CBL

Chr 11ADSomatic

Cbl proto-oncogene

Also known as: C-CBL, CBL2, FRA11B, NSLL, RNF55

NCBI Gene: 867ENSG00000110395UniProt: 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.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

?Juvenile myelomonocytic leukemiaMIM #607785
ADSomatic
Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemiaMIM #613563
AD
4
Active trials
414
Pubs (1 yr)
3
P/LP submissions
67%
P/LP missense
0.50
LOEUF
GOF
Mechanism· G2P
Clinical Summary— CBL
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Gene-Disease Validity (ClinGen)
CBL-related disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
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ClinVar Variants
3 unique Pathogenic / Likely Pathogenic· 342 VUS of 500 total submissions
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Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — CBL
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

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 OE0.32 (0.21–0.50)
0≤0.351.4
Missense OE0.87 (0.80–0.94)
0≤0.61.4
Synonymous OE1.06
0≤1.21.6
LoF obs/exp: 14 / 43.5Missense obs/exp: 432 / 496.8Syn Z: -0.65
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveCBL-related Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemiaGOFAD
DN
0.6938th %ile
GOF
0.6639th %ile
LOF
0.4332th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation
GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThey are largely small in-frame deletions or missense changes affecting the RING-finger domain and/or the adjacent linker region, and they appear to act in a dominant-negative fashion by uncoupling CBL binding to activated RTKs from their ubiquitylation and degradation.PMID:20619386
GOFStructural Determinants of the Gain-of-Function Phenotype of Human Leukemia-associated Mutant CBL Oncogene.PMID:28082680

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1
Likely Pathogenic2
VUS342
Likely Benign145
Benign1
1
Pathogenic
2
Likely Pathogenic
342
VUS
145
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
1
0
1
Likely Pathogenic
0
2
0
0
2
VUS
15
305
20
2
342
Likely Benign
0
5
30
110
145
Benign
0
0
1
0
1
Total1531252112491

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CBL · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Evaluating the Effectiveness of an Integrated PBL-CBL-TBL Teaching Model in Postgraduate Clinical Training.
Liu C et al.·Adv Med Educ Pract
2026Open AccessFunctional
Application of the combined PBL-CBL teaching method of anaphylactic shock prevention and care in the fundamental nursing course.
Jiang X et al.·BMC Med Educ
2026
A c-Cbl/Cbl-b antagonist inhibits EGFR ubiquitylation and sustains EGFR phosphorylation to enhance corneal re-epithelialization.
Tarvestad-Laise K et al.·Proc Natl Acad Sci U S A
2026
Palmitoylation modification of SPI1 promotes nasopharyngeal carcinoma radioresistance through inhibiting c-CBL-mediated ubiquitination and degradation.
Jiang L et al.·Drug Resist Updat
2026
Case-based learning (CBL) in undergraduate health professions education: A realist review.
Daly R et al.·Med Educ
2026Review
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients