# NM_000536.4(RAG2):c.1391G>A (p.Arg464His)

https://sugi.bio/variant/rag2-p-arg464his

## Summary

**RAG2 p.Arg464His (c.1391G>A)** is classified **Conflicting classifications of pathogenicity** in RAG2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0751); Ultra-rare (popmax 0.0334%, nfe); Associated with combined immunodeficiency with skin granulomas.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs147748696 · 4 submitters · 3 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0334%, nfe)

## For patients & families {#patients}

This is a change in the RAG2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, 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.Arg464His |
| Coding change (HGVS c.) | c.1391G>A |
| MANE Select transcript | [NM_000536](https://www.ncbi.nlm.nih.gov/nuccore/NM_000536) |
| dbSNP | [rs147748696](https://www.ncbi.nlm.nih.gov/snp/rs147748696/) |
| Variant type | single nucleotide variant |
| Location | chr11:36592778-36592778 (GRCh38) |
| ClinVar | [VCV432772](https://www.ncbi.nlm.nih.gov/clinvar/variation/432772/) |

**All HGVS expressions:** `LRG_99:g.10459G>A`, `NC_000011.10:g.36592778C>T`, `NC_000011.9:g.36614328C>T`, `NG_007573.1:g.10459G>A`, `NG_033154.1:g.3286C>T`, `NM_000536.4:c.1391G>A`, `NM_001243785.2:c.1391G>A`, `NM_001243786.2:c.1391G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0751)
- REVEL 0.246 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.82 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -1.05, GERP -4.65 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 12.39**. 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): grpmax **0.0334%** (nfe) · FAF95 0.0306% · FAF99 0.0295% · 394/1,180,014 in the highest group · 594/1,613,910 alleles overall — ultra-rare (popmax 0.0334%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.321% | 312 |
| Finnish (not grpmax-eligible) | 0.125% | 800 |
| European (non-Finnish) (grpmax) | 0.0334% | 2,995 |
| Remaining individuals (not grpmax-eligible) | 0.0304% | 3,289 |
| African / African-American | 0.00401% | 24,957 |
| Admixed American | 0.00333% | 29,991 |
| South Asian | 0.0011% | 91,078 |

Ashkenazi Jewish 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 **464** lies in an α-helix.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (3 Uncertain significance, 2 Likely benign).

**Submission history:** 5 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2020-04-13 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |

## Associated conditions {#conditions}

[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):** Combined immunodeficiency with skin granulomas, not provided, Histiocytic medullary reticulosis, Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, none provided, 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, Omenn syndrome, SEVERE COMBINED IMMUNODEFICIENCY WITH HYPEREOSINOPHILIA.

## Similar variants {#similar}

Related RAG2 variant pages (same residue, condition, or type): [RAG2 p.Arg464Cys](/variant/rag2-p-arg464cys), [RAG2 p.Arg464Pro](/variant/rag2-p-arg464pro), [RAG2 p.Arg464=](/variant/rag2-p-arg464), [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).

### 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 432772). 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.*