Is AIRE p.Arg139Ter (c.415C>T) pathogenic?

AIRE p.Arg139Ter (c.415C>T) is classified Pathogenic in AIRE (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-03). Very rare (popmax 0.00267%, afr); Associated with AIRE-related disorder.

What condition is associated with AIRE p.Arg139Ter (c.415C>T)?

AIRE p.Arg139Ter (c.415C>T) is associated with AIRE-related disorder, autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Arg139Ter (c.415C>T) in the general population?

AIRE p.Arg139Ter (c.415C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

AIRE p.Arg139Ter

c.415C>T · rs121434256 · VCV3310

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

AIRE-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 14
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -1.1, phastCons 0.62
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,024 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00112% 18/1,612,216 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,512
East Asian	0.00223%	44,868
Admixed American	0.00167%	60,010
European (non-Finnish)	0.00119%	84,272

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AIRE
Protein: p.Arg139Ter
Coding: c.415C>T
MANE Select: NM_000383
dbSNP: rs121434256
Type: single nucleotide variant
Location: chr21:44287085 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 139: the 'disordered' region

Full AIRE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AIRE-related disorder

Also linked: autoimmune polyendocrine syndrome type 1

Similar variants

AIRE p.Arg139Pro Uncertain significance ★ ⚠ same residue
AIRE p.Arg139Gly Likely benign ★ same residue
AIRE c.1095+2T>C Pathogenic/Likely pathogenic ★★ same condition
AIRE c.1096-1G>A Pathogenic ★★ same condition
AIRE c.1278+1G>A Likely pathogenic ★★ same condition
AIRE c.1279-2A>G Likely pathogenic ★★ same condition
AIRE c.1503+1G>A Likely pathogenic ★★ same condition
AIRE c.1503+1G>T Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/aire-p-arg139ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown