Is AIRE p.Asp198= (c.594C>T) pathogenic?

AIRE p.Asp198= (c.594C>T) is classified Likely benign in AIRE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-23). Ultra-rare (popmax 0.0334%, afr); Associated with autoimmune polyendocrine syndrome type 1.

What condition is associated with AIRE p.Asp198= (c.594C>T)?

AIRE p.Asp198= (c.594C>T) is associated with autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Asp198= (c.594C>T) in the general population?

AIRE p.Asp198= (c.594C>T) is ultra-rare (popmax 0.0334%, 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.Asp198=

c.594C>T · rs376083924 · VCV730695

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, 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 -12	GERP -2.8
Overall
CADD	0.172	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0334% African / African-American · 25/74,944 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00236% 38/1,612,650 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0334%	2,998
Admixed American	0.00333%	30,000
Remaining individualsnot grpmax-eligible	0.0032%	31,228
Finnishnot grpmax-eligible	0.00317%	31,506
East Asian	0.00223%	44,904
South Asian	0.0022%	45,540
European (non-Finnish)	0.000339%	294,916

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.Asp198=
Coding: c.594C>T
MANE Select: NM_000383
dbSNP: rs376083924
Type: single nucleotide variant
Location: chr21:44288400 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 198: the sand 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 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-asp198 (accessed [today's date]).

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