# NM_000383.4(AIRE):c.484C>T (p.Pro162Ser)

https://sugi.bio/variant/aire-p-pro162ser

## Summary

**AIRE p.Pro162Ser (c.484C>T)** is classified **Uncertain significance** in AIRE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-02). AlphaMissense: likely benign (0.0661); Ultra-rare (popmax 0.0215%, eas); Associated with autoimmune polyendocrine syndrome type 1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0215%, eas)

## For patients & families {#patients}

This is a change in the AIRE gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Pro162Ser |
| Coding change (HGVS c.) | c.484C>T |
| MANE Select transcript | [NM_000383](https://www.ncbi.nlm.nih.gov/nuccore/NM_000383) |
| Variant type | single nucleotide variant |
| Location | chr21:44287537-44287537 (GRCh38) |
| ClinVar | [VCV3703908](https://www.ncbi.nlm.nih.gov/clinvar/variation/3703908/) |

**All HGVS expressions:** `LRG_18:g.6658C>T`, `LRG_18t1:c.484C>T`, `NC_000021.8:g.45707420C>T`, `NC_000021.9:g.44287537C>T`, `NG_009556.1:g.6658C>T`, `NM_000383.4:c.484C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0661)
- REVEL 0.162 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.241 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.3, GERP -2.46, phastCons 0.038 — weakly conserved position
- CADD: **PHRED 0.719**. 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 **0.0215%** (eas) · FAF95 0.0112% · FAF99 0.00828% · 9/41,890 in the highest group · 13/1,557,416 alleles overall — ultra-rare (popmax 0.0215%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0215% | 4,654 |
| European (non-Finnish) | 0.000348% | 287,709 |

*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 **162** 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.Pro162Ser 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-02.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-02 |

## 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, Whitaker syndrome, AUTOIMMUNE POLYENDOCRINE SYNDROME, TYPE I, WITH OR WITHOUT REVERSIBLE METAPHYSEAL DYSPLASIA, APS I, Autoimmune polyendocrinopathy syndrome, type I, HYPOADRENOCORTICISM WITH HYPOPARATHYROIDISM AND SUPERFICIAL MONILIASIS, PGA I, Autoimmune polyendocrine syndrome type 1, Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia.

## Similar variants {#similar}

Related AIRE variant pages (same residue, condition, or type): [AIRE p.Pro162Leu](/variant/aire-p-pro162leu), [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 3703908). 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.*