Is AIRE p.Ser278Arg (c.834C>G) pathogenic?

AIRE p.Ser278Arg (c.834C>G) is classified Benign in AIRE (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0549); Common (popmax 35.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autoimmune polyendocrine syndrome type 1.

What condition is associated with AIRE p.Ser278Arg (c.834C>G)?

AIRE p.Ser278Arg (c.834C>G) 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.

What do computational predictors say about AIRE p.Ser278Arg (c.834C>G)?

AlphaMissense predicts likely benign (score 0.0549) — an in-silico prediction, not a clinical call.

AIRE p.Ser278Arg

Q: How common is AIRE p.Ser278Arg (c.834C>G) in the general population?

AIRE p.Ser278Arg (c.834C>G) is common (popmax 35.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.834C>G · rs1800520 · VCV128340

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0549 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 35.9%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune polyendocrine syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0549	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.35	donor loss · deltas
Pangolin	Δ0.39	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.24	GERP -1.2, phastCons 0.009
Regional constraint	o/e 0.97	unconstrained · MANE · 5,090 bp · p 0.58 · regional, not allelic
Overall
CADD	1.42	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 35.9% East Asian · 16,054/44,710 alleles

Filtering AF 35.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.3%

Overall 12% 193,019/1,610,112 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	35.9%	3
African / African-American	29.2%	3
South Asian	18.1%	6
Remaining individualsnot grpmax-eligible	13.4%	7
Middle Eastern	12.6%	8
Ashkenazi Jewishnot grpmax-eligible	12%	8
Admixed American	11%	9
Finnishnot grpmax-eligible	11%	9
European (non-Finnish)	9.55%	10
Amishnot grpmax-eligible	2.2%	46

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.Ser278Arg
Coding: c.834C>G
MANE Select: NM_000383
dbSNP: rs1800520
Type: single nucleotide variant
Location: chr21:44290023 (GRCh38)
Gene constraint: LOEUF 1.169 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.30 · 4 PDB
Residue 278: the sand domain; a UniProt-annotated variant site (in); the 'disordered' region

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.Ser278= 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-ser278arg (accessed [today's date]).

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