# NM_000417.3(IL2RA):c.84G>A (p.Pro28=)

https://sugi.bio/variant/il2ra-p-pro28

## Summary

**IL2RA p.Pro28= (c.84G>A)** is classified **Benign** in IL2RA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 20.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency due to CD25 deficiency.

**At a glance:** Benign · review: Multiple submitters · rsID rs2228150 · 5 submitters · 1 linked condition · common (popmax 20.6%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the IL2RA gene that is classified as benign — not considered disease-causing, submitted by 5 submitters, and is linked to immunodeficiency due to CD25 deficiency.

*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) | Infancy |
| Diagnostic panels | IL2RA is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017049/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [IL2RA](https://sugi.bio/atlas/gene/IL2RA/) |
| Protein change (HGVS p.) | p.Pro28= |
| Coding change (HGVS c.) | c.84G>A |
| MANE Select transcript | [NM_000417](https://www.ncbi.nlm.nih.gov/nuccore/NM_000417) |
| dbSNP | [rs2228150](https://www.ncbi.nlm.nih.gov/snp/rs2228150/) |
| Variant type | single nucleotide variant |
| Location | chr10:6026006-6026006 (GRCh38) |
| ClinVar | [VCV300261](https://www.ncbi.nlm.nih.gov/clinvar/variation/300261/) |

**All HGVS expressions:** `LRG_73:g.41304G>A`, `LRG_73t1:c.84G>A`, `NC_000010.10:g.6067969C>T`, `NC_000010.11:g.6026006C>T`, `NG_007403.1:g.41304G>A`, `NM_000417.3:c.84G>A`, `NM_001308242.2:c.84G>A`, `NM_001308243.2:c.84G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 20.6%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -8.707, GERP -3.47 — fast-evolving / accelerated position
- CADD: **PHRED 0.413**. 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 **20.6%** (afr) · FAF95 20.3% · FAF99 20.2% · 15,420/74,918 in the highest group · 61,639/1,613,062 alleles overall — common (popmax 20.6%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 20.6% | 5 |
| Amish (not grpmax-eligible) | 8.68% | 12 |
| South Asian | 6.72% | 15 |
| Middle Eastern | 5.41% | 18 |
| Remaining individuals (not grpmax-eligible) | 4.24% | 24 |
| Admixed American | 3.51% | 29 |
| Ashkenazi Jewish (not grpmax-eligible) | 3.33% | 30 |
| European (non-Finnish) | 2.8% | 36 |
| Finnish (not grpmax-eligible) | 1.41% | 71 |
| East Asian | 0.105% | 955 |

*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}

**IL2RA** population constraint: LOEUF 0.906, pLI 5.2506e-06, missense-Z 0.90473; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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):

- **immunodeficiency due to CD25 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **28** lies in an α-helix; the sushi 1 domain.

AlphaFold model confidence (whole protein): pLDDT 72.72, 43% of residues very-high.

**10 experimental structure(s)** (PDB): [1Z92](https://www.rcsb.org/structure/1Z92), [2B5I](https://www.rcsb.org/structure/2B5I), [2ERJ](https://www.rcsb.org/structure/2ERJ), [3IU3](https://www.rcsb.org/structure/3IU3), [3NFP](https://www.rcsb.org/structure/3NFP), [6VWU](https://www.rcsb.org/structure/6VWU).

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

*Describes the biological roles of IL2RA (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:** IL2RA's established molecular role includes interleukin-2 receptor activity. p.Pro28= falls in the sushi 1 domain.


### Pathways affected {#pathways}

IL2RA participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interleukin receptor SHC signaling](https://reactome.org/content/detail/R-HSA-912526) | curated |
| [Interleukin-2 signaling](https://reactome.org/content/detail/R-HSA-9020558) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)](https://reactome.org/content/detail/R-HSA-8877330) | curated |

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

**Molecular function:** interleukin-2 receptor activity.

**Biological process:** regulation of T cell tolerance induction, interleukin-2-mediated signaling pathway.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (5/5 Benign).

**Submission history:** 5 submissions (2016–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2016-03-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2018-06-11 |

## Associated conditions {#conditions}

[immunodeficiency due to CD25 deficiency](https://sugi.bio/atlas/disease/immunodeficiency-due-to-cd25-deficiency/).

**Reported phenotype names (ClinVar):** Immunodeficiency due to CD25 deficiency, not specified, not provided, AllHighlyPenetrant, none provided, IMMUNODEFICIENCY 41 WITH LYMPHOPROLIFERATION AND AUTOIMMUNITY, CD25 DEFICIENCY, IL2RA DEFICIENCY.

## Similar variants {#similar}

Related IL2RA variant pages (same residue, condition, or type): [IL2RA p.Pro28Leu](/variant/il2ra-p-pro28leu), [IL2RA p.Gln101Ter](/variant/il2ra-p-gln101ter), [IL2RA c.655+4C>T](/variant/il2ra-c-655-plus-4c-t), [IL2RA c.*1026G>T](/variant/il2ra-c-star-1026g-t), [IL2RA p.Arg206Cys](/variant/il2ra-p-arg206cys), [IL2RA p.Arg206His](/variant/il2ra-p-arg206his), [IL2RA p.Arg263Trp](/variant/il2ra-p-arg263trp), [IL2RA p.Arg56His](/variant/il2ra-p-arg56his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 300261). 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.*