Recombinase activating gene 1 deficiency

Summary

Recombinase activating gene 1 deficiency (MONDO:0000572) is a disease caused by RAG1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: RAG1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 46

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	recombinase activating gene 1 deficiency
Mondo ID	MONDO:0000572
DOID	DOID:0060011
GARD	0022805
Is cancer (heuristic)	no

Also known as: recombinase activating gene 1 deficiency

Data availability: 46 ClinVar variants · 52 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 1 deficiency

Related subtypes (10): recombinase activating gene 2 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

46 retrieved; paginated sample, class counts are floors:

17 uncertain significance, 14 pathogenic, 9 benign, 3 likely pathogenic, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1034220	NM_000448.3(RAG1):c.2487_2488delinsTT (p.Arg829_Lys830delinsSerTer)	RAG1	Pathogenic	reviewed by expert panel
1072413	NM_000448.3(RAG1):c.1211G>A (p.Arg404Gln)	RAG1	Pathogenic	reviewed by expert panel
13146	NM_000448.3(RAG1):c.1187G>A (p.Arg396His)	RAG1	Pathogenic	reviewed by expert panel
13148	NM_000448.3(RAG1):c.1681C>T (p.Arg561Cys)	RAG1	Pathogenic	reviewed by expert panel
235411	NM_000448.3(RAG1):c.775del (p.Ser259fs)	RAG1	Pathogenic	reviewed by expert panel
285045	NM_000448.3(RAG1):c.256_257del (p.Lys86fs)	RAG1	Pathogenic	reviewed by expert panel
2943710	NM_000448.3(RAG1):c.612G>A (p.Trp204Ter)	RAG1	Pathogenic	reviewed by expert panel
36714	NM_000448.3(RAG1):c.322C>T (p.Arg108Ter)	RAG1	Pathogenic	reviewed by expert panel
449383	NM_000448.3(RAG1):c.999T>A (p.Tyr333Ter)	RAG1	Pathogenic	reviewed by expert panel
4845208	NM_000448.3(RAG1):c.2930del (p.Met977fs)	RAG1	Pathogenic	reviewed by expert panel
488725	NM_000448.3(RAG1):c.2689C>T (p.Arg897Ter)	RAG1	Pathogenic	reviewed by expert panel
626157	NM_000448.3(RAG1):c.424C>T (p.Arg142Ter)	RAG1	Pathogenic	reviewed by expert panel
68681	NM_000448.3(RAG1):c.1331C>T (p.Ala444Val)	RAG1	Pathogenic	reviewed by expert panel
967900	NM_000448.3(RAG1):c.2877G>A (p.Trp959Ter)	RAG1	Pathogenic	reviewed by expert panel
13141	NM_000448.3(RAG1):c.2814T>G (p.Tyr938Ter)	RAG1	Likely pathogenic	reviewed by expert panel
418448	NM_000448.3(RAG1):c.2147G>A (p.Arg716Gln)	RAG1	Likely pathogenic	reviewed by expert panel
68689	NM_000448.3(RAG1):c.2095C>T (p.Arg699Trp)	RAG1	Likely pathogenic	reviewed by expert panel
1050623	NM_000448.3(RAG1):c.2291G>A (p.Arg764His)	RAG1	Uncertain significance	reviewed by expert panel
1348464	NM_000448.3(RAG1):c.40G>A (p.Ala14Thr)	RAG1	Uncertain significance	reviewed by expert panel
1515226	NM_000448.3(RAG1):c.29G>T (p.Gly10Val)	RAG1	Uncertain significance	reviewed by expert panel
2079766	NM_000448.3(RAG1):c.86A>G (p.Lys29Arg)	RAG1	Uncertain significance	reviewed by expert panel
2098676	NM_000448.3(RAG1):c.17C>T (p.Pro6Leu)	RAG1	Uncertain significance	reviewed by expert panel
2269371	NM_000448.3(RAG1):c.76T>C (p.Ser26Pro)	RAG1	Uncertain significance	reviewed by expert panel
304491	NM_000448.3(RAG1):c.1A>G (p.Met1Val)	RAG1	Uncertain significance	reviewed by expert panel
304492	NM_000448.3(RAG1):c.37T>G (p.Ser13Ala)	RAG1	Uncertain significance	reviewed by expert panel
36712	NM_000448.3(RAG1):c.2603C>T (p.Ala868Val)	RAG1	Uncertain significance	reviewed by expert panel
36713	NM_000448.3(RAG1):c.2904C>A (p.Asn968Lys)	RAG1	Uncertain significance	reviewed by expert panel
372487	NM_000448.3(RAG1):c.527G>T (p.Cys176Phe)	RAG1	Uncertain significance	reviewed by expert panel
418449	NM_000448.3(RAG1):c.2442G>T (p.Glu814Asp)	RAG1	Uncertain significance	reviewed by expert panel
418451	NM_000448.3(RAG1):c.2690G>A (p.Arg897Gln)	RAG1	Uncertain significance	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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
RAG1	Definitive	Autosomal recessive	recombinase activating gene 1 deficiency	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAG1	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG1	Orphanet:231154	Combined immunodeficiency due to partial RAG1 deficiency
RAG1	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG1	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
RAG1	HGNC:9831	ENSG00000166349	P15918	V(D)J recombination-activating protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAG1	V(D)J recombination-activating protein 1	Catalytic 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)
RAG1	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS

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
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAG1	164	broad	marker	thymus, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAG1	3,549

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAG1	P15918	81.68

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	RAG1
MAPK6/MAPK4 signaling	1	135.9×	0.007	RAG1

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
pre-B cell allelic exclusion	1	5617.3×	0.002	RAG1
regulation of behavioral fear response	1	4213.0×	0.002	RAG1
V(D)J recombination	1	2106.5×	0.002	RAG1
negative regulation of thymocyte apoptotic process	1	1685.2×	0.002	RAG1
T cell homeostasis	1	455.5×	0.005	RAG1
positive regulation of T cell differentiation	1	455.5×	0.005	RAG1
T cell differentiation in thymus	1	411.0×	0.005	RAG1
DNA recombination	1	337.0×	0.005	RAG1
thymus development	1	337.0×	0.005	RAG1
visual learning	1	306.4×	0.005	RAG1
protein autoubiquitination	1	234.1×	0.006	RAG1
B cell differentiation	1	218.9×	0.006	RAG1
chromatin organization	1	99.1×	0.012	RAG1
adaptive immune response	1	84.3×	0.013	RAG1
immune response	1	47.1×	0.021	RAG1

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
RAG1	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	RAG1

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)
RAG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.