Is AIRE p.Leu87Val (c.259C>G) pathogenic?

AIRE p.Leu87Val (c.259C>G) is classified Uncertain significance in AIRE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-23). AlphaMissense: likely benign (0.0767); Absent from gnomAD v4.1; Associated with autoimmune polyendocrine syndrome type 1.

What condition is associated with AIRE p.Leu87Val (c.259C>G)?

AIRE p.Leu87Val (c.259C>G) is associated with autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Leu87Val (c.259C>G) in the general population?

AIRE p.Leu87Val (c.259C>G) is absent from gnomAD v4.1 (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.Leu87Val (c.259C>G)?

AlphaMissense predicts likely benign (score 0.0767) — an in-silico prediction, not a clinical call.

AIRE p.Leu87Val

c.259C>G · VCV3711577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0767 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autoimmune polyendocrine syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0767	likely benign
REVEL	0.485	indeterminate
SaProt	LLR -8.92	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 0.51	GERP -0.74, phastCons 0.69
Regional constraint	o/e 0.97	unconstrained · MANE · 5,090 bp · p 0.58 · regional, not allelic
Overall
CADD	20.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AIRE
Protein: p.Leu87Val
Coding: c.259C>G
MANE Select: NM_000383
Type: single nucleotide variant
Location: chr21:44286683 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 87: the hsr domain

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.Leu87Pro Likely pathogenic ★★ same residue
AIRE p.Leu87= Likely benign ★ same residue
AIRE p.Leu87fs Pathogenic ★★ 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-leu87val (accessed [today's date]).

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