RAG2

Summary

RAG2 (recombination activating 2, HGNC:9832) is a protein-coding gene on chromosome 11p12, encoding V(D)J recombination-activating protein 2 (P55895). Core component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.

This gene encodes a protein that is involved in the initiation of V(D)J recombination during B and T cell development. This protein forms a complex with the product of the adjacent recombination activating gene 1, and this complex can form double-strand breaks by cleaving DNA at conserved recombination signal sequences. The recombination activating gene 1 component is thought to contain most of the catalytic activity, while the N-terminal of the recombination activating gene 2 component is thought to form a six-bladed propeller in the active core that serves as a binding scaffold for the tight association of the complex with DNA. A C-terminal plant homeodomain finger-like motif in this protein is necessary for interactions with chromatin components, specifically with histone H3 that is trimethylated at lysine 4. Mutations in this gene cause Omenn syndrome, a form of severe combined immunodeficiency associated with autoimmune-like symptoms.

Source: NCBI Gene 5897 — RefSeq curated summary.

At a glance

• Gene–disease (curated): recombinase activating gene 2 deficiency (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 624 total — 47 pathogenic, 83 likely-pathogenic
• Phenotypes (HPO): 120
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000536

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9832
Approved symbol	RAG2
Name	recombination activating 2
Location	11p12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000175097
Ensembl biotype	protein_coding
OMIM	179616
Entrez	5897

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000311485, ENST00000524423, ENST00000527033, ENST00000528428, ENST00000529083, ENST00000530276, ENST00000532616, ENST00000534379

RefSeq mRNA: 3 — MANE Select: NM_000536 NM_000536, NM_001243785, NM_001243786

CCDS: CCDS7903

Canonical transcript exons

ENST00000311485 — 2 exons

Exon	Start	End
ENSE00001185205	36591943	36594195
ENSE00003901937	36598102	36598236

Expression profiles

Bgee: expression breadth ubiquitous, 119 present calls, max score 80.65.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0960 / max 767.4834, expressed in 28 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119395	1.0960	28

Top tissues by expression

251 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	80.65	gold quality
bone marrow	UBERON:0002371	65.59	gold quality
left lobe of thyroid gland	UBERON:0001120	65.19	gold quality
right lobe of thyroid gland	UBERON:0001119	64.35	gold quality
thyroid gland	UBERON:0002046	64.35	gold quality
endometrium epithelium	UBERON:0004811	64.18	gold quality
frontal pole	UBERON:0002795	63.00	gold quality
middle frontal gyrus	UBERON:0002702	62.91	gold quality
paraflocculus	UBERON:0005351	62.41	gold quality
bone marrow cell	CL:0002092	62.02	silver quality
lower lobe of lung	UBERON:0008949	57.50	silver quality
adrenal tissue	UBERON:0018303	52.32	gold quality
corpus callosum	UBERON:0002336	51.41	gold quality
Brodmann (1909) area 10	UBERON:0013541	51.02	gold quality
granulocyte	CL:0000094	50.43	silver quality
quadriceps femoris	UBERON:0001377	49.73	gold quality
metanephric glomerulus	UBERON:0004736	49.61	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
vastus lateralis	UBERON:0001379	49.21	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
epithelial cell of pancreas	CL:0000083	48.81	gold quality
oviduct epithelium	UBERON:0004804	48.66	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	15.86
E-ANND-3	yes	3.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, FOXO1, FOXP1, GATA3, HMGA1, ID3, LEF1, MAZ, MYB, NFATC1, PAX5, PREB, SP1, SPI1, TCF3

miRNA regulators (miRDB)

44 targeting RAG2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-609	99.82	64.26	505
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-154-5P	98.92	66.65	733
HSA-MIR-1288-5P	98.85	67.01	734
HSA-MIR-3945	98.68	64.21	553
HSA-MIR-496	98.66	69.80	931
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-3668	98.52	68.76	951

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• RAG expression is up-regulated in peripheral IgD+ and VpreB+ B cells of patients with active SLE. (PMID:12115231)
• No sequence changes in RAG2 were found in a series of hematologic leukemias or their cell lines. (PMID:12145704)
• B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG1 and RAG2 proteins. (PMID:12200379)
• RAG2 expression and non-functional TCR rearrangements continuously take place in peripheral mature T cells of all activation/differentiation stages (PMID:12355431)
• Data show that a mature nonmalignant human B cell clone producing IgMlambda-ICA can express RAG-1/RAG-2 transcripts (PMID:12757263)
• intrinsic RAG-2 NLS functions in the nuclear uptake of RAG-2 following its reexpression in cycling cells (PMID:12861017)
• DNA methylation inhibits the cleavage activity of the RAG1/RAG2 complex by two different mechanisms, depending on the position of the mCpG around the recombination signal sequences (PMID:12897800)
• Erk and Abl kinases suppress RAG-1 and -2 gene expression through T cell receptor-independent basal signaling (PMID:14624253)
• RAG1 and RAG2 interact with recombination signal sequence DNA in the coding region in pre-and post-cleavage type synaptic complexes (PMID:15249552)
• expressed in peripheral blood mononuclear cells (PBMCs) from 42% of patients with infectious mononucleosis but not from health control subjects. (PMID:15295705)
• Activated mature CD5-positive human tonsil B cells coexpress both RAG2 and RAG1 mRNA and protein, and display DNA cleavage resulting from their recombinase activity. (PMID:15843554)
• SKP2 mediates ubiquitylation of RAG-2 in vitro and degradation of RAG-2 in vivo. (PMID:15949444)
• The carboxyl terminus of Rag2 plays a unique role as a direct bridge between chromatin and recombinase during chromosomal V(D)J recombination (PMID:16111638)
• Ths review focusses on the variation of inherited hypomorphic mutations of recombination activating genes either 1 or 2 (RAG1/2) that have been detected in most Omenn syndrome patients. (PMID:17075247)
• A knockin murine model carrying the Rag2 R229Q mutation previously described in several patients with Omenn syndrome (OS)supports the notion that impaired immune tolerance and defective immune regulation are involved in the pathophysiology of OS. (PMID:17476358)
• IL-6 initiates the expression of RAG2 in circulating B cells, and extends those in tonsil B cells. (PMID:17982069)
• a conserved tryptophan residue (W453) that constitutes a key structural component of the K4me3-binding surface and is essential for RAG2’s recognition of H3K4me3 is mutated in patients with immunodeficiency syndromes (PMID:18033247)
• the RAG-7-mer interaction is a critical step for coding DNA distortion and hairpin formation in the context of the 12/23 rule. (PMID:18089566)
• We describe three girls with a primary immunodeficiency disease associated with hypomorphic mutations in one of the two recombinase activating genes (RAG1 and RAG2). (PMID:18463379)
• Studies in B and T lymphocytes demonstrate that the reduction in RAG expression at the immature B and double-positive (DP) T cell stages is mediated through tonic (foreign antigen independent) receptor signaling. (PMID:19359154)
• Two independent signals are required for the induction of RAG gene expression in B cells that infiltrate the synovium of patients with RA. (PMID:19404965)
• Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination. (PMID:20234091)
• study reports 5 cases of RAG deficiency; genetic defects were heterogeneous and included 6 novel RAG mutations; all missense mutations except for Met443Ile in RAG2 were located in active core regions of RAG1 or RAG2 (PMID:21131235)
• study demonstrates that exogenous TCR alpha and beta chains transferred into the human immature RAG(+) T cell line Sup-T1 by lentiviral transduction inhibit RAG expression through tonic signaling (PMID:21481940)
• In the RAG1 gene we detected two novel mutations: L454Q and 469 fs-4bpdel. In the RAG 2 gene: 3 novel mutations: D65Y, G157V, and E480X. One T-B- SCID patient had a compound heterozygote for new mutations in the adenosine deaminase gene: W264X and R235W. (PMID:21624848)
• IL7R and RAG1/2 genes mutations/polymorphisms in patients with SCID. (PMID:21625022)
• The results indicate that in cancer cells E2A, FOXO1 and FOXP1 regulate RAG1 and RAG2 expression, which initiates Ig gene rearrangement much in the way similar to B lymphocytes. (PMID:21655267)
• USF-1 but not USF-2 is strongly enriched at Dbeta2 in chromatin from either Rag2-/- deficient thymocytes or Rag2-/- deficient thymocytes that express a rearranged Tcrb transgene. (PMID:22287717)
• Homozygous mutation of p.R394Q/p.R394Q and p.R776Q, 3047-3049 del GCC mutations are novel and they are causing serious T-B-NK + SCID. (PMID:22424479)
• analysis of multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor (PMID:22737248)
• A novel homozygous mutation with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome (PMID:22841008)
• Bidirectional activity of the NWC promoter is responsible for RAG-2 transcription in non-lymphoid cells (PMID:22984564)
• The results indicate that the contribution of immune dysregulatory disease due to RAG2 mutations present in the general population may be much higher than previously estimated. (PMID:24472623)
• Observations indicate that the RAG proteins exert fine control over every step of V(D)J cleavage. (PMID:24797073)
• found that Ikaros, a lymphocyte-specific transcription factor, acts as a repressor of NWC promoter–thus identifying a new Ikaros target–but is insufficient for inducing methylation which depends on the antisense transcription driven by RAG-2 promoter (PMID:25198102)
• Investigate the factors that regulate RAG1 and RAG2 cleavage on non-B DNA structures. We find that RAG binding and cleavage on heteroduplex DNA is dependent on the length of the double-stranded flanking region. (PMID:25327637)
• DNA damage triggers relocalization of RAG2 from the nucleus to centrosomes, suggesting a novel mechanism for modulating cellular responses to double strand breaks in developing lymphocytes. (PMID:25625798)
• analysis of regions of RAG1 necessary for interaction with RAG2 and measurement of the RAG1-RAG2 binding affinity (PMID:25745109)
• analysis of individual molecular events of RAG-mediated V(D)J DNA cleavage (PMID:25831509)
• This study reports on the prevalence of RAG1 and RAG2 mutations in ten severe combined immunodeficiency disorder patients in Egypt. (PMID:25869295)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rag2	ENSDARG00000052121
mus_musculus	Rag2	ENSMUSG00000032864
rattus_norvegicus	Rag2	ENSRNOG00000004623

Protein

Protein identifiers

V(D)J recombination-activating protein 2 — P55895 (reviewed: P55895)

All UniProt accessions (3): E9PPU5, E9PQB9, P55895

UniProt curated annotations — full annotation on UniProt →

Function. Core 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. DNA cleavage by the RAG complex 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 the RAG complex, RAG2 is not the catalytic component but is required for all known catalytic activities mediated by RAG1. It probably acts as a sensor of chromatin state that recruits the RAG complex to H3K4me3.

Subunit / interactions. Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2.

Subcellular location. Nucleus.

Tissue specificity. Cells of the B- and T-lymphocyte lineages.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry. Omenn syndrome (OS) [MIM:603554] Severe immunodeficiency characterized by the presence of activated, anergic, oligoclonal T-cells, hypereosinophilia, and high IgE levels. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The atypical PHD-type zinc finger recognizes and binds histone H3 trimethylated on ‘Lys-4’ (H3K4me3). The presence Tyr-445 instead of a carboxylate in classical PHD-type zinc fingers results in an enhanced binding to H3K4me3 in presence of dimethylated on ‘Arg-2’ (H3R2me2) rather than inhibited. The atypical PHD-type zinc finger also binds various phosphoinositides, such as phosphatidylinositol 3,4-bisphosphate binding (PtdIns(3,4)P2), phosphatidylinositol 3,5-bisphosphate binding (PtdIns(3,5)P2), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate binding (PtdIns(3,4,5)P3).

Similarity. Belongs to the RAG2 family.

RefSeq proteins (3): NP_000527, NP_001230714, NP_001230715 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004321	RAG2	Family
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR011043	Gal_Oxase/kelch_b-propeller	Homologous_superfamily
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR025162	RAG2_PHD	Domain

Pfam: PF03089, PF13341

UniProt features (22 total): binding site 8, sequence variant 7, sequence conflict 2, compositionally biased region 2, chain 1, zinc finger region 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8T4R	X-RAY DIFFRACTION	1.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55895-F1	75.98	0.52

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (8): 458; 478; 481; 419; 423; 446; 452; 455

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1266695	Interleukin-7 signaling
R-HSA-5687128	MAPK6/MAPK4 signaling

MSigDB gene sets: 339 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_DN, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_GROWTH, GOBP_B_CELL_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, TAL1ALPHAE47_01, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_CELL_CELL_ADHESION, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION

GO Biological Process (16): mature B cell differentiation involved in immune response (GO:0002313), B cell lineage commitment (GO:0002326), pre-B cell allelic exclusion (GO:0002331), B cell homeostatic proliferation (GO:0002358), T cell lineage commitment (GO:0002360), B cell differentiation (GO:0030183), T cell differentiation in thymus (GO:0033077), negative regulation of T cell differentiation in thymus (GO:0033085), V(D)J recombination (GO:0033151), organ growth (GO:0035265), defense response to bacterium (GO:0042742), positive regulation of organ growth (GO:0046622), DN2 thymocyte differentiation (GO:1904155), DNA recombination (GO:0006310), chromatin organization (GO:0006325), T cell differentiation (GO:0030217)

GO Molecular Function (12): chromatin binding (GO:0003682), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), phosphatidylinositol-3,4,5-trisphosphate binding (GO:0005547), zinc ion binding (GO:0008270), phosphatidylinositol binding (GO:0035091), phosphatidylinositol-3,4-bisphosphate binding (GO:0043325), sequence-specific DNA binding (GO:0043565), phosphatidylinositol-3,5-bisphosphate binding (GO:0080025), histone H3K4me3 reader activity (GO:0140002), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleoplasm (GO:0005654), DNA recombinase complex (GO:0097519), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Interleukins	1
MAPK family signaling cascades	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphatidylinositol phosphate binding	3
phosphatidylinositol bisphosphate binding	3
cell fate commitment	2
T cell differentiation	2
lymphocyte differentiation	2
T cell differentiation in thymus	2
binding	2
anion binding	2
B cell activation involved in immune response	1
mature B cell differentiation	1
immune response	1
B cell differentiation	1
pre-B cell differentiation	1
regulation of gene expression	1
B cell proliferation	1
homeostatic process	1
B cell activation	1
regulation of T cell differentiation in thymus	1
negative regulation of T cell differentiation	1
somatic diversification of immune receptors via germline recombination within a single locus	1
multicellular organismal process	1
developmental growth	1
defense response	1
response to bacterium	1
organ growth	1
regulation of organ growth	1
positive regulation of developmental growth	1
positive regulation of multicellular organismal process	1
DNA metabolic process	1
cellular component organization	1
T cell activation	1
transition metal ion binding	1
DNA binding	1
histone H3 reader activity	1
nucleic acid binding	1
cation binding	1
nuclear lumen	1
cellular anatomical structure	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2298 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAG2	RAG1	P15918	999
RAG2	H3-3A	P06351	978
RAG2	H3-5	Q6NXT2	978
RAG2	H3-4	Q16695	978
RAG2	H3C14	Q71DI3	977
RAG2	H3C1	P02295	977
RAG2	H3-7	Q5TEC6	977
RAG2	IL2RG	P31785	878
RAG2	CD4	P01730	865
RAG2	PRKDC	P78527	854
RAG2	CD8A	P01732	818
RAG2	DCLRE1C	Q96SD1	814
RAG2	IFNG	P01579	805
RAG2	IGHV4-38-2	P0DP08	777
RAG2	PTPRC	P08575	763

IntAct

2 interactions, top by confidence:

A	B	Type	Score
RAG2	CRNN	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (19): RAG2 (Biochemical Activity), RAG1 (Reconstituted Complex), IPO5 (Affinity Capture-Western), RAG1 (Affinity Capture-Western), RAG1 (Reconstituted Complex), RAG2 (Co-purification), RAG2 (Synthetic Lethality), RAG2 (Affinity Capture-Western), CRNN (Affinity Capture-MS), RAG2 (Co-localization), RAG2 (Reconstituted Complex), RAG2 (Affinity Capture-RNA), RAG2 (Protein-peptide), VPRBP (Co-purification), DDB1 (Co-purification)

ESM2 similar proteins: A0A2R8VHF7, A0JM23, A2QRA0, A4IIA7, A4IIV4, A6NFN9, A6NHR9, A7MBF6, F4IG73, F4JSE7, O17482, O95876, P12540, P21784, P34089, P38899, P55895, P56696, Q08AW4, Q0D2D7, Q12789, Q13829, Q28DC9, Q2WGJ8, Q3E7Y5, Q3UUE9, Q4R907, Q4VXA5, Q5BK83, Q5EA90, Q5F476, Q5HZS2, Q5M9F0, Q5RAX4, Q5RBH4, Q5RD21, Q6AYL6, Q6DGA7, Q6PIY5, Q70XZ2

Diamond homologs: O13034, P21784, P25022, P34089, P55895, Q91193, Q91830

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
AminoAcids	up-regulates	RAG2
RAG2	up-regulates	MTOR	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

624 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	47
Likely pathogenic	83
Uncertain significance	247
Likely benign	194
Benign	9

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1014836	NM_000536.4(RAG2):c.826G>A (p.Gly276Ser)	Pathogenic
1069162	NC_000011.9:g.(?36614125)(36615728_?)del	Pathogenic
1073477	NM_000536.4(RAG2):c.442C>T (p.Arg148Ter)	Pathogenic
1075543	NM_000536.4(RAG2):c.1275_1278dup (p.Ile427fs)	Pathogenic
1075544	NM_000536.4(RAG2):c.829dup (p.Tyr277fs)	Pathogenic
1076086	NM_000536.4(RAG2):c.895del (p.Ile299fs)	Pathogenic
13130	NM_000536.4(RAG2):c.686G>A (p.Arg229Gln)	Pathogenic
13134	NM_000536.4(RAG2):c.817_819del (p.Ile273del)	Pathogenic
13136	NM_000536.4(RAG2):c.115A>G (p.Arg39Gly)	Pathogenic
13138	NM_000536.4(RAG2):c.1352G>C (p.Gly451Ala)	Pathogenic
1360692	NM_000536.4(RAG2):c.47_57del (p.Gln16fs)	Pathogenic
1412375	NM_000536.4(RAG2):c.130G>T (p.Gly44Ter)	Pathogenic
1438791	NM_000536.4(RAG2):c.724del (p.Leu242fs)	Pathogenic
1441601	NM_000536.4(RAG2):c.743del (p.Asn248fs)	Pathogenic
1452768	NM_000536.4(RAG2):c.859del (p.Cys287fs)	Pathogenic
1456090	NM_000536.4(RAG2):c.770_771del (p.Ser257fs)	Pathogenic
1457376	NM_000536.4(RAG2):c.535del (p.Leu179fs)	Pathogenic
1457563	NM_000536.4(RAG2):c.863del (p.Asn288fs)	Pathogenic
1459767	NM_000536.4(RAG2):c.1053dup (p.Glu352Ter)	Pathogenic
1460395	NM_000536.4(RAG2):c.358del (p.Val120fs)	Pathogenic
2018007	NM_000536.4(RAG2):c.1491_1506A[6]GCCTCCAATGGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTAGGGAGGCCGAGGCGGGTGGATCATGAGGTCAGGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAAAGCCTCCAATG[1] (p.Lys503delinsGlyArgAlaArgTrpLeuThrProValIleProAlaLeuArgGluAlaGluAlaGlyGlySerTer)	Pathogenic
2020432	NM_000536.4(RAG2):c.1348del (p.Asp450fs)	Pathogenic
2029414	NM_000536.4(RAG2):c.1024G>T (p.Gly342Ter)	Pathogenic
2030370	NM_000536.4(RAG2):c.1334dup (p.Tyr445Ter)	Pathogenic
2090696	NM_000536.4(RAG2):c.189dup (p.Lys64Ter)	Pathogenic
2678215	NM_000536.4(RAG2):c.171del (p.Lys58fs)	Pathogenic
2928095	NM_000536.4(RAG2):c.1257C>G (p.Cys419Trp)	Pathogenic
2933346	NM_000536.4(RAG2):c.1210G>T (p.Glu404Ter)	Pathogenic
2935560	NM_000536.4(RAG2):c.1441C>G (p.His481Asp)	Pathogenic
2938106	NM_000536.4(RAG2):c.1442A>G (p.His481Arg)	Pathogenic

SpliceAI

821 predictions. Top by Δscore:

Variant	Effect	Δscore
11:36594774:G:GT	donor_gain	0.9900
11:36594913:G:GT	donor_gain	0.9900
11:36598097:CCTA:C	donor_loss	0.9900
11:36598099:TACC:T	donor_loss	0.9900
11:36598101:CCTG:C	donor_loss	0.9900
11:36595450:CAAA:C	acceptor_gain	0.9800
11:36594620:G:GT	donor_gain	0.9700
11:36595014:G:T	donor_gain	0.9700
11:36595059:A:AG	donor_gain	0.9700
11:36576083:TTC:T	donor_gain	0.9500
11:36595453:A:C	acceptor_gain	0.9500
11:36594845:T:TA	donor_gain	0.9300
11:36595456:T:TC	acceptor_gain	0.9300
11:36598100:A:AC	donor_gain	0.9300
11:36598101:C:CC	donor_gain	0.9300
11:36594196:C:CC	acceptor_gain	0.9100
11:36594933:TTG:T	donor_gain	0.9100
11:36594192:TTGT:T	acceptor_gain	0.8900
11:36597641:A:G	acceptor_gain	0.8900
11:36598098:CTACC:C	donor_gain	0.8900
11:36598099:TACCT:T	donor_gain	0.8900
11:36576036:A:AG	donor_gain	0.8800
11:36576037:G:GG	donor_gain	0.8800
11:36594191:TTTGT:T	acceptor_gain	0.8800
11:36594929:G:GT	donor_gain	0.8800
11:36575986:A:AG	donor_gain	0.8700
11:36575987:G:GG	donor_gain	0.8700
11:36594681:G:GT	donor_gain	0.8700
11:36594879:A:T	donor_gain	0.8700
11:36576079:G:GT	donor_gain	0.8600

AlphaMissense

3515 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:36593250:A:G	W307R	0.997
11:36593250:A:T	W307R	0.997
11:36594063:A:G	W36R	0.997
11:36594063:A:T	W36R	0.997
11:36593220:A:G	W317R	0.996
11:36593220:A:T	W317R	0.996
11:36592881:A:G	W430R	0.995
11:36592881:A:T	W430R	0.995
11:36592879:C:A	W430C	0.994
11:36592879:C:G	W430C	0.994
11:36594061:C:A	W36C	0.994
11:36594061:C:G	W36C	0.994
11:36594074:C:T	G32E	0.994
11:36594031:G:C	F46L	0.993
11:36594031:G:T	F46L	0.993
11:36594033:A:G	F46L	0.993
11:36592812:A:G	W453R	0.992
11:36592812:A:T	W453R	0.992
11:36592810:C:A	W453C	0.991
11:36592810:C:G	W453C	0.991
11:36593655:A:G	W172R	0.991
11:36593655:A:T	W172R	0.991
11:36593551:A:C	F206L	0.990
11:36593551:A:T	F206L	0.990
11:36593553:A:G	F206L	0.990
11:36593389:A:C	S260R	0.989
11:36593389:A:T	S260R	0.989
11:36593391:T:G	S260R	0.989
11:36593693:C:G	R159P	0.989
11:36594052:T:A	R39S	0.989

dbSNP variants (sampled 300 via entrez): RS1000616544 (11:36595746 A>T), RS1000707417 (11:36597896 C>G,T), RS1000988323 (11:36598197 C>G), RS1001392507 (11:36595985 C>A), RS1001444700 (11:36596318 G>A), RS1001788600 (11:36591694 C>T), RS1002138395 (11:36597034 T>G), RS1002169469 (11:36597373 T>A), RS1002434424 (11:36594834 C>A,T), RS1003119954 (11:36598010 A>G), RS1003132911 (11:36595383 T>C), RS1003225714 (11:36591127 A>T), RS1003769068 (11:36591422 A>G), RS1004333803 (11:36598539 C>T), RS1004691065 (11:36594939 G>C)

Disease associations

OMIM: gene MIM:179616 | disease phenotypes: MIM:233650, MIM:601457, MIM:603554, MIM:607594, MIM:604369, MIM:608971

GenCC curated gene-disease

Disease	Classification	Inheritance
recombinase activating gene 2 deficiency	Definitive	Autosomal recessive
Omenn syndrome	Definitive	Autosomal recessive
severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
recombinase activating gene 2 deficiency	Definitive	AR

Mondo (9): combined immunodeficiency with skin granulomas (MONDO:0009306), severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (MONDO:0011086), Omenn syndrome (MONDO:0011338), recombinase activating gene 2 deficiency (MONDO:0000573), inborn error of immunity (MONDO:0003778), severe combined immunodeficiency (MONDO:0015974), common variable immunodeficiency (MONDO:0015517), Salla disease (MONDO:0011449), immunodeficiency 104 (MONDO:0012163)

Orphanet (8): Combined immunodeficiency with granulomatosis (Orphanet:157949), Severe combined immunodeficiency due to complete RAG1/2 deficiency (Orphanet:331206), Omenn syndrome (Orphanet:39041), Primary immunodeficiency (Orphanet:101997), Severe combined immunodeficiency (Orphanet:183660), OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Salla disease (Orphanet:309334), Free sialic acid storage disease (Orphanet:834)

HPO phenotypes

120 total (30 of 120 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000100	Nephrotic syndrome
HP:0000265	Mastoiditis
HP:0000388	Otitis media
HP:0000509	Conjunctivitis
HP:0000561	Absent eyelashes
HP:0000778	Hypoplasia of the thymus
HP:0000821	Hypothyroidism
HP:0000944	Abnormal metaphysis morphology
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000964	Eczematoid dermatitis
HP:0000969	Edema
HP:0000980	Pallor
HP:0000988	Skin rash
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001036	Parakeratosis
HP:0001072	Thickened skin
HP:0001250	Seizure
HP:0001287	Meningitis
HP:0001369	Arthritis
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001581	Recurrent skin infections
HP:0001596	Alopecia
HP:0001744	Splenomegaly
HP:0001831	Short toe
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002318_161	Rheumatoid arthritis	1.000000e-07
GCST002318_35	Rheumatoid arthritis	3.000000e-07

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D017074	Common Variable Immunodeficiency	C20.673.330
D007153	Immunologic Deficiency Syndromes	C20.673
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750
C567115	Combined Cellular And Humoral Immune Defects With Granulomas (supp.)
C563822	Severe Combined Immunodeficiency, Autosomal Recessive, T Cell Negative, B Cell Positive, NK Cell Positive (supp.)
C563311	Severe Combined Immunodeficiency, Autosomal Recessive, T Cell-Negative, B Cell-Negative, NK Cell-Positive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
perfluorooctanoic acid	decreases expression	2
perfluorooctane sulfonic acid	decreases expression	2
perfluoro-n-nonanoic acid	decreases expression	2
perfluorohexanesulfonic acid	decreases expression	2
5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid	decreases expression	2
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	decreases expression	1
deoxynivalenol	increases expression	1
perfluorodecanoic acid	decreases expression	1
perfluorohexanoic acid	decreases expression	1
perfluorobutanesulfonic acid	decreases expression	1
bisphenol S	increases expression	1
(+)-JQ1 compound	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

128 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT00520494	PHASE4	COMPLETED	Efficacy and Safety of Vivaglobin® in Previously Untreated Patients With Primary Immunodeficiency
NCT01289847	PHASE4	COMPLETED	A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
NCT01946906	PHASE4	COMPLETED	The Rifaximin Study in CVID
NCT05193552	PHASE4	RECRUITING	Usage of Spirometry in Managing IgG Therapy in CVID With Airway Disease
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00468273	PHASE3	COMPLETED	A Clinical Study of Intravenous Immunoglobulin
NCT00811174	PHASE3	TERMINATED	Efficacy, Safety and Kinetics Study of Octagam 10% in Primary Immunodeficiency Diseases
NCT01012323	PHASE3	COMPLETED	A Study of NewGam, Human Immunoglobulin 10%, in Patients With Primary Immunodeficiency Diseases
NCT01313507	PHASE3	COMPLETED	High Infusion Rate Study of Immunoglobulin Intravenous (Human) 10% (NewGam)
NCT01406470	PHASE3	COMPLETED	Phase 3 Study of Immune Globulin Intravenous (Human)IVIG-SN™ in Subjects With Primary Immunodeficiency
NCT02783482	PHASE3	COMPLETED	Study of Immune Globulin Intravenous (Human) GC5107 in Subjects With Primary Humoral Immunodeficiency
NCT02810444	PHASE3	COMPLETED	Study to Investigate Efficacy, Safety and Pharmacokinetics of BT595 in Subjects With PID
NCT03961009	PHASE3	COMPLETED	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in PID Patients
NCT04842643	PHASE3	COMPLETED	An Extension Study of TAK-664 for Japanese People With Primary Immunodeficiency Disease
NCT04944979	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in Pediatric PID Patients (KIDCARES10)
NCT06089122	PHASE3	UNKNOWN	Efficacy, Safety, and Pharmacokinetics of Shu Yang IVIG
NCT06150833	PHASE3	UNKNOWN	Efficacy and Safety and Pharmacokinetics of Boya IVIG
NCT07346859	PHASE3	RECRUITING	Study of BP-SCIG 20% in Patients With Primary Immunodeficiency (PID)
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00168012	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IVIG-F10 in Patients With Primary Immunodeficiencies (PID)
NCT00168025	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00322556	PHASE3	COMPLETED	Safety and Efficacy of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00542997	PHASE3	COMPLETED	Study of Subcutaneous Immune Globulin in Patients Requiring IgG Replacement Therapy
NCT01884311	PHASE3	COMPLETED	Pharmacokinetics (PK) and Safety of Subgam-VF in Primary Immunodeficiency Diseases
NCT01963143	PHASE3	COMPLETED	Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Gammaplex® 10 and Gammaplex® 5% in Primary Immunodeficiency Diseases
NCT02247141	PHASE3	COMPLETED	A Multi-centre Open Study to Assess the Safety and Efficacy of Subgam®
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00001438	PHASE2	COMPLETED	A Pilot Study of the Combination of Retinoic Acid and Interferon-Alpha2a for the Treatment of Lymphoproliferative Disorders in Children With Immunodeficiency Syndromes
NCT00176865	PHASE2	COMPLETED	Stem Cell Transplant for Immunologic or Histiocytic Disorders
NCT00389324	PHASE2	COMPLETED	A Trial of the Pharmacokinetics, Safety, and Tolerability of Subcutaneous Gamunex® in Primary Immunodeficiency
NCT00598481	PHASE2	COMPLETED	ADA Gene Transfer Into Hematopoietic Stem/Progenitor Cells for the Treatment of ADA-SCID
NCT01856582	PHASE2	TERMINATED	CD34+ Stem Cell Infusion to Augment Graft Function
NCT06199427	PHASE2	RECRUITING	PTCy and and Ruxolitinib for GVHD Prophylaxis After HSCT With Thymoglobulin in Conditioning Regimen in Patients With Inborn Errors of Immunity
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies