Is AIRE p.Ala343Pro (c.1027G>C) pathogenic?

AIRE p.Ala343Pro (c.1027G>C) is classified Uncertain significance in AIRE (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely benign (0.0984); Very rare (popmax 0.00116%, sas); Associated with autoimmune polyendocrine syndrome type 1.

What condition is associated with AIRE p.Ala343Pro (c.1027G>C)?

AIRE p.Ala343Pro (c.1027G>C) is associated with autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Ala343Pro (c.1027G>C) in the general population?

AIRE p.Ala343Pro (c.1027G>C) is very rare (popmax 0.00116%, sas) (gnomAD).

How is Autoimmune polyendocrinopathy type 1 inherited?

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

What do computational predictors say about AIRE p.Ala343Pro (c.1027G>C)?

AlphaMissense predicts likely benign (score 0.0984) — an in-silico prediction, not a clinical call.

AIRE p.Ala343Pro

c.1027G>C · VCV4069328

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00116%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autoimmune polyendocrine syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0984	likely benign
REVEL	0.414	indeterminate
SaProt	LLR -10.63	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP -0.9, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 5,406 bp · p 0.00076 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00116% South Asian · 1/86,024 alleles

Overall 7.01e-05% 1/1,425,576 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.Ala343Pro
Coding: c.1027G>C
MANE Select: NM_000383
Type: single nucleotide variant
Location: chr21:44292333 (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 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
AIRE c.463+2T>C Pathogenic/Likely pathogenic ★★ same condition
AIRE c.652+2T>C 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-ala343pro (accessed [today's date]).

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