Is AIRE p.Ser220Phe (c.659C>T) pathogenic?

AIRE p.Ser220Phe (c.659C>T) is classified Uncertain significance in AIRE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-04). AlphaMissense: likely benign (0.2621); Ultra-rare (popmax 0.04%, afr); Associated with Inborn genetic diseases.

What condition is associated with AIRE p.Ser220Phe (c.659C>T)?

AIRE p.Ser220Phe (c.659C>T) is associated with Inborn genetic diseases, autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Ser220Phe (c.659C>T) in the general population?

AIRE p.Ser220Phe (c.659C>T) is ultra-rare (popmax 0.04%, afr) (gnomAD).

What do computational predictors say about AIRE p.Ser220Phe (c.659C>T)?

AlphaMissense predicts likely benign (score 0.2621) — an in-silico prediction, not a clinical call.

AIRE p.Ser220Phe

c.659C>T · rs753236604 · VCV659221

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2621 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2621	likely benign
REVEL	0.494	indeterminate
SaProt	LLR -7.29	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 5.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 5,090 bp · p 0.58 · regional, not allelic
Overall
CADD	24.0	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

Grpmax group 0.04% African / African-American · 30/74,914 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00229% 37/1,612,654 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.04%	2,497
Remaining individualsnot grpmax-eligible	0.0064%	15,615
Admixed American	0.00167%	60,002
European (non-Finnish)	0.000169%	589,981

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.Ser220Phe
Coding: c.659C>T
MANE Select: NM_000383
dbSNP: rs753236604
Type: single nucleotide variant
Location: chr21:44289663 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 220: the sand domain

Full AIRE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autoimmune polyendocrine syndrome type 1

Similar variants

AIRE p.Ser220= 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
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-ser220phe (accessed [today's date]).

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