Is AIRE p.Arg328Trp (c.982C>T) pathogenic?

AIRE p.Arg328Trp (c.982C>T) is classified Uncertain significance in AIRE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1048); Ultra-rare (popmax 0.0307%, nfe); Associated with autoimmune polyendocrine syndrome type 1.

What condition is associated with AIRE p.Arg328Trp (c.982C>T)?

AIRE p.Arg328Trp (c.982C>T) is associated with autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Arg328Trp (c.982C>T) in the general population?

AIRE p.Arg328Trp (c.982C>T) is ultra-rare (popmax 0.0307%, 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.Arg328Trp (c.982C>T)?

AlphaMissense predicts likely benign (score 0.1048) — an in-silico prediction, not a clinical call.

AIRE p.Arg328Trp

c.982C>T · rs74162063 · VCV964804

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1048 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autoimmune polyendocrine syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.1048	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -10.18	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 1.1	GERP -0.8
Regional constraint	o/e 0.55	unconstrained · MANE · 1,219 bp · p 0.00032 · regional, not allelic
Overall
CADD	22.9	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 0.0307% European (non-Finnish) · 362/1,179,686 alleles

Filtering AF 0.0281% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.027%

Overall 0.0263% 422/1,602,588 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0434%	2,307
Finnishnot grpmax-eligible	0.0388%	2,578
European (non-Finnish)grpmax	0.0307%	3,259
Middle Eastern	0.0189%	5,284
Admixed American	0.0133%	7,496
African / African-American	0.00267%	37,428
East Asian	0.00223%	44,884

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg328Trp
Coding: c.982C>T
MANE Select: NM_000383
dbSNP: rs74162063
Type: single nucleotide variant
Location: chr21:44291197 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 328: a UniProt-annotated variant site (found in a patient with acrofacial vitiligo and gastric parietal cell autoantibodies; no effect on doted nuclear localization; dominant-negative effect on regulation of target gene transcription); a UniProt-annotated variant site (in)

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.Arg328Gln Uncertain significance ★★ ⚠ same residue
AIRE p.Arg328= 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
AIRE c.1503+1G>T Pathogenic/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-arg328trp (accessed [today's date]).

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