# NM_000536.4(RAG2):c.133_146del (p.Val45fs)

https://sugi.bio/variant/rag2-p-val45fs

## Summary

**RAG2 p.Val45fs (c.133_146del)** is classified **Likely pathogenic** in RAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-29). Very rare (popmax 6.2e-05%); Associated with combined immunodeficiency with skin granulomas.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1397294905 · 1 submitter · 1 linked condition · very rare (popmax 6.2e-05%)

## For patients & families {#patients}

This is a change in the RAG2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to combined immunodeficiency with skin granulomas.

*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 |
| Diagnostic panels | RAG2 is a diagnostic-grade gene on 6 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013587/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.Val45fs |
| Coding change (HGVS c.) | c.133_146del |
| MANE Select transcript | [NM_000536](https://www.ncbi.nlm.nih.gov/nuccore/NM_000536) |
| dbSNP | [rs1397294905](https://www.ncbi.nlm.nih.gov/snp/rs1397294905/) |
| Variant type | Deletion |
| Location | chr11:36594023-36594036 (GRCh38) |
| ClinVar | [VCV2678218](https://www.ncbi.nlm.nih.gov/clinvar/variation/2678218/) |

**All HGVS expressions:** `LRG_99:g.9201_9214del`, `LRG_99t1:c.128_141del`, `NC_000011.10:g.36594028_36594041del`, `NC_000011.9:g.36615578_36615591del`, `NG_007573.1:g.9201_9214del`, `NG_033154.1:g.4536_4549del`, `NM_000536.4:c.133_146del`, `NM_001243785.2:c.133_146del`, `NM_001243786.2:c.133_146del`

## 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 0.995, GERP -4.72, phastCons 0.019 — weakly conserved position
- 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.
- CADD: **PHRED 34.0**. 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** — 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 (gnomAD v4.1): global (via dbSNP) **6.2e-05%** · 1/1,614,068 alleles overall — very rare (popmax 6.2e-05%).

*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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-29.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-06-29 |

## Associated conditions {#conditions}

[combined immunodeficiency with skin granulomas](https://sugi.bio/atlas/disease/combined-immunodeficiency-with-skin-granulomas/).

**Reported phenotype names (ClinVar):** Combined immunodeficiency with skin granulomas.

## Similar variants {#similar}

Related RAG2 variant pages (same residue, condition, or type): [RAG2 p.Val45Ile](/variant/rag2-p-val45ile), [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.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 2678218). 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.*