# NM_000383.4(AIRE):c.740G>A (p.Arg247His)

https://sugi.bio/variant/aire-p-arg247his

## Summary

**AIRE p.Arg247His (c.740G>A)** is classified **Conflicting classifications of pathogenicity** in AIRE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-08). AlphaMissense: likely benign (0.1944); Ultra-rare (popmax 0.0667%, amr); Associated with autoimmune polyendocrine syndrome type 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs763487370 · 2 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0667%, amr)

## For patients & families {#patients}

This is a change in the AIRE gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to autoimmune polyendocrine syndrome type 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Childhood |
| Prevalence | 1-9 / 100 000 (Finland) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AIRE is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Autoimmune polyendocrinopathy type 1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypoparathyroidism — Very frequent (99-80%)
- Chronic mucocutaneous candidiasis — Very frequent (99-80%)
- Autoimmunity — Very frequent (99-80%)
- Increased circulating cortisol level — Very frequent (99-80%)
- Decreased circulating aldosterone level — Very frequent (99-80%)
- Primary adrenal insufficiency — Very frequent (99-80%)
- Adrenal hyperplasia — Very frequent (99-80%)
- Abnormality of calcium-phosphate metabolism — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008466/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AIRE](https://sugi.bio/atlas/gene/AIRE/) |
| Protein change (HGVS p.) | p.Arg247His |
| Coding change (HGVS c.) | c.740G>A |
| MANE Select transcript | [NM_000383](https://www.ncbi.nlm.nih.gov/nuccore/NM_000383) |
| dbSNP | [rs763487370](https://www.ncbi.nlm.nih.gov/snp/rs763487370/) |
| Variant type | single nucleotide variant |
| Location | chr21:44289744-44289744 (GRCh38) |
| ClinVar | [VCV1412681](https://www.ncbi.nlm.nih.gov/clinvar/variation/1412681/) |

**All HGVS expressions:** `LRG_18:g.8865G>A`, `LRG_18t1:c.740G>A`, `NC_000021.8:g.45709627G>A`, `NC_000021.9:g.44289744G>A`, `NG_009556.1:g.8865G>A`, `NM_000383.2:c.740G>A`, `NM_000383.4:c.740G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1944)
- REVEL 0.52 (indeterminate)
- SaProt LLR -8.424 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 6.241, GERP 1.45, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.6**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.97** across the covering region of the MANE Select transcript (44,286,007–44,291,097), spanning 5,090 bp. Chi-square p 0.58. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0667%** (amr) · FAF95 0.0503% · FAF99 0.0446% · 40/60,010 in the highest group · 69/1,612,674 alleles overall — ultra-rare (popmax 0.0667%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0667% | 1,500 |
| South Asian | 0.00659% | 15,182 |
| East Asian | 0.00446% | 22,446 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,232 |
| European (non-Finnish) | 0.00153% | 65,554 |
| African / African-American | 0.00133% | 74,938 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**AIRE** population constraint: LOEUF 1.169, pLI 2.864e-16, missense-Z -1.0396. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **autoimmune polyendocrine syndrome type 1** — Definitive (AR)

## Protein context {#protein}

Residue **247** lies in the sand domain; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 62.30, 24% of residues very-high.

**4 experimental structure(s)** (PDB): [1XWH](https://www.rcsb.org/structure/1XWH), [2KE1](https://www.rcsb.org/structure/2KE1), [2KFT](https://www.rcsb.org/structure/2KFT), [2LRI](https://www.rcsb.org/structure/2LRI).

## What this gene does {#gene-function}

*Describes the biological roles of AIRE (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** AIRE's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. p.Arg247His falls in the sand domain.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, chromatin binding, zinc ion binding, histone binding, identical protein binding.

**Biological process:** central tolerance induction to self antigen, regulation of DNA-templated transcription, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-09-08.

**Submitter consensus:** conflicting (1 Likely benign, 1 Uncertain significance).

**Submission history:** 2 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-08 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-04 |

## Associated conditions {#conditions}

[autoimmune polyendocrine syndrome type 1](https://sugi.bio/atlas/disease/autoimmune-polyendocrine-syndrome-type-1/).

**Reported phenotype names (ClinVar):** Polyglandular autoimmune syndrome, type 1, not provided, PGA I, APS I, Autoimmune polyendocrine syndrome type 1, Autoimmune polyendocrinopathy syndrome, type I, Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, AUTOIMMUNE POLYENDOCRINE SYNDROME, TYPE I, WITH OR WITHOUT REVERSIBLE METAPHYSEAL DYSPLASIA, HYPOADRENOCORTICISM WITH HYPOPARATHYROIDISM AND SUPERFICIAL MONILIASIS, Whitaker syndrome.

## Similar variants {#similar}

Related AIRE variant pages (same residue, condition, or type): [AIRE p.Arg247Cys](/variant/aire-p-arg247cys), [AIRE p.Arg247=](/variant/aire-p-arg247), [AIRE c.1095+2T>C](/variant/aire-c-1095-plus-2t-c), [AIRE c.1096-1G>A](/variant/aire-c-1096-minus-1g-a), [AIRE c.1278+1G>A](/variant/aire-c-1278-plus-1g-a), [AIRE c.1279-2A>G](/variant/aire-c-1279-minus-2a-g), [AIRE c.1503+1G>A](/variant/aire-c-1503-plus-1g-a), [AIRE c.1503+1G>T](/variant/aire-c-1503-plus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1412681). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*