# NM_000448.3(RAG1):c.2880A>G (p.Ala960=)

https://sugi.bio/variant/rag1-p-ala960

## Summary

**RAG1 p.Ala960= (c.2880A>G)** is classified **Benign/Likely benign** in RAG1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 9.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with combined immunodeficiency with skin granulomas.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs1980131 · 9 submitters · 3 linked conditions · common (popmax 9.9%, mid) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the RAG1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 9 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 | RAG1 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 | [RAG1](https://sugi.bio/atlas/gene/RAG1/) |
| Protein change (HGVS p.) | p.Ala960= |
| Coding change (HGVS c.) | c.2880A>G |
| MANE Select transcript | [NM_000448](https://www.ncbi.nlm.nih.gov/nuccore/NM_000448) |
| dbSNP | [rs1980131](https://www.ncbi.nlm.nih.gov/snp/rs1980131/) |
| Variant type | single nucleotide variant |
| Location | chr11:36576184-36576184 (GRCh38) |
| ClinVar | [VCV256190](https://www.ncbi.nlm.nih.gov/clinvar/variation/256190/) |

**All HGVS expressions:** `LRG_98:g.13172A>G`, `LRG_98t1:c.2880A>G`, `NC_000011.10:g.36576184A>G`, `NC_000011.9:g.36597734A>G`, `NG_007528.1:g.13172A>G`, `NM_000448.3:c.2880A>G`, `NM_001377277.1:c.2880A>G`, `NM_001377278.1:c.2880A>G`, `NM_001377279.1:c.2880A>G`, `NM_001377280.1:c.2880A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 9.9%, mid) — too common for a highly-penetrant pathogenic allele.

- **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 -2.527, GERP -5.62 — fast-evolving / accelerated position
- CADD: **PHRED 1.129**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **9.9%** (mid) · FAF95 9.24% · FAF99 8.98% · 600/6,062 in the highest group · 118,899/1,614,052 alleles overall — common (popmax 9.9%, mid) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 13% | 8 |
| Middle Eastern (grpmax) | 9.9% | 10 |
| African / African-American | 7.85% | 13 |
| Remaining individuals (not grpmax-eligible) | 7.81% | 13 |
| European (non-Finnish) | 7.77% | 13 |
| Ashkenazi Jewish (not grpmax-eligible) | 7.74% | 13 |
| Finnish (not grpmax-eligible) | 6.93% | 14 |
| South Asian | 6.16% | 16 |
| Admixed American | 5.64% | 18 |
| East Asian | 0.136% | 736 |

Amish 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}

**RAG1** population constraint: LOEUF 0.703, pLI 2.2369e-05, missense-Z 1.7802. *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 1 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **960** lies in a UniProt-annotated variant site (in t(-)b(-)nk(+) scid; uncertain significance); a UniProt-annotated variant site (in t(-)b(-)nk(+) scid; uncertain significance; also found in patients with an atypical form of severe combined immunodeficiency/omenn syndrome; uncertain significance; loss of recombination activity); a UniProt-annotated variant site (in t(-)b(-)nk(+) scid; decreased recombination activity).

AlphaFold model confidence (whole protein): pLDDT 81.68, 57% of residues very-high.

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

*Describes the biological roles of RAG1 (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}

RAG1 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 |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** V(D)J recombination.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (8 Benign, 1 Likely benign, 1 not provided).

**Submission history:** 10 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| GenomeConnect, ClinGen | not provided | no classification provided | phenotyping only |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2018-08-24 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-07-02 |

## 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 specified, Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, Histiocytic medullary reticulosis, not 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, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related RAG1 variant pages (same residue, condition, or type): [RAG1 p.Ala960Ser](/variant/rag1-p-ala960ser), [RAG1 p.Ala960Val](/variant/rag1-p-ala960val), [RAG1 p.Ala444Val](/variant/rag1-p-ala444val), [RAG1 p.Arg108Ter](/variant/rag1-p-arg108ter), [RAG1 p.Arg142Ter](/variant/rag1-p-arg142ter), [RAG1 p.Arg394Gln](/variant/rag1-p-arg394gln), [RAG1 p.Arg394Trp](/variant/rag1-p-arg394trp), [RAG1 p.Arg396His](/variant/rag1-p-arg396his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 256190). 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.*