Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency

Summary

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency (MONDO:0013954) is a disease caused by IL12B (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IL12B (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 225

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		49	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency
Mondo ID	MONDO:0013954
OMIM	614890
Orphanet	319558
DOID	DOID:0111950
UMLS	C4013948
MedGen	862385
GARD	0012976
Is cancer (heuristic)	no

Also known as: autosomal recessive mendelian susceptibility to mycobacterial diseases due to a complete deficiency caused by mutation in IL12B · IL12B autosomal recessive mendelian susceptibility to mycobacterial diseases due to a complete deficiency · IMD29 · immunodeficiency 29 · immunodeficiency type 29 · Mendelian susceptibility to mycobacterial diseases due to complete interleukin 12B deficiency · MSMD due to complete IL12B deficiency · MSMD due to complete interleukin 12B deficiency

Data availability: 225 ClinVar variants · 4 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 IL12B deficiency

Related subtypes (13): immunodeficiency 27A, Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 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

225 retrieved; paginated sample, class counts are floors:

102 uncertain significance, 85 likely benign, 12 pathogenic, 10 benign, 8 conflicting classifications of pathogenicity, 6 likely pathogenic, 1 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323111	NM_002187.3(IL12B):c.510C>A (p.Cys170Ter)	IL12B	Pathogenic	criteria provided, single submitter
14053	NC_000005.10:g.(159317671_159317673)_(159322312_159322314)del	IL12B	Pathogenic	no assertion criteria provided
14054	NM_002187.3(IL12B):c.320dup (p.Glu108fs)	IL12B	Pathogenic	criteria provided, single submitter
183390	NM_002187.3(IL12B):c.298_305del (p.Ser100fs)	IL12B	Pathogenic	no assertion criteria provided
2424368	NC_000005.9:g.(?158753683)(158753790_?)del	IL12B	Pathogenic	criteria provided, single submitter
2859768	NM_002187.3(IL12B):c.383_386del (p.Thr127_Phe128insTer)	IL12B	Pathogenic	criteria provided, single submitter
2893379	NM_002187.3(IL12B):c.507dup (p.Cys170fs)	IL12B	Pathogenic	criteria provided, single submitter
3663107	NM_002187.3(IL12B):c.862dup (p.Arg288fs)	IL12B	Pathogenic	criteria provided, single submitter
4734468	NM_002187.3(IL12B):c.130G>T (p.Glu44Ter)	IL12B	Pathogenic	criteria provided, single submitter
571326	NM_002187.3(IL12B):c.259C>T (p.Gln87Ter)	IL12B	Pathogenic	criteria provided, single submitter
632459	NM_002187.3(IL12B):c.660T>A (p.Tyr220Ter)	IL12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
847134	NM_002187.3(IL12B):c.30G>A (p.Trp10Ter)	IL12B	Pathogenic	criteria provided, single submitter
970534	NM_002187.3(IL12B):c.900C>A (p.Cys300Ter)	IL12B	Pathogenic	criteria provided, single submitter
1366710	NM_002187.3(IL12B):c.697+5G>A	IL12B	Likely pathogenic	criteria provided, single submitter
2701815	NM_002187.3(IL12B):c.364+1G>T	IL12B	Likely pathogenic	criteria provided, single submitter
3383385	NM_002187.3(IL12B):c.527_528del (p.Ser176fs)	IL12B	Likely pathogenic	criteria provided, single submitter
3779762	NM_002187.3(IL12B):c.855+1G>A	IL12B	Likely pathogenic	criteria provided, single submitter
4071541	NM_002187.3(IL12B):c.282dup (p.Glu95fs)	IL12B	Likely pathogenic	criteria provided, single submitter
4278399	NM_002187.3(IL12B):c.179G>A (p.Trp60Ter)	IL12B	Likely pathogenic	criteria provided, single submitter
352571	NM_002187.3(IL12B):c.960C>T (p.Ser320=)	IL12B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352577	NM_002187.3(IL12B):c.300G>A (p.Ser100=)	IL12B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
474972	NM_002187.3(IL12B):c.506C>T (p.Thr169Met)	IL12B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541814	NM_002187.3(IL12B):c.283G>A (p.Glu95Lys)	IL12B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541815	NM_002187.3(IL12B):c.749G>A (p.Arg250Gln)	IL12B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904894	NM_002187.3(IL12B):c.822C>T (p.Cys274=)	IL12B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904895	NM_002187.3(IL12B):c.643G>A (p.Val215Ile)	IL12B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906497	NM_002187.3(IL12B):c.105G>A (p.Leu35=)	IL12B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1005516	NM_002187.3(IL12B):c.382T>A (p.Phe128Ile)	IL12B	Uncertain significance	criteria provided, single submitter
1007074	NM_002187.3(IL12B):c.149G>A (p.Cys50Tyr)	IL12B	Uncertain significance	criteria provided, single submitter
1018823	NM_002187.3(IL12B):c.634G>C (p.Val212Leu)	IL12B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
IL12B	Definitive	Autosomal recessive	Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL12B	Orphanet:319558	Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency
IL12B	Orphanet:3287	Takayasu arteritis

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
IL12B	HGNC:5970	ENSG00000113302	P29460	Interleukin-12 subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL12B	Interleukin-12 subunit beta	Cytokine that can act as a growth factor for activated T and NK cells, enhance the lytic activity of NK/lymphokine-activated killer cells, and stimulate the production of IFN-gamma by resting PBMC.

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)
IL12B	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_L_F3_CS, Ig_sub2, FN3_dom

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
decidua	1
hair follicle	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL12B	33	tissue_specific	marker	primordial germ cell in gonad, decidua, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL12B	804

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL12B	P29460	20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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×	0.003	IL12B
Interleukin-12 signaling	1	407.9×	0.005	IL12B
Interleukin-10 signaling	1	233.1×	0.006	IL12B
Interleukin-4 and Interleukin-13 signaling	1	102.9×	0.010	IL12B

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
positive regulation of mononuclear cell proliferation	1	4213.0×	0.002	IL12B
T-helper cell differentiation	1	3370.4×	0.002	IL12B
positive regulation of NK T cell activation	1	3370.4×	0.002	IL12B
positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target	1	2808.7×	0.002	IL12B
positive regulation of tissue remodeling	1	2808.7×	0.002	IL12B
positive regulation of NK T cell proliferation	1	2808.7×	0.002	IL12B
positive regulation of smooth muscle cell apoptotic process	1	2407.4×	0.002	IL12B
positive regulation of natural killer cell activation	1	2106.5×	0.002	IL12B
negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	2106.5×	0.002	IL12B
positive regulation of T-helper 17 cell lineage commitment	1	2106.5×	0.002	IL12B
response to UV-B	1	1872.4×	0.002	IL12B
interleukin-12-mediated signaling pathway	1	1872.4×	0.002	IL12B
T-helper 1 type immune response	1	1872.4×	0.002	IL12B
positive regulation of memory T cell differentiation	1	1872.4×	0.002	IL12B
positive regulation of lymphocyte proliferation	1	1872.4×	0.002	IL12B
positive regulation of T-helper 1 type immune response	1	1685.2×	0.002	IL12B
positive regulation of natural killer cell proliferation	1	1404.3×	0.002	IL12B
positive regulation of T-helper 17 type immune response	1	1404.3×	0.002	IL12B
negative regulation of vascular endothelial growth factor signaling pathway	1	1296.3×	0.002	IL12B
negative regulation of interleukin-17 production	1	1053.2×	0.002	IL12B
natural killer cell activation involved in immune response	1	991.3×	0.002	IL12B
positive regulation of granulocyte macrophage colony-stimulating factor production	1	991.3×	0.002	IL12B
oocyte development	1	936.2×	0.002	IL12B
negative regulation of protein secretion	1	887.0×	0.002	IL12B
negative regulation of interleukin-10 production	1	732.7×	0.003	IL12B
positive regulation of activated T cell proliferation	1	674.1×	0.003	IL12B
negative regulation of smooth muscle cell proliferation	1	624.1×	0.003	IL12B
negative regulation of inflammatory response to antigenic stimulus	1	601.9×	0.003	IL12B
positive regulation of interleukin-17 production	1	601.9×	0.003	IL12B
defense response to protozoan	1	601.9×	0.003	IL12B

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
IL12B	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	1	IL12B
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)
IL12B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.