Is AIRE p.Pro166fs (c.496_497insA) pathogenic?

AIRE p.Pro166fs (c.496497insA) is classified Likely pathogenic in AIRE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-05). Absent from gnomAD; Associated with autoimmune polyendocrine syndrome type 1.

What condition is associated with AIRE p.Pro166fs (c.496_497insA)?

AIRE p.Pro166fs (c.496_497insA) is associated with autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Pro166fs (c.496_497insA) in the general population?

AIRE p.Pro166fs (c.496_497insA) is absent from gnomAD (gnomAD).

How is Autoimmune polyendocrinopathy type 1 inherited?

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

AIRE p.Pro166fs

c.496_497insA · rs2517877732 · VCV1724323

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 4 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.85	GERP -2.5, phastCons 0.35

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: AIRE
Protein: p.Pro166fs
Coding: c.496_497insA
MANE Select: NM_000383
dbSNP: rs2517877732
Type: Insertion
Location: chr21:44287549 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 166: the 'disordered' region

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.Pro166= Likely benign ★★ same residue
AIRE p.Pro166Leu Benign/Likely benign ★★ same residue
AIRE p.Arg433fs Pathogenic/Likely pathogenic ★★ same condition
AIRE p.Leu32fs Pathogenic/Likely pathogenic ★★ same condition
AIRE p.Met388fs Pathogenic ★★ same condition
AIRE p.Glu375delinsLeuSerLeuIleHisIleTer Likely pathogenic ★ same condition
AIRE p.Pro39fs Likely pathogenic ★ same condition
AIRE c.879+7_879+8insA Likely benign ★ 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-pro166fs (accessed [today's date]).

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