# NM_000536.4(RAG2):c.1486C>T (p.Pro496Ser)

https://sugi.bio/variant/rag2-p-pro496ser

## Summary

**RAG2 p.Pro496Ser (c.1486C>T)** is classified **Uncertain significance** in RAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.0929); Very rare (popmax 6.2e-05%); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2133310879 · 1 submitter · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 6.2e-05%)

## For patients & families {#patients}

This is a change in the RAG2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Pro496Ser |
| Coding change (HGVS c.) | c.1486C>T |
| MANE Select transcript | [NM_000536](https://www.ncbi.nlm.nih.gov/nuccore/NM_000536) |
| dbSNP | [rs2133310879](https://www.ncbi.nlm.nih.gov/snp/rs2133310879/) |
| Variant type | single nucleotide variant |
| Location | chr11:36592683-36592683 (GRCh38) |
| ClinVar | [VCV1351921](https://www.ncbi.nlm.nih.gov/clinvar/variation/1351921/) |

**All HGVS expressions:** `LRG_99:g.10554C>T`, `NC_000011.10:g.36592683G>A`, `NC_000011.9:g.36614233G>A`, `NG_007573.1:g.10554C>T`, `NG_033154.1:g.3191G>A`, `NM_000536.4:c.1486C>T`, `NM_001243785.2:c.1486C>T`, `NM_001243786.2:c.1486C>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** (0.0929)
- REVEL 0.308 (indeterminate)
- SaProt LLR -6.095 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 3.973, GERP -1.05, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.4**. 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 0.99** across the covering region of the MANE Select transcript (36,592,588–36,594,168), spanning 1,580 bp. Chi-square p 0.79. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-09-01.

**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 | 2021-09-01 |

## 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, SCID, AR, T-cell negative, B-cell negative, NK cell-positive, SCID, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-POSITIVE, Severe combined immunodeficiency due to complete RAG1/2 deficiency.

## Similar variants {#similar}

Related RAG2 variant pages (same residue, condition, or type): [RAG2 p.Pro496=](/variant/rag2-p-pro496), [RAG2 p.Arg229Gln](/variant/rag2-p-arg229gln), [RAG2 p.Arg229Trp](/variant/rag2-p-arg229trp), [RAG2 p.Arg39Gly](/variant/rag2-p-arg39gly), [RAG2 p.Arg73Cys](/variant/rag2-p-arg73cys), [RAG2 p.Asp65Tyr](/variant/rag2-p-asp65tyr), [RAG2 p.Cys446Trp](/variant/rag2-p-cys446trp), [RAG2 p.Glu437Lys](/variant/rag2-p-glu437lys).

### 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 1351921). 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.*