Is AIRE p.Ser196= (c.588C>T) pathogenic?

AIRE p.Ser196= (c.588C>T) is classified Benign in AIRE (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). Common (popmax 25.9%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with autoimmune polyendocrine syndrome type 1.

What condition is associated with AIRE p.Ser196= (c.588C>T)?

AIRE p.Ser196= (c.588C>T) is associated with autoimmune polyendocrine syndrome type 1 (ClinVar).

How is Autoimmune polyendocrinopathy type 1 inherited?

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

AIRE p.Ser196=

Q: How common is AIRE p.Ser196= (c.588C>T) in the general population?

AIRE p.Ser196= (c.588C>T) is common (popmax 25.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.588C>T · rs878081 · VCV128338

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Common

common (popmax 25.9%, nfe) — too common for a highly-penetrant pathogenic allele

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 -9.7	GERP -2.8
Overall
CADD	0.192	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 25.9% European (non-Finnish) · 304,929/1,179,056 alleles

Filtering AF 25.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 25.8%

Overall 23.7% 382,411/1,612,002 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	26.1%	4
European (non-Finnish)grpmax	25.9%	4
Ashkenazi Jewishnot grpmax-eligible	25%	4
Middle Eastern	24.3%	4
Amishnot grpmax-eligible	24.3%	4
Remaining individualsnot grpmax-eligible	22.6%	4
Admixed American	19.8%	5
South Asian	17.6%	6
East Asian	14.6%	7
African / African-American	4.43%	23

Finnish 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.Ser196=
Coding: c.588C>T
MANE Select: NM_000383
dbSNP: rs878081
Type: single nucleotide variant
Location: chr21:44288394 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 196: 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 p.Ser196Tyr 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
AIRE c.1503+1G>T Pathogenic/Likely pathogenic ★★ same condition
AIRE c.463+2T>C 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-ser196 (accessed [today's date]).

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