Is AIRE p.Leu327Phe (c.979C>T) pathogenic?

AIRE p.Leu327Phe (c.979C>T) is classified Uncertain significance in AIRE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-15). AlphaMissense: ambiguous (0.5131); Very rare (popmax 6.89e-05%).

How common is AIRE p.Leu327Phe (c.979C>T) in the general population?

AIRE p.Leu327Phe (c.979C>T) is very rare (popmax 6.89e-05%) (gnomAD).

What do computational predictors say about AIRE p.Leu327Phe (c.979C>T)?

AlphaMissense predicts ambiguous (score 0.5131) — an in-silico prediction, not a clinical call.

AIRE p.Leu327Phe

c.979C>T · rs1029648118 · VCV2501925

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5131 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.89e-05%)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5131	ambiguous
REVEL	0.649	pathogenic-leaning
SaProt	LLR -13.41	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 1,219 bp · p 0.00032 · 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 6.89e-05%

Overall 6.89e-05% 1/1,451,166 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.Leu327Phe
Coding: c.979C>T
MANE Select: NM_000383
dbSNP: rs1029648118
Type: single nucleotide variant
Location: chr21:44291194 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB

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

Similar variants

AIRE p.Leu327Ile Uncertain significance ★ ⚠ same residue
AIRE p.Leu327= Likely benign ★ same residue
AIRE c.1095+2T>C Pathogenic/Likely pathogenic ★★ same type
AIRE c.1096-1G>A Pathogenic ★★ same type
AIRE c.1278+1G>A Likely pathogenic ★★ same type
AIRE c.1279-2A>G Likely pathogenic ★★ same type
AIRE c.1503+1G>A Likely pathogenic ★★ same type
AIRE c.1503+1G>T Pathogenic/Likely pathogenic ★★ same type

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-leu327phe (accessed [today's date]).

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