Is AIRE p.Val484fs (c.1449_1476del) pathogenic?

AIRE p.Val484fs (c.14491476del) is classified Pathogenic in AIRE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-03). Very rare (popmax 8.57e-05%, nfe); Associated with autoimmune polyendocrine syndrome type 1.

What condition is associated with AIRE p.Val484fs (c.1449_1476del)?

AIRE p.Val484fs (c.1449_1476del) is associated with autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Val484fs (c.1449_1476del) in the general population?

AIRE p.Val484fs (c.1449_1476del) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

How is Autoimmune polyendocrinopathy type 1 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

AIRE p.Val484fs

c.1449_1476del · rs1268377224 · VCV2757391

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Conditions

autoimmune polyendocrine syndrome type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.39	GERP -2.1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.57e-05% European (non-Finnish) · 1/1,167,398 alleles

Overall 7.03e-05% 1/1,421,620 alleles · very rare

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.Val484fs
Coding: c.1449_1476del
MANE Select: NM_000383
dbSNP: rs1268377224
Type: Deletion
Location: chr21:44294439 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 484: a UniProt-annotated variant site (found in a patient with acrofacial vitiligo and gastric parietal cell autoantibodies; uncertain significance)

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

Disease context

autoimmune polyendocrine syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autoimmune polyendocrinopathy type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

AIRE p.Val484Met Uncertain significance ★★ ⚠ same residue
AIRE p.Val484Ala Uncertain significance ★ ⚠ same residue
AIRE p.Val484= Likely benign ★ same residue
AIRE c.1203_1278+28del Likely pathogenic ★★ same condition
AIRE c.1278+1del Likely pathogenic ★★ same condition
AIRE p.Ala117fs Pathogenic ★★ same condition
AIRE p.Ala264fs Pathogenic ★★ same condition
AIRE p.Arg110fs 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-val484fs (accessed [today's date]).

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