Is AIRE p.Pro326= (c.978G>A) pathogenic?

AIRE p.Pro326= (c.978G>A) is classified Likely benign in AIRE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-19). Very rare (popmax 0.00133%, afr); Associated with autoimmune polyendocrine syndrome type 1.

What condition is associated with AIRE p.Pro326= (c.978G>A)?

AIRE p.Pro326= (c.978G>A) is associated with autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Pro326= (c.978G>A) in the general population?

AIRE p.Pro326= (c.978G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Autoimmune polyendocrinopathy type 1 inherited?

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

AIRE p.Pro326=

c.978G>A · rs972756453 · VCV732196

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

autoimmune polyendocrine syndrome type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.3	GERP -3.6
Overall
CADD	0.203	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,954 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000748% 12/1,603,254 alleles · very rare exomes 12/1,451,214 · genomes 0/152,040 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0128%	7,789
African / African-Americangrpmax	0.00133%	74,954
European (non-Finnish)	0.000254%	393,174

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.Pro326=
Coding: c.978G>A
MANE Select: NM_000383
dbSNP: rs972756453
Type: single nucleotide variant
Location: chr21:44291193 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 326: a UniProt-annotated variant site (in aps1; no significant effect on structure, but may alter protein interactions; no effect on doted nuclear localization; dominant-negative effect on regulation of target gene transcription); a UniProt-annotated variant site (in aps1; alters folding of the phd-type 1 zinc finger)

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.Pro326Leu Pathogenic/Likely pathogenic ★★ same residue
AIRE p.Pro326fs Likely pathogenic same residue
AIRE p.Pro326Ala Uncertain significance ★ ⚠ 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-pro326 (accessed [today's date]).

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