# NM_000383.4(AIRE):c.351C>T (p.Ala117=)

https://sugi.bio/variant/aire-p-ala117

## Summary

**AIRE p.Ala117= (c.351C>T)** is classified **Likely benign** in AIRE (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-01). Ultra-rare (popmax 0.0538%, sas); Associated with autoimmune polyendocrine syndrome type 1.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs201929488 · 6 submitters · 1 linked condition · ultra-rare (popmax 0.0538%, sas)

## For patients & families {#patients}

This is a change in the AIRE gene that is classified as likely benign — not considered disease-causing, submitted by 6 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.Ala117= |
| Coding change (HGVS c.) | c.351C>T |
| MANE Select transcript | [NM_000383](https://www.ncbi.nlm.nih.gov/nuccore/NM_000383) |
| dbSNP | [rs201929488](https://www.ncbi.nlm.nih.gov/snp/rs201929488/) |
| Variant type | single nucleotide variant |
| Location | chr21:44287021-44287021 (GRCh38) |
| ClinVar | [VCV762633](https://www.ncbi.nlm.nih.gov/clinvar/variation/762633/) |

**All HGVS expressions:** `LRG_18:g.6142C>T`, `NC_000021.8:g.45706904C>T`, `NC_000021.9:g.44287021C>T`, `NG_009556.1:g.6142C>T`, `NM_000383.4:c.351C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -8.212, GERP -2.83 — fast-evolving / accelerated position
- CADD: **PHRED 0.692**. 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.*
- 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 **0.0538%** (sas) · FAF95 0.0418% · FAF99 0.0375% · 49/91,080 in the highest group · 97/1,612,816 alleles overall — ultra-rare (popmax 0.0538%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0538% | 1,859 |
| Middle Eastern | 0.033% | 3,029 |
| East Asian | 0.0245% | 4,080 |
| African / African-American | 0.0133% | 7,505 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,927 |
| European (non-Finnish) | 0.00153% | 65,555 |

*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 **117** lies in 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.Ala117= falls in the disordered region.


### 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-01.

**Submitter consensus:** conflicting (5 Likely benign, 1 Uncertain significance).

**Submission history:** 6 submissions (2020–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-01-24 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-02 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-09-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-14 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-13 |

## 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, AIRE-related disorder, not provided, not specified, AIRE-related condition, none provided, Autoimmune polyendocrinopathy syndrome, type I, PGA I, APS I, HYPOADRENOCORTICISM WITH HYPOPARATHYROIDISM AND SUPERFICIAL MONILIASIS.

## Same-residue context {#hotspot}

Residue **117** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AIRE p.Ala117fs](/variant/aire-p-ala117fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AIRE variant pages (same residue, condition, or type): [AIRE p.Ala117fs](/variant/aire-p-ala117fs), [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), [AIRE c.463+2T>C](/variant/aire-c-463-plus-2t-c).

### 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 762633). 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.*