# NM_000536.4(RAG2):c.895del (p.Ile299fs)

https://sugi.bio/variant/rag2-p-ile299fs

## Summary

**RAG2 p.Ile299fs (c.895del)** is classified **Pathogenic** in RAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-20). No gnomAD frequency available for this variant; Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2133313100 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the RAG2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

*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 |
| Prevalence | 1-9 / 100 000 (Europe) |
| Diagnostic panels | RAG2 is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Severe combined immunodeficiency due to complete RAG1/2 deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased circulating IgA level — Very frequent (99-80%)
- Decreased circulating total IgM — Very frequent (99-80%)
- Decreased circulating antibody level — Very frequent (99-80%)
- Decreased circulating IgG level — Very frequent (99-80%)
- Abnormal B cell count — Very frequent (99-80%)
- Abnormal T cell count — Very frequent (99-80%)
- Recurrent viral infections — Frequent (79-30%)
- Failure to thrive — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010339/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RAG2](https://sugi.bio/atlas/gene/RAG2/) |
| Protein change (HGVS p.) | p.Ile299fs |
| Coding change (HGVS c.) | c.895del |
| MANE Select transcript | [NM_000536](https://www.ncbi.nlm.nih.gov/nuccore/NM_000536) |
| dbSNP | [rs2133313100](https://www.ncbi.nlm.nih.gov/snp/rs2133313100/) |
| Variant type | Deletion |
| Location | chr11:36593274-36593274 (GRCh38) |
| ClinVar | [VCV1076086](https://www.ncbi.nlm.nih.gov/clinvar/variation/1076086/) |

**All HGVS expressions:** `LRG_99:g.9963del`, `NC_000011.10:g.36593276del`, `NC_000011.9:g.36614826del`, `NG_007573.1:g.9963del`, `NG_033154.1:g.3784del`, `NM_000536.4:c.895del`, `NM_001243785.2:c.895del`, `NM_001243786.2:c.895del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.273, GERP 2.72, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.733, pLI 0.022372. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**RAG2** population constraint: LOEUF 0.733, pLI 0.022372, missense-Z 0.5834. *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):

- **recombinase activating gene 2 deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.98, 52% of residues very-high.

**1 experimental structure(s)** (PDB): [8T4R](https://www.rcsb.org/structure/8T4R).

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

*Describes the biological roles of RAG2 (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.*


### Pathways affected {#pathways}

RAG2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [MAPK6/MAPK4 signaling](https://reactome.org/content/detail/R-HSA-5687128) | curated |
| [Interleukin-7 signaling](https://reactome.org/content/detail/R-HSA-1266695) | electronic |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-01-20.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-20 |

## Associated conditions {#conditions}

[severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive](https://sugi.bio/atlas/disease/severe-combined-immunodeficiency-autosomal-recessive-t-cell-negative-b-cell-negative-nk-cell-positive/), [combined immunodeficiency with skin granulomas](https://sugi.bio/atlas/disease/combined-immunodeficiency-with-skin-granulomas/).

**Reported phenotype names (ClinVar):** Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, Combined immunodeficiency with skin granulomas, Severe combined immunodeficiency due to complete RAG1/2 deficiency, SCID, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-POSITIVE, SCID, AR, T-cell negative, B-cell negative, NK cell-positive.

## Similar variants {#similar}

Related RAG2 variant pages (same residue, condition, or type): [RAG2 p.Cys287fs](/variant/rag2-p-cys287fs), [RAG2 p.His468fs](/variant/rag2-p-his468fs), [RAG2 p.Leu129fs](/variant/rag2-p-leu129fs), [RAG2 p.Phe378fs](/variant/rag2-p-phe378fs), [RAG2 p.Asn101fs](/variant/rag2-p-asn101fs), [RAG2 p.Asn248fs](/variant/rag2-p-asn248fs), [RAG2 p.Asn288fs](/variant/rag2-p-asn288fs), [RAG2 p.Asp450fs](/variant/rag2-p-asp450fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1076086). 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.*