Is AIRE p.Arg465Pro (c.1394G>C) pathogenic?

AIRE p.Arg465Pro (c.1394G>C) is classified Uncertain significance in AIRE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-23). AlphaMissense: likely benign (0.117); Very rare (popmax 8.48e-05%, nfe); Associated with autoimmune polyendocrine syndrome type 1.

What condition is associated with AIRE p.Arg465Pro (c.1394G>C)?

AIRE p.Arg465Pro (c.1394G>C) is associated with autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Arg465Pro (c.1394G>C) in the general population?

AIRE p.Arg465Pro (c.1394G>C) is very rare (popmax 8.48e-05%, nfe) (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.Arg465Pro (c.1394G>C)?

AlphaMissense predicts likely benign (score 0.117) — an in-silico prediction, not a clinical call.

AIRE p.Arg465Pro

c.1394G>C · rs139835427 · VCV2849400

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autoimmune polyendocrine syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.117	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -4.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.19	GERP -2.4, phastCons 0.001
Regional constraint	o/e 1.20	unconstrained · MANE · 5,406 bp · p 0.00076 · regional, not allelic
Overall
CADD	14.05	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,488 alleles

Overall 6.92e-05% 1/1,444,552 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.Arg465Pro
Coding: c.1394G>C
MANE Select: NM_000383
dbSNP: rs139835427
Type: single nucleotide variant
Location: chr21:44293904 (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.Arg465Trp Uncertain significance ★★ ⚠ same residue
AIRE p.Arg465= Likely benign ★ same residue
AIRE p.Arg465Gln 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

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-arg465pro (accessed [today's date]).

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