CBL

Chr 11

Cbl proto-oncogene

NCBI Gene: 867 ENSG00000110395 UniProt: P22681

The protein functions as a RING finger E3 ubiquitin ligase that transfers ubiquitin to tyrosine-phosphorylated substrates, targeting them for proteasome degradation and thereby negatively regulating multiple signal transduction pathways. Mutations cause Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia through autosomal dominant inheritance, while somatic mutations can lead to juvenile myelomonocytic leukemia. The pathogenic mechanism involves disruption of the protein's negative regulatory function in cellular signaling pathways.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors (PubMed:10514377, PubMed:11896602, PubMed:14661060, PubMed:14739300, PubMed:15190072, PubMed:17509076, PubMed:18374639, PubMed:19689429, PubMed:21596750, PubMed:28381567, PubMed:40101708). Accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome (PubMed:10514377, PubMed:14661060, PubMed:14739300, PubMed:17094949, PubMed:17509076, PubMed:17974561). Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, CSF1R, EPHA8 and KDR and mediates their ubiquitination to terminate signaling (PubMed:15190072, PubMed:18374639, PubMed:21596750). Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation (PubMed:11896602). Ubiquitinates EGFR and SPRY2 (PubMed:17094949, PubMed:17974561). Involved in LAG3-mediated inhibition of TCR signaling: following ligand-binding to LAG3, catalyzes 'Lys-63'-linked ubiquitination of LAG3, unleashing the LAG3 C-terminus from the membrane, and initiating a signaling that prevents TCR activation (PubMed:40101708). Ubiquitinates NECTIN1 following association between NECTIN1 and herpes simplex virus 1/HHV-1 envelope glycoprotein D, leading to NECTIN1 removal from cell surface (PubMed:28381567). Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis (PubMed:15190072, PubMed:18374639). Essential for osteoclastic bone resorption (PubMed:14739300). The 'Tyr-731' phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function (PubMed:14739300). In association with CBLB, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA (By similarity)

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtNoonan syndrome-like disorder with or without juvenile myelomonocytic leukemia

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · CBL-related disorder · AD · ClinGen 2019
Strong · juvenile myelomonocytic leukemia · AD · Labcorp Genetics (formerly Invitae)
Supportive · Noonan syndrome · AD · Orphanet

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

671

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.50

LOEUF

GOF

Mechanism· G2P

📖

GeneReview available — CBL

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.50LOEUF

pLI 0.001

Z-score 4.14

OE 0.32 (0.21–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.03Z-score

OE missense 0.87 (0.80–0.94)

432 obs / 496.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.21–0.50)

0≤0.351.4

Missense OE?0.87 (0.80–0.94)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 14 / 43.5Missense obs/exp: 432 / 496.8Syn Z: -0.65

Background carrier burden — how many people carry a rare variant somewhere in CBL?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 64

1,141 rare PASS variants

Rare truncating (LoF)

1 in 320

116 rare PASS variants

Rare synonymous (reference)

1 in 120

455 rare PASS variants

Rare missense and truncating variants are carried at similar rates in CBL; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 85	1 in 690
South Asian	~43k	1 in 74	1 in 680
Remaining (unassigned)	~30k	1 in 59	1 in 300
European (Finnish)	~27k	1 in 180	1 in 2,000
Admixed American	~22k	1 in 52	1 in 1,400
African / African American	~21k	1 in 42	1 in 2,500
East Asian	~20k	1 in 56	1 in 3,300
Ashkenazi Jewish	~13k	1 in 130	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 79	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 16 coding exons well covered in gnomAD exomes; exons 7, 13 marginal. Genomes: all 16.? see exons ↓