Autoimmune disease, multisystem, infantile-onset, 3

Summary

Autoimmune disease, multisystem, infantile-onset, 3 (MONDO:0957388) is a disease caused by CBLB (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CBLB (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune disease, multisystem, infantile-onset, 3
Mondo ID	MONDO:0957388
OMIM	620430
DOID	DOID:0061162
UMLS	C5830600
MedGen	1841236
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autoimmune disease, multisystem, infantile-onset › autoimmune disease, multisystem, infantile-onset, 3

Related subtypes (3): STAT3-related early-onset multisystem autoimmune disease, autoimmune disease, multisystem, infantile-onset, 2, autoimmune disease, multisystem, infantile-onset, 5

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

5 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2506976	NM_170662.5(CBLB):c.770A>T (p.His257Leu)	CBLB	Pathogenic	no assertion criteria provided
2506977	NM_170662.5(CBLB):c.1402C>T (p.Arg468Ter)	CBLB	Pathogenic	no assertion criteria provided
2506978	NM_170662.5(CBLB):c.1308C>G (p.Cys436Trp)	CBLB	Pathogenic	no assertion criteria provided
4849425	NM_170662.5(CBLB):c.2689+2del	CBLB	Likely pathogenic	criteria provided, single submitter
3902046	NM_170662.5(CBLB):c.2569+1609A>C	CBLB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 1 · 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
CBLB	Strong	Autosomal recessive	autoimmune disease, multisystem, infantile-onset, 3	2
MMAB	Strong	Autosomal recessive	autoimmune disease, multisystem, infantile-onset, 3	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MMAB	Orphanet:79311	Vitamin B12-responsive methylmalonic acidemia type cblB

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CBLB	HGNC:1542	ENSG00000114423	Q13191	E3 ubiquitin-protein ligase CBL-B	gencc,clinvar
MMAB	HGNC:19331	ENSG00000139428	Q96EY8	Corrinoid adenosyltransferase MMAB	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CBLB	E3 ubiquitin-protein ligase CBL-B	E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome.
MMAB	Corrinoid adenosyltransferase MMAB	Converts cob(I)alamin to adenosylcobalamin (adenosylcob(III)alamin), a coenzyme for methylmalonyl-CoA mutase, therefore participates in the final step of the vitamin B12 conversion.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CBLB	Transcription factor	no		Znf_RING, Adaptor_Cbl_N_hlx, EF-hand-dom_pair
MMAB	Enzyme (other)	yes	2.5.1.17	CblAdoTrfase-like, PduO-typ, CblAdoTrfase-like_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
pericardium	1
right adrenal gland	1
right adrenal gland cortex	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CBLB	274	ubiquitous	marker	pericardium, colonic epithelium, calcaneal tendon
MMAB	235	ubiquitous	marker	right lobe of liver, right adrenal gland cortex, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CBLB	1,158
MMAB	1,121

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CBLB	Q13191	24
MMAB	Q96EY8	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective MMAB causes MMA, cblB type	1	2855.0×	0.005	MMAB
Cobalamin (Cbl) metabolism	1	634.4×	0.009	MMAB
Defects in cobalamin (B12) metabolism	1	407.9×	0.009	MMAB
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	317.2×	0.009	MMAB
Defects in vitamin and cofactor metabolism	1	300.5×	0.009	MMAB
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.026	MMAB
Metabolism of vitamins and cofactors	1	58.3×	0.034	MMAB
Diseases of metabolism	1	40.2×	0.043	MMAB
Class I MHC mediated antigen processing & presentation	1	35.0×	0.044	CBLB
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.074	CBLB
Adaptive Immune System	1	14.9×	0.084	CBLB
Disease	1	6.5×	0.160	MMAB
Immune System	1	6.5×	0.160	CBLB
Metabolism	1	5.8×	0.165	MMAB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation protein catabolic process at postsynapse	1	2808.7×	0.003	CBLB
regulation of platelet-derived growth factor receptor-alpha signaling pathway	1	2808.7×	0.003	CBLB
T cell anergy	1	2106.5×	0.003	CBLB
positive regulation of T cell anergy	1	1404.3×	0.004	CBLB
CD4-positive, alpha-beta T cell proliferation	1	936.2×	0.004	CBLB
cobalamin metabolic process	1	766.0×	0.004	MMAB
negative regulation of CD4-positive, alpha-beta T cell proliferation	1	702.2×	0.004	CBLB
NLS-bearing protein import into nucleus	1	401.2×	0.006	CBLB
negative regulation of epidermal growth factor receptor signaling pathway	1	383.0×	0.006	CBLB
regulation of postsynaptic neurotransmitter receptor internalization	1	312.1×	0.007	CBLB
negative regulation of T cell activation	1	263.3×	0.007	CBLB
negative regulation of T cell receptor signaling pathway	1	183.2×	0.010	CBLB
protein K63-linked ubiquitination	1	133.8×	0.012	CBLB
protein catabolic process	1	118.7×	0.013	CBLB
positive regulation of protein ubiquitination	1	106.7×	0.013	CBLB
positive regulation of protein catabolic process	1	101.5×	0.013	CBLB
T cell receptor signaling pathway	1	75.9×	0.016	CBLB
protein stabilization	1	33.4×	0.035	CBLB
immune response	1	23.5×	0.046	CBLB
intracellular signal transduction	1	19.1×	0.054	CBLB
signal transduction	1	8.0×	0.121	CBLB

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 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
CBLB	0	0
MMAB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CBLB	58	Binding:58
MMAB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMAB	2.5.1.17	corrinoid adenosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	MMAB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CBLB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CBLB	58	—
MMAB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.