# BCL2 G101V and the other venetoclax binding-site mutations

Source: https://onco.cc/biomarkers/bcl2-g101v/  
OnCo record `bcl2-g101v` (Biomarker). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A change in the pocket of the survival protein BCL-2 where venetoclax has to fit. The protein still works and the drug no longer binds it. It can be detected in blood months before the disease starts growing again.

## Summary

Glycine 101 sits in the BH3-binding groove of BCL-2. The valine substitution reduces the affinity of the protein for venetoclax about 180-fold on surface plasmon resonance, so the drug can no longer displace the pro-apoptotic proteins that BCL-2 is holding, while the protein continues to do its job for the cell.

Paired samples from 15 patients progressing on venetoclax in clinical trials showed G101V in seven at progression and in none at study entry. It first became detectable between 19 and 42 months of continuous treatment, and its emergence preceded clinical progression by many months (Blombery 2019). Other substitutions in the same groove have since been described, usually at low allele fraction and often several at once in one patient, which suggests convergent selection rather than a single escape route.

## Fields

- Kind: Biomarker
- Last checked: 2026-09-30
- Also known as: BCL2 Gly101Val; BCL2 G101V; venetoclax resistance mutation; BCL2 D103Y
- Tags: biomarker; resistance; lymphoma

## Sources

- Blombery et al., Cancer Discov 2019: the recurrent BCL2 Gly101Val mutation confers resistance to venetoclax: https://doi.org/10.1158/2159-8290.CD-18-1119

## Connected records

- biomarkers: [BCL2 rearrangement, t(14;18)](https://onco.cc/biomarkers/bcl2-rearrangement/), [BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors](https://onco.cc/biomarkers/btk-c481s/)
- cancers: [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- targets: [BCL-2](https://onco.cc/targets/bcl2/), [MCL1](https://onco.cc/targets/mcl1/)
- drugs: [Sonrotoclax](https://onco.cc/drugs/sonrotoclax/), [Venetoclax](https://onco.cc/drugs/venetoclax/)
- pathways: [Intrinsic apoptosis (BCL-2 family)](https://onco.cc/pathways/apoptosis-bcl2/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)
- terms: [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Minimal / molecular residual disease (MRD)](https://onco.cc/terms/mrd/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/)

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