# NM_000536.4(RAG2):c.1095T>C (p.Ser365=)

https://sugi.bio/variant/rag2-p-ser365

## Summary

**RAG2 p.Ser365= (c.1095T>C)** is classified **Likely benign** in RAG2 (ClinVar, Expert panel, 10 submitters; last evaluated 2023-11-14). Rare (popmax 0.204%, nfe); Associated with recombinase activating gene 2 deficiency.

**At a glance:** Likely benign · review: Expert panel · rsID rs140519815 · 10 submitters · 4 linked conditions · rare (popmax 0.204%, nfe)

## For patients & families {#patients}

This is a change in the RAG2 gene that is classified as likely benign — not considered disease-causing, submitted by 10 submitters, and is linked to recombinase activating gene 2 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022806/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.Ser365= |
| Coding change (HGVS c.) | c.1095T>C |
| MANE Select transcript | [NM_000536](https://www.ncbi.nlm.nih.gov/nuccore/NM_000536) |
| dbSNP | [rs140519815](https://www.ncbi.nlm.nih.gov/snp/rs140519815/) |
| Variant type | single nucleotide variant |
| Location | chr11:36593074-36593074 (GRCh38) |
| ClinVar | [VCV304552](https://www.ncbi.nlm.nih.gov/clinvar/variation/304552/) |

**All HGVS expressions:** `LRG_99:g.10163T>C`, `NC_000011.10:g.36593074A>G`, `NC_000011.9:g.36614624A>G`, `NG_007573.1:g.10163T>C`, `NG_033154.1:g.3582A>G`, `NM_000536.4:c.1095T>C`, `NM_001243785.2:c.1095T>C`, `NM_001243786.2:c.1095T>C`

## 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 4.217, GERP 2.72, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 7.175**. 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** — 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): grpmax **0.204%** (nfe) · FAF95 0.197% · FAF99 0.194% · 2,402/1,179,976 in the highest group · 2,844/1,614,116 alleles overall — rare (popmax 0.204%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.326% | 306 |
| European (non-Finnish) (grpmax) | 0.204% | 491 |
| Remaining individuals (not grpmax-eligible) | 0.157% | 638 |
| South Asian | 0.0648% | 1,544 |
| Admixed American | 0.0633% | 1,579 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0405% | 2,467 |
| African / African-American | 0.0333% | 3,002 |
| Middle Eastern | 0.0165% | 6,062 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **365** lies in the 'disordered' region.

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 benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2023-11-14.

**Submitter consensus:** conflicting (8 Likely benign, 2 Benign, 1 Likely Benign).

**Submission history:** 8 submissions (2018–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — Severe Combined Immunodeficiency Disease VCEP (recombinase activating gene 2 deficiency). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS1`, `BP7`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000536.4:c.1095T>C variant is a synonymous (silent) variant (p.Ser365=) with no predicted splice impact (BP7). This variant has not been reported in the literature in individuals with RAG2-related conditions. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00314 (79/25120) in the Finnish population, which is higher than the ClinGen SCID VCEP's threshold for BS1 (>0.00195). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG criteria applied BS1 and BP7, as specified by the ClinGen SCID VCEP (VCEP specifications 1).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50091 · approved 2024-01-17 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/3454b9e8-3665-4835-8fc9-2cc823ee5ebc).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Benign | criteria provided, single submitter | clinical testing | 2024-10-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2020-04-13 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Likely benign | reviewed by expert panel | curation | 2023-11-14 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-01 |

## Associated conditions {#conditions}

[recombinase activating gene 2 deficiency](https://sugi.bio/atlas/disease/recombinase-activating-gene-2-deficiency/), [combined immunodeficiency with skin granulomas](https://sugi.bio/atlas/disease/combined-immunodeficiency-with-skin-granulomas/), [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/), [Omenn syndrome](https://sugi.bio/atlas/disease/omenn-syndrome/).

**Reported phenotype names (ClinVar):** Recombinase activating gene 2 deficiency, Histiocytic medullary reticulosis, Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, Combined immunodeficiency with skin granulomas, not provided, not specified, SCID, AR, T-cell negative, B-cell negative, NK cell-positive, Severe combined immunodeficiency due to complete RAG1/2 deficiency, SCID, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-POSITIVE, RAG2 deficiency.

## Similar variants {#similar}

Related RAG2 variant pages (same residue, condition, or type): [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), [RAG2 p.Gly319Ter](/variant/rag2-p-gly319ter).

### 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 304552). 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.*