Is AIRE p.Arg257Pro (c.770G>C) pathogenic?

AIRE p.Arg257Pro (c.770G>C) is classified Uncertain significance in AIRE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-18). AlphaMissense: likely benign (0.2697); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with AIRE p.Arg257Pro (c.770G>C)?

AIRE p.Arg257Pro (c.770G>C) is associated with Inborn genetic diseases (ClinVar).

How common is AIRE p.Arg257Pro (c.770G>C) in the general population?

AIRE p.Arg257Pro (c.770G>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about AIRE p.Arg257Pro (c.770G>C)?

AlphaMissense predicts likely benign (score 0.2697) — an in-silico prediction, not a clinical call.

AIRE p.Arg257Pro

c.770G>C · rs752537921 · VCV2468570

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2697	likely benign
REVEL	0.647	pathogenic-leaning
SaProt	LLR -5.38	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 5,090 bp · p 0.58 · regional, not allelic
Overall
CADD	23.9	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 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,460,418 alleles · very rare

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.Arg257Pro
Coding: c.770G>C
MANE Select: NM_000383
dbSNP: rs752537921
Type: single nucleotide variant
Location: chr21:44289774 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 257: the sand domain; the 'disordered' region

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

Similar variants

AIRE p.Arg257Ter Pathogenic ★★ same residue
AIRE p.Ala152Thr Uncertain significance ★★ ⚠ same condition
AIRE p.Ala170Thr Uncertain significance ★★ ⚠ same condition
AIRE p.Ala265Thr Uncertain significance ★★ ⚠ same condition
AIRE p.Ala493Thr Uncertain significance ★★ ⚠ same condition
AIRE p.Ala540Val Uncertain significance ★★ ⚠ same condition
AIRE p.Arg174Cys Uncertain significance ★★ ⚠ same condition
AIRE p.Arg203Gln Uncertain significance ★★ ⚠ 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-arg257pro (accessed [today's date]).

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