Recombinase activating gene 2 deficiency

Summary

Recombinase activating gene 2 deficiency (MONDO:0000573) is a disease caused by RAG2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: RAG2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 63

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	recombinase activating gene 2 deficiency
Mondo ID	MONDO:0000573
DOID	DOID:0060012
GARD	0022806
Is cancer (heuristic)	no

Also known as: recombinase activating gene 2 deficiency

Data availability: 63 ClinVar variants · 45 ClinGen variant curations · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › recombinase activating gene 2 deficiency

Related subtypes (10): recombinase activating gene 1 deficiency, janus kinase-3 deficiency, T-cell immunodeficiency, congenital alopecia, and nail dystrophy, T-B- severe combined immunodeficiency, severe combined immunodeficiency due to CARMIL2 deficiency, immunodeficiency 79, familial severe combined immunodeficiency, severe combined immunodeficiency due to CD70 deficiency, T-B+ severe combined immunodeficiency, T+ B+ severe combined immunodeficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

63 retrieved; paginated sample, class counts are floors:

21 likely pathogenic, 19 uncertain significance, 8 pathogenic, 6 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 3 benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075544	NM_000536.4(RAG2):c.829dup (p.Tyr277fs)	RAG2	Pathogenic	reviewed by expert panel
13130	NM_000536.4(RAG2):c.686G>A (p.Arg229Gln)	RAG2	Pathogenic	reviewed by expert panel
13131	NM_000536.4(RAG2):c.123C>G (p.Cys41Trp)	RAG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13136	NM_000536.4(RAG2):c.115A>G (p.Arg39Gly)	RAG2	Pathogenic	reviewed by expert panel
13138	NM_000536.4(RAG2):c.1352G>C (p.Gly451Ala)	RAG2	Pathogenic	reviewed by expert panel
1412375	NM_000536.4(RAG2):c.130G>T (p.Gly44Ter)	RAG2	Pathogenic	reviewed by expert panel
1452768	NM_000536.4(RAG2):c.859del (p.Cys287fs)	RAG2	Pathogenic	criteria provided, multiple submitters, no conflicts
36716	NM_000536.4(RAG2):c.104G>C (p.Gly35Ala)	RAG2	Pathogenic	reviewed by expert panel
418453	NM_000536.4(RAG2):c.539C>A (p.Pro180His)	RAG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496618	NM_000536.4(RAG2):c.104G>T (p.Gly35Val)	RAG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496624	NM_000536.4(RAG2):c.685C>T (p.Arg229Trp)	RAG2	Pathogenic	reviewed by expert panel
952544	NM_000536.4(RAG2):c.385_389del (p.Leu129fs)	RAG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13132	NM_000536.4(RAG2):c.854T>G (p.Met285Arg)	RAG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
13133	NM_000536.4(RAG2):c.283G>A (p.Gly95Arg)	RAG2	Likely pathogenic	reviewed by expert panel
13137	NM_000536.4(RAG2):c.230C>A (p.Thr77Asn)	RAG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2019436	NM_000536.4(RAG2):c.3G>A (p.Met1Ile)	RAG2	Likely pathogenic	reviewed by expert panel
36717	NM_000536.4(RAG2):c.1247G>T (p.Trp416Leu)	RAG2	Likely pathogenic	reviewed by expert panel
36718	NM_000536.4(RAG2):c.1309G>A (p.Glu437Lys)	RAG2	Likely pathogenic	reviewed by expert panel
36719	NM_000536.4(RAG2):c.217C>T (p.Arg73Cys)	RAG2	Likely pathogenic	reviewed by expert panel
427020	NM_000536.4(RAG2):c.193G>T (p.Asp65Tyr)	RAG2	Likely pathogenic	reviewed by expert panel
4814220	NM_000536.4(RAG2):c.1324G>A (p.Ala442Thr)	RAG2	Likely pathogenic	criteria provided, single submitter
496619	NM_000536.4(RAG2):c.186C>A (p.Phe62Leu)	RAG2	Likely pathogenic	criteria provided, single submitter
496622	NM_000536.4(RAG2):c.470G>T (p.Gly157Val)	RAG2	Likely pathogenic	criteria provided, single submitter
496623	NM_000536.4(RAG2):c.583T>G (p.Tyr195Asp)	RAG2	Likely pathogenic	criteria provided, single submitter
496626	NM_000536.4(RAG2):c.1320A>C (p.Lys440Asn)	RAG2	Likely pathogenic	criteria provided, single submitter
496627	NM_000536.4(RAG2):c.1329G>T (p.Met443Ile)	RAG2	Likely pathogenic	criteria provided, single submitter
496628	NM_000536.4(RAG2):c.1332C>G (p.Ile444Met)	RAG2	Likely pathogenic	reviewed by expert panel
496629	NM_000536.4(RAG2):c.1338C>G (p.Cys446Trp)	RAG2	Likely pathogenic	reviewed by expert panel
496630	NM_000536.4(RAG2):c.1357T>A (p.Trp453Arg)	RAG2	Likely pathogenic	reviewed by expert panel
496631	NM_000536.4(RAG2):c.1366G>A (p.Ala456Thr)	RAG2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RAG2	Definitive	Autosomal recessive	recombinase activating gene 2 deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAG2	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG2	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG2	Orphanet:39041	Omenn syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAG2	HGNC:9832	ENSG00000175097	P55895	V(D)J recombination-activating protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAG2	V(D)J recombination-activating protein 2	Core component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAG2	Transcription factor	no		RAG2, Znf_FYVE_PHD, Gal_Oxase/kelch_b-propeller

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	1
left lobe of thyroid gland	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAG2	119	tissue_specific	marker	thymus, bone marrow, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAG2	2,319

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAG2	P55895	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-7 signaling	1	317.2×	0.006	RAG2
MAPK6/MAPK4 signaling	1	135.9×	0.007	RAG2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
B cell homeostatic proliferation	1	8426.0×	6e-04	RAG2
pre-B cell allelic exclusion	1	5617.3×	6e-04	RAG2
mature B cell differentiation involved in immune response	1	4213.0×	6e-04	RAG2
DN2 thymocyte differentiation	1	4213.0×	6e-04	RAG2
B cell lineage commitment	1	3370.4×	6e-04	RAG2
T cell lineage commitment	1	3370.4×	6e-04	RAG2
negative regulation of T cell differentiation in thymus	1	2808.7×	7e-04	RAG2
V(D)J recombination	1	2106.5×	8e-04	RAG2
positive regulation of organ growth	1	1404.3×	0.001	RAG2
organ growth	1	732.7×	0.002	RAG2
T cell differentiation in thymus	1	411.0×	0.003	RAG2
B cell differentiation	1	218.9×	0.005	RAG2
defense response to bacterium	1	108.0×	0.009	RAG2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAG2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RAG2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RAG2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.