RAG1

recombination activating 1, the group of DNA transposon derived genes|Ring finger proteins

Basic information

Region (hg38): 11:36510371-36593156

Links

ENSG00000166349 ∙ NCBI:5896 ∙ OMIM:179615 ∙ HGNC:9831 ∙ Uniprot:P15918 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Omenn syndrome (Strong), mode of inheritance: AR
• Omenn syndrome (Supportive), mode of inheritance: AR
• combined immunodeficiency due to partial RAG1 deficiency (Supportive), mode of inheritance: AR
• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (Supportive), mode of inheritance: AR
• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (Strong), mode of inheritance: AR
• Omenn syndrome (Definitive), mode of inheritance: AR
• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (Strong), mode of inheritance: AR
• recombinase activating gene 1 deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Severe combined immunodeficienc, autosomal recessive, T cell-negative (T-), B cell-negative (B-), natural killer cell-positive (NK+); Omenn syndrome; Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity; Combined cellular and humoral immune defects with granulomas	AR	Allergy/Immunology/Infectious	Antiinfectious prophylaxis (though special consideration is necessary related to the use of live vaccines) and early and aggressive treatment of infections may be beneficial; HSCT has been reported	Allergy/Immunology/Infectious; Dermatologic; Gastrointestinal	9630231; 10226883; 11313270; 16276422; 18463379; 20956421; 20489056; 21131235; 21624848; 21184155; 21732012; 21625022; 21771083; 22424479

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RAG1 gene.

• Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (312 variants)
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas (272 variants)
• Histiocytic medullary reticulosis (179 variants)
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (145 variants)
• not provided (106 variants)
• Combined immunodeficiency due to partial RAG1 deficiency (78 variants)
• not specified (32 variants)
• Combined immunodeficiency with skin granulomas (27 variants)
• Severe combined immunodeficiency disease (27 variants)
• Inborn genetic diseases (20 variants)
• Recombinase activating gene 1 deficiency (19 variants)
• Recombinase activating gene 2 deficiency (7 variants)
• Severe combined immunodeficiency, B cell-negative (6 variants)
• - (5 variants)
• Combined immunodeficiency due to partial RAG1 deficiency;Combined immunodeficiency with skin granulomas;Histiocytic medullary reticulosis;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (5 variants)
• Recombinase activating gene 2 deficiency;Inborn error of immunity;Histiocytic medullary reticulosis (4 variants)
• Combined immunodeficiency due to partial RAG1 deficiency;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Histiocytic medullary reticulosis;Combined immunodeficiency with skin granulomas (3 variants)
• RAG1-Related Disorders (3 variants)
• Combined immunodeficiency due to partial RAG1 deficiency;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas;Histiocytic medullary reticulosis (3 variants)
• RAG1-related condition (3 variants)
• Histiocytic medullary reticulosis;Combined immunodeficiency due to partial RAG1 deficiency;Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (2 variants)
• Immunodeficiency 104 (2 variants)
• Recombinase activating gene 2 deficiency;Inborn error of immunity (2 variants)
• Inherited Immunodeficiency Diseases (2 variants)
• Histiocytic medullary reticulosis;Recombinase activating gene 2 deficiency;Inborn error of immunity (2 variants)
• Common variable immunodeficiency (1 variants)
• Combined immunodeficiency with skin granulomas;Recombinase activating gene 2 deficiency;Inborn error of immunity (1 variants)
• Combined immunodeficiency due to partial RAG1 deficiency;Histiocytic medullary reticulosis;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas (1 variants)
• Microcephaly (1 variants)
• Primary ciliary dyskinesia (1 variants)
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas;Histiocytic medullary reticulosis (1 variants)
• Combined immunodeficiency with skin granulomas;Histiocytic medullary reticulosis;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1 variants)
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Recombinase activating gene 2 deficiency;Inborn error of immunity (1 variants)
• Immunodeficiency (1 variants)
• Histiocytic medullary reticulosis;Combined immunodeficiency with skin granulomas;Atypical severe combined immunodeficiency due to complete RAG1/2 deficiency;Recombinase activating gene 2 deficiency;Inborn error of immunity (1 variants)
• Cataract 3 multiple types (1 variants)
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency due to partial RAG1 deficiency;Histiocytic medullary reticulosis;Combined immunodeficiency with skin granulomas (1 variants)
• Inborn error of immunity;Recombinase activating gene 2 deficiency (1 variants)
• Atypical severe combined immunodeficiency due to complete RAG1/2 deficiency;Recombinase activating gene 2 deficiency;Inborn error of immunity (1 variants)
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Histiocytic medullary reticulosis;Combined immunodeficiency due to partial RAG1 deficiency;Combined immunodeficiency with skin granulomas (1 variants)
• Combined immunodeficiency with skin granulomas;Combined immunodeficiency due to partial RAG1 deficiency;Histiocytic medullary reticulosis;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1 variants)
• Histiocytic medullary reticulosis;Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency due to partial RAG1 deficiency (1 variants)
• Combined immunodeficiency with skin granulomas;Histiocytic medullary reticulosis;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency due to partial RAG1 deficiency (1 variants)
• Histiocytic medullary reticulosis;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency due to partial RAG1 deficiency;Combined immunodeficiency with skin granulomas (1 variants)
• Recombinase activating gene 2 deficiency;Inborn error of immunity;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1 variants)
• Combined immunodeficiency due to partial RAG1 deficiency;Histiocytic medullary reticulosis;Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1 variants)
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Histiocytic medullary reticulosis;Combined immunodeficiency with skin granulomas (1 variants)
• RAG2-related condition (1 variants)
• RECOMBINATION ACTIVATING GENE 1 POLYMORPHISM (1 variants)
• Recombinase activating gene 2 deficiency;Histiocytic medullary reticulosis;Inborn error of immunity (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RAG1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	112	4	123
missense	21	30	266	9	8	334
nonsense	12	16				28
start loss			1			1
frameshift	16	15				31
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding	9	15	107	60	17	208
Total	58	76	383	181	29

Highest pathogenic variant AF is 0.0000854

Variants in RAG1

This is a list of pathogenic ClinVar variants found in the RAG1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-36568023-G-A		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive • Histiocytic medullary reticulosis	Uncertain significance (Jan 13, 2018)
11-36568072-A-G		Histiocytic medullary reticulosis • Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Benign (Jan 12, 2018)
11-36568134-A-G		Histiocytic medullary reticulosis • Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (Jan 13, 2018)
11-36573295-C-T		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive • Histiocytic medullary reticulosis	Uncertain significance (Jan 13, 2018)
11-36573305-A-G		Histiocytic medullary reticulosis • Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive • Severe combined immunodeficiency disease • Recombinase activating gene 1 deficiency	Uncertain significance (Oct 10, 2023)
11-36573313-C-T		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Likely benign (Jan 02, 2024)
11-36573319-C-G		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Uncertain significance (Nov 13, 2019)
11-36573321-C-T		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Uncertain significance (Feb 18, 2022)
11-36573331-G-A		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (Apr 24, 2023)
11-36573333-G-T		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Uncertain significance (Oct 04, 2022)
11-36573341-T-G		Histiocytic medullary reticulosis • Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive • Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive • Recombinase activating gene 1 deficiency	Uncertain significance (Jan 24, 2024)
11-36573344-G-A		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas • Inborn genetic diseases	Uncertain significance (Jun 27, 2023)
11-36573351-A-G		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas • Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 04, 2023)
11-36573356-AT-A		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Pathogenic (Jul 15, 2023)
11-36573364-C-T		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (Dec 29, 2023)
11-36573367-A-C		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Likely benign (Feb 27, 2023)
11-36573367-A-T		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (Jul 25, 2018)
11-36573370-T-C		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Likely benign (Jul 17, 2023)
11-36573380-T-C		Inborn genetic diseases	Uncertain significance (Jan 04, 2022)
11-36573382-A-G		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Likely benign (Oct 05, 2023)
11-36573386-T-C		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Uncertain significance (Jan 20, 2019)
11-36573390-A-G		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Uncertain significance (Jul 25, 2022)
11-36573398-C-G		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Uncertain significance (Apr 14, 2022)
11-36573402-T-A		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Uncertain significance (Aug 30, 2023)
11-36573405-G-A		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas • Combined immunodeficiency due to partial RAG1 deficiency;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Histiocytic medullary reticulosis;Combined immunodeficiency with skin granulomas	Uncertain significance (May 03, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RAG1	protein_coding	protein_coding	ENST00000299440	1	82448

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000277	0.997	125662	0	80	125742	0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.581	504	542	0.930	0.0000314	6929
Missense in Polyphen		242	314.27	0.77003		4022
Synonymous	0.0833	205	207	0.993	0.0000112	2011
Loss of Function	2.60	12	26.4	0.454	0.00000151	380

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000685	0.000684
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000490	0.000489
Finnish	0.000185	0.000185
European (Non-Finnish)	0.000318	0.000317
Middle Eastern	0.000490	0.000489
South Asian	0.000229	0.000229
Other	0.000818	0.000815

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalytic component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination. V(D)J recombination assembles a diverse repertoire of immunoglobulin and T-cell receptor genes in developing B and T- lymphocytes through rearrangement of different V (variable), in some cases D (diversity), and J (joining) gene segments. In the RAG complex, RAG1 mediates the DNA-binding to the conserved recombination signal sequences (RSS) and catalyzes the DNA cleavage activities by introducing a double-strand break between the RSS and the adjacent coding segment. RAG2 is not a catalytic component but is required for all known catalytic activities. DNA cleavage occurs in 2 steps: a first nick is introduced in the top strand immediately upstream of the heptamer, generating a 3'- hydroxyl group that can attack the phosphodiester bond on the opposite strand in a direct transesterification reaction, thereby creating 4 DNA ends: 2 hairpin coding ends and 2 blunt, 5'- phosphorylated ends. The chromatin structure plays an essential role in the V(D)J recombination reactions and the presence of histone H3 trimethylated at 'Lys-4' (H3K4me3) stimulates both the nicking and haipinning steps. The RAG complex also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. The introduction of DNA breaks by the RAG complex on one immunoglobulin allele induces ATM-dependent repositioning of the other allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. In addition to its endonuclease activity, RAG1 also acts as an E3 ubiquitin-protein ligase that mediates monoubiquitination of histone H3. Histone H3 monoubiquitination is required for the joining step of V(D)J recombination. Mediates polyubiquitination of KPNA1 (By similarity). {ECO:0000250}.
• Disease: DISEASE: Combined cellular and humoral immune defects with granulomas (CHIDG) [MIM:233650]: Immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. Other characteristics include hypogammaglobulinemia, a diminished number of T and B-cells, and sparse thymic tissue on ultrasonography. {ECO:0000269|PubMed:18463379}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-negative/NK-cell-positive (T(-)B(-)NK(+) SCID) [MIM:601457]: A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. {ECO:0000269|PubMed:19912631, ECO:0000269|PubMed:8810255}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Omenn syndrome (OS) [MIM:603554]: Severe immunodeficiency characterized by the presence of activated, anergic, oligoclonal T-cells, hypereosinophilia, and high IgE levels. {ECO:0000269|PubMed:10606976, ECO:0000269|PubMed:11133745, ECO:0000269|PubMed:19912631, ECO:0000269|PubMed:21624848, ECO:0000269|PubMed:21771083, ECO:0000269|PubMed:9630231}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Alpha/beta T-cell lymphopenia, with gamma/delta T-cell expansion, severe cytomegalovirus infection and autoimmunity (T- CMVA) [MIM:609889]: An immunological disorder characterized by oligoclonal expansion of TCR gamma/delta T-cells, TCR alpha/beta T-cell lymphopenia, severe, disseminated cytomegalovirus infection and autoimmune cytopenia. {ECO:0000269|PubMed:16276422}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Primary immunodeficiency - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);MAPK6-MAPK4 signaling;Signal Transduction;MAPK6/MAPK4 signaling;MAPK family signaling cascades (Consensus)

Recessive Scores

• pRec: 0.572

Intolerance Scores

• loftool: 0.156
• rvis_EVS: -0.37
• rvis_percentile_EVS: 28.29

Haploinsufficiency Scores

• pHI: 0.269
• hipred: Y
• hipred_score: 0.800
• ghis: 0.396

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.712

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Rag1
• Phenotype: hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; vision/eye phenotype; immune system phenotype; renal/urinary system phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; endocrine/exocrine gland phenotype; neoplasm; pigmentation phenotype; cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype

Zebrafish Information Network

• Gene name: rag1
• Affected structure: mature B cell
• Phenotype tag: abnormal
• Phenotype quality: absent

Gene ontology

• Biological process: adaptive immune response;pre-B cell allelic exclusion;DNA recombination;immune response;visual learning;histone monoubiquitination;B cell differentiation;T cell differentiation in thymus;V(D)J recombination;T cell homeostasis;negative regulation of cysteine-type endopeptidase activity involved in apoptotic process;positive regulation of T cell differentiation;thymus development;protein autoubiquitination;negative regulation of thymocyte apoptotic process;nucleic acid phosphodiester bond hydrolysis;regulation of behavioral fear response
• Cellular component: nucleus;nucleoplasm
• Molecular function: DNA binding;endonuclease activity;ubiquitin-protein transferase activity;protein binding;zinc ion binding;histone binding;protein homodimerization activity;sequence-specific DNA binding;metal ion binding;ubiquitin protein ligase activity