NM_000383.4(AIRE):c.415C>T (p.Arg139Ter) AND Polyglandular autoimmune syndrome, type 1

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Feb 3, 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:: RCV000169129.23

Allele description [Variation Report for NM_000383.4(AIRE):c.415C>T (p.Arg139Ter)]

NM_000383.4(AIRE):c.415C>T (p.Arg139Ter)

Gene:

AIRE:autoimmune regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_000383.4(AIRE):c.415C>T (p.Arg139Ter)

HGVS:

NC_000021.9:g.44287085C>T
NG_009556.1:g.6206C>T
NM_000383.4:c.415C>TMANE SELECT
NP_000374.1:p.Arg139Ter
LRG_18t1:c.415C>T
LRG_18:g.6206C>T
LRG_18p1:p.Arg139Ter
NC_000021.8:g.45706968C>T
NM_000383.2:c.415C>T
NM_000383.3:c.415C>T

Protein change:

R139*; ARG139TER

Links:

OMIM: 607358.0004; dbSNP: rs121434256

Molecular consequence:

NM_000383.4:c.415C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Polyglandular autoimmune syndrome, type 1 (APS1)
Synonyms:: AUTOIMMUNE POLYENDOCRINE SYNDROME, TYPE I, WITH OR WITHOUT REVERSIBLE METAPHYSEAL DYSPLASIA; APS I; HYPOADRENOCORTICISM WITH HYPOPARATHYROIDISM AND SUPERFICIAL MONILIASIS; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009411; MedGen: C0085859; Orphanet: 3453; OMIM: 240300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023632	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2009)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9856486, 19807739
SCV000220339	Counsyl	no assertion criteria provided	Pathogenic (May 21, 2014)	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 16166780, 9856486, 19807739, 18616706
SCV001363575	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 5, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9856486, 28446514 Citation Link,
SCV001452106	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Pathogenic (Dec 17, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28446514, 16166780 Citation Link,
SCV001591356	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2026)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11524731, 26141571, 9856486, 22024611, 28492532
SCV002517544	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV004036171	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 14, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9856486, 16166780, 22024611, 25741868
SCV007636885	Otogenetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 3, 2026)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34003463, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Two novel AIRE mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) among Indians.

Zaidi G, Sahu RP, Zhang L, George G, Bhavani N, Shah N, Bhatia V, Bhansali A, Jevalikar G, Jayakumar RV, Eisenbarth GS, Bhatia E.

Clin Genet. 2009 Nov;76(5):441-8. doi: 10.1111/j.1399-0004.2009.01280.x. Epub 2009 Oct 6.

PubMed [citation]

PMID:: 19807739

Evaluation of the autoimmune regulator (AIRE) gene mutations in a cohort of Italian patients with autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) and in their relatives.

Cervato S, Mariniello B, Lazzarotto F, Morlin L, Zanchetta R, Radetti G, De Luca F, Valenzise M, Giordano R, Rizzo D, Giordano C, Betterle C.

Clin Endocrinol (Oxf). 2009 Mar;70(3):421-8. doi: 10.1111/j.1365-2265.2008.03318.x. Epub 2008 Jun 27.

PubMed [citation]

PMID:: 18616706

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000023632.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

Rosatelli et al. (1998) found that a single Sardinian mutation, arg139-to-ter (R139X), accounted for 18 of 22 independent Sardinian AIRE alleles in patients with APECED (APS1; 240300).

In a 24-year-old Indian man with APS1, Zaidi et al. (2009) identified homozygosity for the R139X mutation in the AIRE gene. The patient presented at age 15 years with hypoparathyroidism and Addison disease, and also had primary hypothyroidism, alopecia, and vitiligo.

#	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		not provided	not provided	not provided	not provided

From Counsyl, SCV000220339.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

Description

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

#	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, SCV001363575.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: AIRE c.415C>T (p.Arg139X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.5e-05 in 242012 control chromosomes (gnomAD). c.415C>T has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Autoimmune Polyglandular Syndrome Type 1 (e.g. Rosatelli_1998, Zaidi_2017). The variant has been found predominantly in individuals and families of Italian (Sardinian) origin therefore, suggesting it is a founder mutation. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. 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 Natera, Inc., SCV001452106.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.415C>T variant in AIRE is a nonsense variant predicted to introduce a stop codon at amino acid 139. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 28446514, 16166780). Given the available evidence, this variant is 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001591356.6

#	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 creates a premature translational stop signal (p.Arg139*) in the AIRE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs121434256, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with autosomal recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (PMID: 9856486, 22024611). ClinVar contains an entry for this variant (Variation ID: 3310). 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 Mendelics, SCV002517544.1

#	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 National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health, SCV004036171.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	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 Otogenetics, SCV007636885.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

PVS1: Stop gain variant introduces premature stop codon in gene with loss of function as mechanism of disease, predicted to undergo NMD; PM2: Maximum gnomAD MAF of 0.0071% in African (AFR) subpopulation (<0.13% threshold); PM3_Strong: Variant reported in homozygous state in numerous affected individuals and reported in trans with four pathogenic variants in five individuals affected with Autoimmune polyendocrinopathy syndrome (PMID: 34003463)

#	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

Last Updated: Sep 27, 2026

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