# NM_005188.4(CBL):c.1622A>T (p.Asp541Val)

https://sugi.bio/variant/cbl-p-asp541val

## Summary

**CBL p.Asp541Val (c.1622A>T)** is classified **Uncertain significance** in CBL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.6411); Very rare (popmax 0.00153%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs147285276 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00153%, nfe)

## For patients & families {#patients}

This is a change in the CBL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 submitters, and is linked to Cardiovascular phenotype.

*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.*

**Support & next steps:** [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.Asp541Val |
| Coding change (HGVS c.) | c.1622A>T |
| MANE Select transcript | [NM_005188](https://www.ncbi.nlm.nih.gov/nuccore/NM_005188) |
| dbSNP | [rs147285276](https://www.ncbi.nlm.nih.gov/snp/rs147285276/) |
| Variant type | single nucleotide variant |
| Location | chr11:119285247-119285247 (GRCh38) |
| ClinVar | [VCV503531](https://www.ncbi.nlm.nih.gov/clinvar/variation/503531/) |

**All HGVS expressions:** `LRG_608:g.83968A>T`, `LRG_608t1:c.1622A>T`, `NC_000011.10:g.119285247A>T`, `NC_000011.9:g.119155957A>T`, `NG_016808.1:g.83968A>T`, `NM_005188.2:c.1622A>T`, `NM_005188.4:c.1622A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6411)
- REVEL 0.45 (indeterminate)
- SaProt LLR -7.135 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 9.28, GERP 2.09, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.2**. 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.*
- Regional missense constraint: **o/e 1.05** across the covering region of the MANE Select transcript (119,277,811–119,299,678), spanning 21,867 bp. Chi-square p 0.19. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00153%** (nfe) · FAF95 0.000953% · FAF99 0.000787% · 18/1,179,970 in the highest group · 21/1,613,688 alleles overall — very rare (popmax 0.00153%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| European (non-Finnish) (grpmax) | 0.00153% | 65,554 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **541** lies in the 'required for ubiquitination of spred2' region; the 'disordered' region.

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.Asp541Val falls in the required for ubiquitination of spred2 region. 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-09.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2018–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-03-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-09 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-04 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-25 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [RASopathy](https://sugi.bio/atlas/disease/rasopathy/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not specified, RASopathy, not provided, AllHighlyPenetrant, rasopathies, Noonan spectrum disorder, none provided.

## Similar variants {#similar}

Related CBL variant pages (same residue, condition, or type): [CBL p.Asp541Gly](/variant/cbl-p-asp541gly), [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 503531). 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.*