Is AIRE p.Met1Val (c.1A>G) pathogenic?

AIRE p.Met1Val (c.1A>G) is classified Pathogenic in AIRE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-10). Very rare (popmax 0.00239%, sas); Associated with Inherited Immunodeficiency Diseases.

What condition is associated with AIRE p.Met1Val (c.1A>G)?

AIRE p.Met1Val (c.1A>G) is associated with Inherited Immunodeficiency Diseases, autoimmune polyendocrine syndrome type 1 (ClinVar).

How common is AIRE p.Met1Val (c.1A>G) in the general population?

AIRE p.Met1Val (c.1A>G) is very rare (popmax 0.00239%, sas) (gnomAD).

AIRE p.Met1Val

c.1A>G · rs121434258 · VCV551136

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00239%, sas)

Conditions

Inherited Immunodeficiency Diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.492	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -3.7
Overall
CADD	3.357	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00239% South Asian · 2/83,712 alleles

Filtering AF 0.000397% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000148%

Overall 0.000196% 3/1,529,992 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00239%	41,856
European (non-Finnish)	8.75e-05%	1,143,448

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.Met1Val
Coding: c.1A>G
MANE Select: NM_000383
dbSNP: rs121434258
Type: single nucleotide variant
Location: chr21:44286007 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 1: the hsr domain

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

Disease context

Inherited Immunodeficiency Diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autoimmune polyendocrine syndrome type 1

Similar variants

AIRE p.Met1Leu Pathogenic ★★ same residue
AIRE p.Met1Arg Pathogenic ★ same residue
AIRE p.Met1Ile Likely pathogenic ★ same residue
AIRE p.Met1Lys Pathogenic ★ same residue
AIRE p.Met1Thr Pathogenic ★ same residue
AIRE p.Met1fs Uncertain significance same residue
AIRE c.1095+2T>C Pathogenic/Likely pathogenic ★★ same condition
AIRE c.1096-1G>A 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-met1val (accessed [today's date]).

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