ser) variant, also referred to as Pi-M(Wurzburg), has been identified in a compound heterozygous state in three patients with alpha-1 antitrypsin deficiency (AATD) (Seixas et al. 2001; Medicina et al. 2009; Zorzetto et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.000513 in the European (non-Finnish) population of the Genome Aggregation Database. Poller et al. (1999) performed in vitro and in vivo functional studies and demonstrated that the p.Pro393Ser variant had defective intracellular transport and secretion into the bloodstream compared to the wild type AAT protein. The Pro393 residue is predicted to form part of a critical domain of the AAT protein. Based on the evidence, the p.Pro393Ser variant is classified as likely pathogenic for alpha-1 antitrypsin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002020069.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060278.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

NM_000295.4(SERPINA1):c.1177C>T(P393S) is a missense variant classified as likely pathogenic in the context of alpha-1 antitrypsin deficiency. P393S has been observed in cases with relevant disease (PMID: 19437508, 18515255, 10878477, 10234508, 27296815, 21474916, 19654085, 23222880). Relevant functional assessments of this variant are available in the literature (PMID: 22723858, 10234508). P393S has been observed in referenced population frequency databases. In summary, NM_000295.4(SERPINA1):c.1177C>T(P393S) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV002519713.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768009.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v2) (81 heterozygotes, 0 homozygotes); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is also known as p.(Pro369Leu) in an alternative nomenclature or as the MWurzburg allele. It has previously been reported in at least 8 alpha-1-1-antitrypsin deficiency patients and is often referred to as a severe deficient allele (ClinVar; PMIDs: 27296815; 18024524; 18515255; 11474657; 19437508; 10878477); This variant has moderate functional evidence supporting abnormal protein function. In vitro and in vivo functional studies have demonstrated that this variant results in intracellular transportation and secretion defects (PMID: 10234508; 22723858); Another missense variants comparable to the one identified in this case have limited previous evidence for pathogenicity. The p.(Pro393Leu) (alternatively known as P369L or MHeerlen) has previously been reported in at least 5 patients and has been suggested to result in extremely low AAT level and no liver disease (ClinVar; PMID: 26321041; 2784123; 27296815; 10234508). In addition, p.(Pro393His) has previously been reported in an adult female patient (compound heterozygote with the 'S' allele) suspected of having AATD however AAT serum level was normal (PMID: 31307431) and p.(Pro393Thr) was previously reported as pathogenic and as a variant of uncertain significance once each in ClinVar; Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from proline to serine; This variant is heterozygous; This gene is associated with autosomal recessive disease; Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2) with p.(Pro393Leu) having the highest allele count (14 heterozygotes, 0 homozygotes); Variant is located in the annotated reactive centre loop (RCL) within the Serpin domain (NCBI conserved domains; Pfam); Loss of function is a known mechanism of disease in this gene and is associated with alpha 1-antitrypsin deficiency (MONDO:0013282), SERPINA1-related; Heterozygous variant detected in trans with a second PATHOGENIC heterozygous variant (NM_000295.5(SERPINA1):c.1158dup; p.(Glu387Argfs*14)) in a recessive disease; This variant has been shown to be maternally inherited (by trio analysis).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004203113.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Positive for the pathogenic variant c.1177C>T (p.P393S) in the SERPINA1 gene. If this individual's partner is a carrier for ALPHA-1 ANTITRYPSIN DEFICIENCY, their chance to have a child with this condition is 1 in 4 (25%). Carrier screening for this individual's partner is suggested. The c.1177C>T (p.P393S) variant in the SERPINA1 gene has been observed at a frequency of 0.0286% in the gnomAD v2.1.1 dataset. This variant has been reported in a homozygous state or in conjunction with another variant in individual(s) with alpha-1 antitrypsin deficiency (PMID: 18024524, 37651384). Experimental studies have demonstrated that this variant reduces gene function (PMID: 10234508, 11474657, 22723858).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005884918.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: SERPINA1 c.1177C>T (p.Pro393Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251474 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SERPINA1 causing Alpha-1-Antitrypsin Deficiency (0.00029 vs 0.005), allowing no conclusion about variant significance. c.1177C>T has been reported in the literature in individuals affected with Alpha-1-Antitrypsin Deficiency (e.g. Jardi_2000, Print_2008, Silva_2016, Scioscia_2024). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a complete intracellular transport block in cell cultures in vitro (Poller_1999). The following publications have been ascertained in the context of this evaluation (PMID: 18024524, 27296815, 10878477, 10234508, 38876920). ClinVar contains an entry for this variant (Variation ID: 289135). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System, SCV006055528.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Variantyx, Inc., SCV007592995.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This is a nonsynonymous variant in the SERPINA1 gene (OMIM: 107400). Pathogenic variants in this gene have been associated with autosomal recessive alpha-1-antitrypsin deficiency. This variant is also referred to as Mwuerzburg allele (PMID: 10234508). This variant has been identified in the homozygous or compound heterozygous state in at least 3 unrelated individuals reported in the published literature (PMID: 19437508, 18515255, 18024524) (PM3). Functional studies have shown that this variant alters SERPINA1 protein function (PMID: 10234508, 27296815) (PS3), and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.817) (PP3). Moreover, an alternate amino acid change at this position (p.Pro393Leu) hasd been previously reported in similarly affected individuals, which suggests that this residue is biologically important (PMID: 2784123, 10234508, 27296815) (PM5). This variant has a 0.0442% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as pathogenic for autosomal recessive alpha-1-antitrypsin deficiency.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 13, 2026

Relating variation to medicine