combined immunodeficiency due to partial RAG1 deficiency

Summary

combined immunodeficiency due to partial RAG1 deficiency (MONDO:0012359) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 121
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0004430	Severe combined immunodeficiency	Very frequent (80-99%)
HP:0005403	Decreased total T cell count	Very frequent (80-99%)
HP:0006515	Interstitial pneumonitis	Very frequent (80-99%)
HP:0010976	Decreased total B cell count	Very frequent (80-99%)
HP:0100806	Sepsis	Very frequent (80-99%)
HP:0001890	Autoimmune hemolytic anemia	Frequent (30-79%)
HP:0001904	Neutropenia in presence of anti-neutropil antibodies	Frequent (30-79%)
HP:0002960	Autoimmunity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency due to partial RAG1 deficiency
Mondo ID	MONDO:0012359
MeSH	C563691
OMIM	609889
Orphanet	231154
SNOMED CT	725290000
UMLS	C1835931
MedGen	372161
GARD	0013712
Is cancer (heuristic)	no

Also known as: CID due to partial RAG1 deficiency · CID with expansion of gamma delta T cells · combined immunodeficiency with expansion of gamma delta T cells

Data availability: 121 ClinVar variants · 1 GenCC gene-disease record.

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 › T-B- severe combined immunodeficiency › combined immunodeficiency due to partial RAG1 deficiency

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, short-limb skeletal dysplasia with severe combined immunodeficiency, combined immunodeficiency with skin granulomas, reticular dysgenesis, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, Omenn syndrome, DNA ligase IV deficiency, neutrophil immunodeficiency syndrome, Cernunnos-XLF deficiency, severe combined immunodeficiency due to LCK deficiency, severe combined immunodeficiency due to DNA-PKcs deficiency, immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, reticular dysgenesis-like 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

121 retrieved; paginated sample, class counts are floors:

35 pathogenic/likely pathogenic, 28 pathogenic, 28 likely pathogenic, 17 uncertain significance, 11 conflicting classifications of pathogenicity, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
624578	NM_000448.2(RAG1):c.[1213A>G;1871G>A]		Pathogenic	no assertion criteria provided
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
1075542	NM_000448.3(RAG1):c.2867T>C (p.Ile956Thr)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13139	NM_000448.3(RAG1):c.2164G>A (p.Glu722Lys)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13140	NM_000448.3(RAG1):c.2320G>T (p.Glu774Ter)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13143	NM_000448.3(RAG1):c.1682G>A (p.Arg561His)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13144	NM_000448.3(RAG1):c.1186C>T (p.Arg396Cys)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
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
13149	NM_000448.3(RAG1):c.2210G>A (p.Arg737His)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13150	NM_000448.3(RAG1):c.1612_1624del (p.Ile538fs)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13154	NM_000448.3(RAG1):c.2521C>T (p.Arg841Trp)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13155	NM_000448.3(RAG1):c.2942A>C (p.Gln981Pro)	RAG1	Pathogenic	no assertion criteria provided
13156	NM_000448.3(RAG1):c.940C>T (p.Arg314Trp)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13158	NM_000448.3(RAG1):c.2333G>A (p.Arg778Gln)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13159	NM_000448.3(RAG1):c.2923C>T (p.Arg975Trp)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13160	NM_000448.3(RAG1):c.983G>A (p.Cys328Tyr)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13161	NM_000448.3(RAG1):c.2326C>T (p.Arg776Trp)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323517	NM_000448.3(RAG1):c.2850del (p.Ile950fs)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1704499	NM_000448.3(RAG1):c.2327G>A (p.Arg776Gln)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1997718	NM_000448.3(RAG1):c.539G>A (p.Trp180Ter)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2095853	NM_000448.3(RAG1):c.1366del (p.Ala456fs)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137056	NM_000448.3(RAG1):c.2522G>A (p.Arg841Gln)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2160473	NM_000448.3(RAG1):c.1501C>T (p.Gln501Ter)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235297	NM_000448.3(RAG1):c.2005G>A (p.Glu669Lys)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235411	NM_000448.3(RAG1):c.775del (p.Ser259fs)	RAG1	Pathogenic	reviewed by expert panel
2506198	NM_000448.3(RAG1):c.2209C>T (p.Arg737Cys)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678195	NM_000448.3(RAG1):c.2615T>A (p.Leu872Ter)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
2678201	NM_000448.3(RAG1):c.736_737delinsA (p.Ala246fs)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

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	immunodeficiency disease	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.