# NM_005188.4(CBL):c.873T>C (p.Tyr291=)

https://sugi.bio/variant/cbl-p-tyr291

## Summary

**CBL p.Tyr291= (c.873T>C)** is classified **Likely benign** in CBL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0367%, amr); Associated with juvenile myelomonocytic leukemia.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs756526812 · 5 submitters · 2 linked conditions · ultra-rare (popmax 0.0367%, amr)

## For patients & families {#patients}

This is a change in the CBL gene that is classified as likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to juvenile myelomonocytic leukemia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Not applicable |
| Age of onset (of this condition) | Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 287 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CBL is a diagnostic-grade gene on 20 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009884/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CBL](https://sugi.bio/atlas/gene/CBL/) |
| Protein change (HGVS p.) | p.Tyr291= |
| Coding change (HGVS c.) | c.873T>C |
| MANE Select transcript | [NM_005188](https://www.ncbi.nlm.nih.gov/nuccore/NM_005188) |
| dbSNP | [rs756526812](https://www.ncbi.nlm.nih.gov/snp/rs756526812/) |
| Variant type | single nucleotide variant |
| Location | chr11:119276000-119276000 (GRCh38) |
| ClinVar | [VCV383007](https://www.ncbi.nlm.nih.gov/clinvar/variation/383007/) |

**All HGVS expressions:** `LRG_608:g.74721T>C`, `LRG_608t1:c.873T>C`, `NC_000011.10:g.119276000T>C`, `NC_000011.9:g.119146710T>C`, `NG_016808.1:g.74721T>C`, `NM_005188.4:c.873T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.034, GERP -1.5, phastCons 0.819 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.119**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.62 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0367%** (amr) · FAF95 0.0248% · FAF99 0.0209% · 22/60,010 in the highest group · 38/1,614,088 alleles overall — ultra-rare (popmax 0.0367%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0367% | 2,728 |
| Middle Eastern | 0.0329% | 3,042 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,622 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,606 |
| African / African-American | 0.00133% | 74,946 |
| South Asian | 0.0011% | 91,096 |
| European (non-Finnish) | 0.000593% | 168,572 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CBL** population constraint: LOEUF 0.622, pLI 0.00033116, missense-Z 1.6974; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **CBL-related disorder** — Definitive (AD)

## Protein context {#protein}

Residue **291** lies in the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the 'sh2-like' region; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 64.27, 36% of residues very-high.

**34 experimental structure(s)** (PDB): [1B47](https://www.rcsb.org/structure/1B47), [1FBV](https://www.rcsb.org/structure/1FBV), [1YVH](https://www.rcsb.org/structure/1YVH), [2CBL](https://www.rcsb.org/structure/2CBL), [2JUJ](https://www.rcsb.org/structure/2JUJ), [2K4D](https://www.rcsb.org/structure/2K4D) — incl. mutant structure 5HKX.

## What this gene does {#gene-function}

*Describes the biological roles of CBL (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CBL's established molecular role includes SH3 domain binding. p.Tyr291= falls in the cbl-ptb domain. In Reactome, CBL is annotated in disease pathway(s) including **Constitutive Signaling by EGFRvIII**, **Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants**.

**Disease mechanism (Reactome):** CBL loss or alteration is curated in [Constitutive Signaling by EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810), [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382), [FLT3 signaling by CBL mutants](https://reactome.org/content/detail/R-HSA-9706377).

### Pathways affected {#pathways}

CBL participates in **20 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810) | curated |
| ⚕ [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382) | curated |
| ⚕ [FLT3 signaling by CBL mutants](https://reactome.org/content/detail/R-HSA-9706377) | curated |
| ⚕ [InlB-mediated entry of Listeria monocytogenes into host cell](https://reactome.org/content/detail/R-HSA-8875360) | electronic |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [EGFR downregulation](https://reactome.org/content/detail/R-HSA-182971) | curated |
| [Interleukin-6 signaling](https://reactome.org/content/detail/R-HSA-1059683) | curated |
| [Negative regulation of FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5654726) | curated |
| [Negative regulation of FGFR2 signaling](https://reactome.org/content/detail/R-HSA-5654727) | curated |
| [Negative regulation of FGFR3 signaling](https://reactome.org/content/detail/R-HSA-5654732) | curated |
| [Negative regulation of FGFR4 signaling](https://reactome.org/content/detail/R-HSA-5654733) | curated |
| [Negative regulation of FLT3](https://reactome.org/content/detail/R-HSA-9706369) | curated |
| [Negative regulation of MET activity](https://reactome.org/content/detail/R-HSA-6807004) | curated |
| [PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1](https://reactome.org/content/detail/R-HSA-8849469) | curated |
| [Regulation of KIT signaling](https://reactome.org/content/detail/R-HSA-1433559) | curated |
| [Spry regulation of FGF signaling](https://reactome.org/content/detail/R-HSA-1295596) | curated |
| [TGF-beta receptor signaling activates SMADs](https://reactome.org/content/detail/R-HSA-2173789) | curated |
| [Regulation of signaling by CBL](https://reactome.org/content/detail/R-HSA-912631) | electronic |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** SH3 domain binding, cadherin binding, ephrin receptor binding, ubiquitin protein ligase activity.

**Biological process:** ubiquitin-dependent protein catabolic process, protein ubiquitination, negative regulation of epidermal growth factor receptor signaling pathway, negative regulation of apoptotic process, positive regulation of receptor-mediated endocytosis, protein stabilization.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-03.

**Submitter consensus:** conflicting (4 Likely benign, 1 Likely Benign).

**Submission history:** 5 submissions (2016–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2016-01-13 |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-07 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-15 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Benign | criteria provided, single submitter | clinical testing | 2024-02-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-03 |

## Associated conditions {#conditions}

[juvenile myelomonocytic leukemia](https://sugi.bio/atlas/disease/juvenile-myelomonocytic-leukemia/), [RASopathy](https://sugi.bio/atlas/disease/rasopathy/).

**Reported phenotype names (ClinVar):** Juvenile myelomonocytic leukemia, not provided, RASopathy, Cardiovascular phenotype, none provided, LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC, Noonan spectrum disorder, rasopathies.

## Similar variants {#similar}

Related CBL variant pages (same residue, condition, or type): [CBL p.Tyr291Cys](/variant/cbl-p-tyr291cys), [CBL c.1096-1G>C](/variant/cbl-c-1096-minus-1g-c), [CBL c.1096-1G>T](/variant/cbl-c-1096-minus-1g-t), [CBL c.1228-2A>G](/variant/cbl-c-1228-minus-2a-g), [CBL p.Arg420Gln](/variant/cbl-p-arg420gln), [CBL p.Arg420Leu](/variant/cbl-p-arg420leu), [CBL p.Gln367Arg](/variant/cbl-p-gln367arg), [CBL p.Gln367Pro](/variant/cbl-p-gln367pro).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 383007). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*