Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Summary

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (MONDO:0013955) is a disease caused by IL12RB1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IL12RB1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 583
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		180	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0011117	Abnormal circulating interleukin concentration	Very frequent (80-99%)
HP:0011274	Recurrent mycobacterial infections	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0020087	BCGosis	Very frequent (80-99%)
HP:0032283	Disseminated nontuberculous mycobacterial infection	Frequent (30-79%)
HP:0005401	Recurrent candida infections	Frequent (30-79%)
HP:0002840	Lymphadenitis	Frequent (30-79%)
HP:0005661	Salmonella osteomyelitis	Occasional (5-29%)
HP:0007408	Tegumentary leishmaniasis susceptibility	Occasional (5-29%)
HP:0002090	Pneumonia	Occasional (5-29%)
HP:0200029	Vasculitis in the skin	Very rare (<1-4%)
HP:0002742	Recurrent Klebsiella infections	Very rare (<1-4%)
HP:0032256	Histoplasmosis	Very rare (<1-4%)
HP:0032249	Coccidioidomycosis	Very rare (<1-4%)
HP:0020105	Severe toxoplasmosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency
Mondo ID	MONDO:0013955
OMIM	614891
Orphanet	319552
DOID	DOID:0111990
UMLS	C4013949
MedGen	862386
GARD	0010984
Is cancer (heuristic)	no

Also known as: autosomal recessive mendelian susceptibility to mycobacterial diseases due to a complete deficiency caused by mutation in IL12RB1 · IL-12Râ1 deficiency · IL12RB1 autosomal recessive mendelian susceptibility to mycobacterial diseases due to a complete deficiency · IMD30 · immunodeficiency 30 · immunodeficiency type 30 · Mendelian susceptibility to interleukin 12 receptor beta 1 deficiency · Mendelian susceptibility to mycobacterial infections due to IL12 deficiency · MSMD due to complete IL12RB1 deficiency · MSMD due to complete interleukin 12 receptor beta 1 deficiency

Data availability: 583 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › inherited susceptibility to mycobacterial diseases › Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Related subtypes (13): immunodeficiency 27A, Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency, Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency, Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency, autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency, X-linked Mendelian susceptibility to mycobacterial diseases, Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency, Mendelian susceptibility to mycobacterial diseases due to a complete deficiency, Mendelian susceptibility to mycobacterial diseases due to a partial deficiency

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

583 retrieved; paginated sample, class counts are floors:

220 likely benign, 216 uncertain significance, 60 pathogenic, 41 conflicting classifications of pathogenicity, 23 benign, 14 likely pathogenic, 7 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075342	NM_005535.3(IL12RB1):c.1495C>T (p.Gln499Ter)	IL12RB1	Pathogenic	criteria provided, single submitter
1076653	NM_005535.3(IL12RB1):c.1456C>T (p.Arg486Ter)	IL12RB1	Pathogenic	criteria provided, single submitter
1321308	NM_005535.3(IL12RB1):c.369dup (p.Glu124fs)	IL12RB1	Pathogenic	no assertion criteria provided
1324575	NM_005535.3(IL12RB1):c.599del (p.Leu200fs)	IL12RB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339542	NM_005535.3(IL12RB1):c.517C>T (p.Arg173Trp)	IL12RB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1375086	NM_005535.3(IL12RB1):c.635G>A (p.Arg212Gln)	IL12RB1	Pathogenic	criteria provided, single submitter
1405092	NM_005535.3(IL12RB1):c.493C>T (p.Gln165Ter)	IL12RB1	Pathogenic	criteria provided, single submitter
1452269	NM_005535.3(IL12RB1):c.1398G>A (p.Trp466Ter)	IL12RB1	Pathogenic	criteria provided, single submitter
1455005	NM_005535.3(IL12RB1):c.790C>T (p.Gln264Ter)	IL12RB1	Pathogenic	criteria provided, single submitter
1456084	NC_000019.9:g.(?18177332)(18177527_?)del	IL12RB1	Pathogenic	criteria provided, single submitter
1456856	NM_005535.3(IL12RB1):c.699del (p.Glu234fs)	IL12RB1	Pathogenic	criteria provided, single submitter
1456899	NM_005535.3(IL12RB1):c.942C>A (p.Tyr314Ter)	IL12RB1	Pathogenic	criteria provided, single submitter
1526194	NM_005535.3(IL12RB1):c.1561C>T (p.Arg521Ter)	IL12RB1	Pathogenic	criteria provided, multiple submitters, no conflicts
155909	NM_005535.3(IL12RB1):c.1061CCA[1] (p.Thr355del)	IL12RB1	Pathogenic	no assertion criteria provided
1687504	NM_005535.3(IL12RB1):c.1238_1239del (p.Cys413fs)	IL12RB1	Pathogenic	criteria provided, single submitter
2015497	NM_005535.3(IL12RB1):c.1690dup (p.Val564fs)	IL12RB1	Pathogenic	criteria provided, single submitter
2094134	NM_005535.3(IL12RB1):c.395_398dup (p.Tyr134fs)	IL12RB1	Pathogenic	criteria provided, single submitter
2097232	NM_005535.3(IL12RB1):c.1327+1del	IL12RB1	Pathogenic	criteria provided, single submitter
2098924	NM_005535.3(IL12RB1):c.304C>T (p.Gln102Ter)	IL12RB1	Pathogenic	criteria provided, single submitter
2138260	NM_005535.3(IL12RB1):c.64+2T>G	IL12RB1	Pathogenic	criteria provided, multiple submitters, no conflicts
2425363	NC_000019.9:g.(?18171912)(18177527_?)del	IL12RB1	Pathogenic	criteria provided, single submitter
2736848	NM_005535.3(IL12RB1):c.1386_1387del (p.Ser463fs)	IL12RB1	Pathogenic	criteria provided, single submitter
2736850	NM_005535.3(IL12RB1):c.64+1G>T	IL12RB1	Pathogenic	criteria provided, single submitter
2786378	NM_005535.3(IL12RB1):c.1897G>T (p.Glu633Ter)	IL12RB1	Pathogenic	criteria provided, single submitter
2812854	NM_005535.3(IL12RB1):c.1791+1G>C	IL12RB1	Pathogenic	criteria provided, single submitter
2908739	NM_005535.3(IL12RB1):c.946del (p.Val316fs)	IL12RB1	Pathogenic	criteria provided, single submitter
3613722	NM_005535.3(IL12RB1):c.1207C>T (p.Arg403Ter)	IL12RB1	Pathogenic	criteria provided, single submitter
3696660	NM_005535.3(IL12RB1):c.1593G>A (p.Trp531Ter)	IL12RB1	Pathogenic	criteria provided, single submitter
3703921	NM_005535.3(IL12RB1):c.1879G>T (p.Glu627Ter)	IL12RB1	Pathogenic	criteria provided, single submitter
3712614	NM_005535.3(IL12RB1):c.1202G>A (p.Trp401Ter)	IL12RB1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · 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
IL12RB1	Strong	Autosomal recessive	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL12RB1	Orphanet:186	Primary biliary cholangitis
IL12RB1	Orphanet:319552	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

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
IL12RB1	HGNC:5971	ENSG00000096996	P42701	Interleukin-12 receptor subunit beta-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL12RB1	Interleukin-12 receptor subunit beta-1	Functions as an interleukin receptor which binds interleukin-12 with low affinity and is involved in IL12 transduction.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL12RB1	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_Gp130_CS, FN3_dom, Ig-like_fold

Expression context

Cohort genes with no expression data: 0.

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
blood	1
granulocyte	1
leukocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL12RB1	177	broad	yes	granulocyte, leukocyte, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL12RB1	2,259

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL12RB1	P42701	7

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-23 signaling	1	1268.9×	0.002	IL12RB1
Interleukin-12 signaling	1	407.9×	0.002	IL12RB1

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
interleukin-23-mediated signaling pathway	1	2808.7×	0.002	IL12RB1
positive regulation of T-helper 17 cell lineage commitment	1	2106.5×	0.002	IL12RB1
interleukin-12-mediated signaling pathway	1	1872.4×	0.002	IL12RB1
positive regulation of memory T cell differentiation	1	1872.4×	0.002	IL12RB1
positive regulation of T-helper 1 type immune response	1	1685.2×	0.002	IL12RB1
positive regulation of T-helper 17 type immune response	1	1404.3×	0.002	IL12RB1
positive regulation of activated T cell proliferation	1	674.1×	0.003	IL12RB1
positive regulation of defense response to virus by host	1	526.6×	0.003	IL12RB1
positive regulation of T cell mediated cytotoxicity	1	510.7×	0.003	IL12RB1
positive regulation of type II interferon production	1	224.7×	0.006	IL12RB1
cellular response to type II interferon	1	208.1×	0.006	IL12RB1
cytokine-mediated signaling pathway	1	130.6×	0.009	IL12RB1
positive regulation of cell population proliferation	1	33.6×	0.032	IL12RB1
signal transduction	1	16.1×	0.062	IL12RB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL12RB1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
IL12RB1	2	Binding:2

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	1	IL12RB1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
IL12RB1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.