CBL-related disorder

Summary

CBL-related disorder (MONDO:0013308) is a disease caused by CBL (GenCC Definitive), with 4 cohort genes and 1 clinical trial. Top therapeutic interventions include fludarabine phosphate.

At a glance

• Causal gene: CBL (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 414
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	CBL-related disorder
Mondo ID	MONDO:0013308
OMIM	613563
Orphanet	363972
UMLS	C3150803
MedGen	462153
GARD	0017577
Is cancer (heuristic)	no

Also known as: Cbl syndrome · CBL-related disorder · Noonan syndrome-like disorder with JMML · Noonan syndrome-like disorder with juvenile myelomonocytic leukaemia · Noonan syndrome-like disorder with juvenile myelomonocytic leukemia · Noonan syndrome-like disorder with or without juvenile myelomonocytic leukaemia · Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia · Noonan-like syndrome · NSLL

Data availability: 414 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › RASopathy › CBL-related disorder

Related subtypes (3): neurofibromatosis-Noonan syndrome, neurofibromatosis type 1, Noonan syndrome and Noonan-related syndrome

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

414 retrieved; paginated sample, class counts are floors:

225 uncertain significance, 64 benign, 57 conflicting classifications of pathogenicity, 28 likely benign, 24 benign/likely benign, 9 pathogenic/likely pathogenic, 5 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13807	NM_005188.4(CBL):c.1100A>C (p.Gln367Pro)	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13809	NM_005188.4(CBL):c.1168G>T (p.Asp390Tyr)	CBL	Pathogenic	no assertion criteria provided
13811	NM_005188.4(CBL):c.1111T>C (p.Tyr371His)	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177959	NM_005188.4(CBL):c.1228-2A>G	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180815	NM_005188.4(CBL):c.1096-1G>T	CBL	Pathogenic	criteria provided, multiple submitters, no conflicts
180827	NM_005188.4(CBL):c.1111T>A (p.Tyr371Asn)	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137268	NM_005188.4(CBL):c.1111T>G (p.Tyr371Asp)	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40401	NM_005188.4(CBL):c.306T>G (p.Tyr102Ter)	CBL	Pathogenic	criteria provided, single submitter
45196	NM_005188.4(CBL):c.1096-1G>C	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
45197	NM_005188.4(CBL):c.1096-4_1096-1del	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523667	NM_005188.4(CBL):c.1099_1101del (p.Gln367del)	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
548022	NM_005188.4(CBL):c.1112A>C (p.Tyr371Ser)	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689750	NM_005188.4(CBL):c.1096-2A>T	CBL	Pathogenic	criteria provided, multiple submitters, no conflicts
13328	NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)	PTPN11	Pathogenic	reviewed by expert panel
1700195	NM_005188.4(CBL):c.1007+2T>A	CBL	Likely pathogenic	criteria provided, single submitter
3033769	NM_005188.4(CBL):c.1096-6_1101delinsATTATGAATTTTTTTAAAT	CBL	Likely pathogenic	no assertion criteria provided
1338196	NM_005188.4(CBL):c.660G>A (p.Glu220=)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1352881	NM_005188.4(CBL):c.1193A>G (p.His398Arg)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1354447	NM_005188.4(CBL):c.2086G>A (p.Glu696Lys)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1380621	NM_005188.4(CBL):c.1455C>G (p.Phe485Leu)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13808	NM_005188.4(CBL):c.1144A>G (p.Lys382Glu)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13810	NM_005188.4(CBL):c.1259G>A (p.Arg420Gln)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1396535	NM_005188.4(CBL):c.1028G>A (p.Arg343Gln)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
140455	NM_005188.4(CBL):c.1228-1G>A	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1549482	NM_005188.4(CBL):c.2034C>T (p.Ala678=)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178012	NM_005188.4(CBL):c.2359C>T (p.Arg787Cys)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179116	NM_005188.4(CBL):c.1754G>T (p.Arg585Leu)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180808	NM_005188.4(CBL):c.107ACC[6] (p.His42del)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180809	NM_005188.4(CBL):c.1829C>A (p.Thr610Lys)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180810	NM_005188.4(CBL):c.2062C>T (p.Pro688Ser)	CBL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 8 · 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
CBL	Definitive	Autosomal dominant	CBL-related disorder	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CBL	Orphanet:363972	Noonan syndrome-like disorder with juvenile myelomonocytic leukemia
CBL	Orphanet:648	Noonan syndrome
CBL	Orphanet:86834	Juvenile myelomonocytic leukemia
CBL	Orphanet:98850	Aggressive systemic mastocytosis
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CBL	HGNC:1541	ENSG00000110395	P22681	E3 ubiquitin-protein ligase CBL	gencc,clinvar
KIFC2	HGNC:29530	ENSG00000167702	Q96AC6	Kinesin-like protein KIFC2	clinvar
FRA11B	HGNC:3837			fragile site, folic acid type, rare, fra(11)(q23.3)	clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CBL	E3 ubiquitin-protein ligase CBL	E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors.
KIFC2	Kinesin-like protein KIFC2	May play a role in microtubule-dependent retrograde axonal transport.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Phosphatase	1	21.0×	0.141
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CBL	Transcription factor	no	2.3.2.27	Znf_RING, Adaptor_Cbl_N_hlx, UBA-like_sf
KIFC2	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
FRA11B	Other/Unknown	no
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2

Expression context

Cohort genes with no expression data: 1.

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)	3
unknown	1

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
trigeminal ganglion	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
dorsal motor nucleus of vagus nerve	1
globus pallidus	1
medial globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CBL	271	ubiquitous	marker	primordial germ cell in gonad, trigeminal ganglion, male germ line stem cell (sensu Vertebrata) in testis
KIFC2	225	ubiquitous	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
FRA11B
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTPN11	6,009
CBL	4,575
KIFC2	2,329
FRA11B	0

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPN11	Q06124	115
CBL	P22681	33

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KIFC2	Q96AC6	63.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 99. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-6 signaling	2	634.4×	3e-04	CBL, PTPN11
Spry regulation of FGF signaling	2	475.8×	3e-04	CBL, PTPN11
Negative regulation of FGFR3 signaling	2	292.8×	3e-04	CBL, PTPN11
Negative regulation of FGFR4 signaling	2	271.9×	3e-04	CBL, PTPN11
Negative regulation of FGFR1 signaling	2	245.6×	3e-04	CBL, PTPN11
Negative regulation of FGFR2 signaling	2	245.6×	3e-04	CBL, PTPN11
FLT3 Signaling	2	230.7×	3e-04	CBL, PTPN11
Signaling by CSF1 (M-CSF) in myeloid cells	2	230.7×	3e-04	CBL, PTPN11
Interleukin-3, Interleukin-5 and GM-CSF signaling	2	211.5×	3e-04	CBL, PTPN11
Signaling by SCF-KIT	2	165.5×	5e-04	CBL, PTPN11
Signaling by EGFRvIII in Cancer	1	761.3×	0.010	CBL
MET activates PTPN11	1	761.3×	0.010	PTPN11
Co-inhibition by BTLA	1	761.3×	0.010	PTPN11
Signaling by Ligand-Responsive EGFR Variants in Cancer	1	634.4×	0.010	CBL
STAT5 Activation	1	543.8×	0.010	PTPN11
FLT3 signaling by CBL mutants	1	543.8×	0.010	CBL
Interleukin-6 family signaling	1	475.8×	0.010	CBL
Netrin mediated repulsion signals	1	423.0×	0.010	PTPN11
PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1	1	423.0×	0.010	CBL
MAPK1 (ERK2) activation	1	380.7×	0.010	PTPN11
Signaling by EGFR in Cancer	1	380.7×	0.010	CBL
Signaling by FGFR3	1	380.7×	0.010	CBL
FLT3 signaling in disease	1	380.7×	0.010	CBL
STAT5 activation downstream of FLT3 ITD mutants	1	380.7×	0.010	PTPN11
MAPK3 (ERK1) activation	1	346.1×	0.010	PTPN11
Signaling by Leptin	1	346.1×	0.010	PTPN11
Signaling by FGFR4	1	346.1×	0.010	CBL
Listeria monocytogenes entry into host cells	1	346.1×	0.010	CBL
Membrane Trafficking	2	24.7×	0.010	CBL, KIFC2
Vesicle-mediated transport	2	23.2×	0.010	CBL, KIFC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of T cell activation	2	351.1×	9e-04	CBL, PTPN11
negative regulation of T cell receptor signaling pathway	2	244.2×	9e-04	CBL, PTPN11
negative regulation of cortisol secretion	1	5617.3×	0.003	PTPN11
negative regulation of growth hormone secretion	1	5617.3×	0.003	PTPN11
cytokine-mediated signaling pathway	2	87.1×	0.003	CBL, PTPN11
microvillus organization	1	2808.7×	0.004	PTPN11
intestinal epithelial cell migration	1	2808.7×	0.004	PTPN11
cerebellar cortex formation	1	1872.4×	0.005	PTPN11
regulation of platelet-derived growth factor receptor-alpha signaling pathway	1	1872.4×	0.005	CBL
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	2	52.2×	0.005	CBL, PTPN11
regulation of Rap protein signal transduction	1	1404.3×	0.005	CBL
regulation of type I interferon-mediated signaling pathway	1	1404.3×	0.005	PTPN11
ERBB signaling pathway	1	1123.5×	0.006	PTPN11
anterograde dendritic transport of neurotransmitter receptor complex	1	802.5×	0.007	KIFC2
negative regulation of neutrophil activation	1	802.5×	0.007	PTPN11
ubiquitin-dependent endocytosis	1	624.1×	0.008	CBL
positive regulation of hormone secretion	1	561.7×	0.008	PTPN11
genitalia development	1	561.7×	0.008	PTPN11
positive regulation of lipopolysaccharide-mediated signaling pathway	1	510.7×	0.008	PTPN11
atrioventricular canal development	1	510.7×	0.008	PTPN11
regulation of protein export from nucleus	1	510.7×	0.008	PTPN11
Bergmann glial cell differentiation	1	510.7×	0.008	PTPN11
negative regulation of cell adhesion mediated by integrin	1	432.1×	0.009	PTPN11
neurotrophin TRK receptor signaling pathway	1	351.1×	0.010	PTPN11
positive regulation of ossification	1	312.1×	0.011	PTPN11
peptidyl-tyrosine dephosphorylation	1	295.6×	0.011	PTPN11
hormone metabolic process	1	295.6×	0.011	PTPN11
positive regulation of insulin receptor signaling pathway	1	280.9×	0.011	PTPN11
synaptic vesicle transport	1	280.9×	0.011	KIFC2
positive regulation of receptor-mediated endocytosis	1	267.5×	0.011	CBL

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PTPN11	8	4
CBL	0	0
KIFC2	0	0
FRA11B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ESTRAMUSTINE PHOSPHATE	4	PTPN11
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
JAB-3068	1	PTPN11
PF-07284892	1	PTPN11
BBP-398	1	PTPN11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PTPN11	588	Binding:585, Functional:2, ADMET:1
CBL	4	Binding:2, Toxicity:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CBL	2.3.2.27	RING-type E3 ubiquitin transferase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

8 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.

Compound	Max phase	Cohort target (bioactivity)
ESTRAMUSTINE PHOSPHATE	4	PTPN11
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
JAB-3068	1	PTPN11
PF-07284892	1	PTPN11
BBP-398	1	PTPN11

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PTPN11
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	3	CBL, KIFC2, FRA11B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CBL	4	—
KIFC2	0	—
FRA11B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05849662	PHASE1/PHASE2	RECRUITING	A Phase I/II Study of Trametinib and Azacitidine for Patients With Newly Diagnosed Juvenile Myelomonocytic Leukemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	1