# BTK C481S, PLCG2 and BCL2 G101V resistance mutations

Source: https://onco.cc/terms/btki-bcl2i-resistance-mutations/  
OnCo record `btki-bcl2i-resistance-mutations` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

When ibrutinib-type drugs stop working in CLL, the usual reason is a mutation at the exact spot the drug binds (BTK C481S) or just downstream (PLCG2); when venetoclax fails, a BCL2 G101V mutation loosens its grip. Each can be seen in blood months before the disease visibly relapses, and each points to a different next drug.

## Summary

What is measured: acquired mutations in BTK, PLCG2 and BCL2 that explain progression on targeted therapy. How: sensitive next-generation sequencing or digital PCR on peripheral blood CLL cells (or cell-free DNA) at progression or on surveillance. BTK C481S accounts for over 80 percent of resistance to the covalent inhibitors (ibrutinib, acalabrutinib, zanubrutinib), with C481R/F/Y variants; T474I and L528W arise on pirtobrutinib and zanubrutinib and, being kinase-dead, also resist pirtobrutinib; PLCG2 gain-of-function mutations (R665W, L845F, S707Y) act downstream; BCL2 G101V (and D103Y and others) appears in about half of venetoclax relapses, often subclonal and up to two years before clinical progression, but not typically in patients treated for a fixed duration and retreated after a gap. What a result changes: covalent BTK inhibitor failure with C481S leads to pirtobrutinib (BRUIN) or a venetoclax-based regimen; kinase-dead mutations lead to venetoclax, BTK degraders in trials, CAR-T (lisocabtagene maraleucel is approved for CLL) or bispecific antibodies; a BCL2 mutation leads to a BTK inhibitor or trials and makes venetoclax retreatment less reliable; a rapidly growing node is biopsied for Richter transformation before any switch. Where it matters: CLL, relapsed CLL, mantle cell lymphoma and Waldenström's.

## Fields

- Kind: Term
- Last checked: 2026-09-17
- Also known as: BTK C481S; C481S; BTK mutation; BTK resistance mutation; PLCG2 mutation; PLCG2; BCL2 G101V; G101V; BCL2 mutation; venetoclax resistance mutation; BTK inhibitor resistance; BTKi resistance; T474I; L528W; kinase-dead BTK mutation; non-covalent BTK inhibitor resistance

## Connected records

- targets: [BCL-2](https://onco.cc/targets/bcl2/), [BTK (Bruton tyrosine kinase)](https://onco.cc/targets/btk/)
- terms: [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [On-target resistance mutations (gatekeeper, solvent-front, compound)](https://onco.cc/terms/gatekeeper-mutation/)
- drugs: [Acalabrutinib](https://onco.cc/drugs/acalabrutinib/), [Ibrutinib](https://onco.cc/drugs/ibrutinib/), [Lisocabtagene maraleucel](https://onco.cc/drugs/lisocabtagene-maraleucel/), [Pirtobrutinib](https://onco.cc/drugs/pirtobrutinib/), [Venetoclax](https://onco.cc/drugs/venetoclax/), [Zanubrutinib](https://onco.cc/drugs/zanubrutinib/)
- cancers: [Chronic lymphocytic leukaemia](https://onco.cc/cancers/cll/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [Relapsed or refractory chronic lymphocytic leukaemia](https://onco.cc/cancers/cll-relapsed/), [Waldenström macroglobulinaemia](https://onco.cc/cancers/waldenstrom/)

---
JSON: https://onco.cc/api/v1/entities/btki-bcl2i-resistance-mutations.json