Is AIRE p.Arg433fs (c.1295_1296insA) pathogenic?

AIRE p.Arg433fs (c.12951296insA) is classified Pathogenic/Likely pathogenic in AIRE (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-02). Very rare (popmax 0.00334%, amr); Associated with autoimmune polyendocrine syndrome type 1.

What condition is associated with AIRE p.Arg433fs (c.1295_1296insA)?

AIRE p.Arg433fs (c.1295_1296insA) is associated with autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Arg433fs (c.1295_1296insA) in the general population?

AIRE p.Arg433fs (c.1295_1296insA) is very rare (popmax 0.00334%, amr) (gnomAD).

How is Autoimmune polyendocrinopathy type 1 inherited?

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

AIRE p.Arg433fs

c.1295_1296insA · rs763695515 · VCV585381

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

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 11 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 1.3, phastCons 1
Overall
CADD	28.8	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 0.00334% Admixed American · 2/59,948 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000376% 6/1,596,422 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,974
European (non-Finnish)	0.000339%	294,879

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.Arg433fs
Coding: c.1295_1296insA
MANE Select: NM_000383
dbSNP: rs763695515
Type: Insertion
Location: chr21:44293805 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB

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.Arg433Cys Uncertain significance ★ ⚠ same residue
AIRE p.Arg433His Uncertain significance ★ ⚠ same residue
AIRE p.Arg433= Likely benign ★ same residue
AIRE p.Leu32fs Pathogenic/Likely pathogenic ★★ same condition
AIRE p.Met388fs Pathogenic ★★ same condition
AIRE p.Glu375delinsLeuSerLeuIleHisIleTer Likely pathogenic ★ same condition
AIRE p.Pro166fs Likely pathogenic ★ same condition
AIRE p.Pro39fs 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-arg433fs (accessed [today's date]).

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