BTK (Tyrosine-protein kinase BTK) variants and mutations
BTK (also known as Tyrosine-protein kinase BTK) is a human protein-coding gene encoding a tyrosine-protein kinase protein. It relays B-cell-receptor signals needed for B-cell maturation, survival, and activation. Loss-of-function variants cause X-linked agammaglobulinemia, while pharmacologic inhibition is highly effective in several B-cell malignancies. This analysis covers 1,261 BTK variants and mutations. Of these, 38% have computational variant effect predictions. Disease context includes X-linked agammaglobulinemia, isolated growth hormone deficiency type III, and Non-acquired isolated growth hormone deficiency. Example BTK variants include M1I, M1T, and A2G.
Variant analysis overview
- Gene: BTK
- Protein: Tyrosine-protein kinase BTK
- UniProt accession: Q06187
- Organism: Homo sapiens
- Variants analyzed: 1261
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 1,088 unspecified-consequence records; 105 synonymous variants; 51 missense variants; 8 splice-region variants; 2 frameshift variants; 1 stop-gained variants; 6 substitution
- Prediction scores: 482 variants have prediction scores (38% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: X-linked agammaglobulinemia, isolated growth hormone deficiency type III, Non-acquired isolated growth hormone deficiency, B-cell chronic lymphocytic leukemia, Bruton-type agammaglobulinemia, mantle cell lymphoma, isolated agammaglobulinemia, neoplasm, Waldenstrom macroglobulinemia, alopecia areata, non-Hodgkin lymphoma, diffuse large B-cell lymphoma.
Protein structure and variant hotspots
- Protein features: 4 domains; 13 binding sites; 15 post-translational modification sites.
- Structural context: 1,004 variants have structural context.
- PTM context: 39 variants overlap post-translational modification sites.
- Experimental data: 59 protein positions have experimental scores. Source: BTK SH3 domain domainome 1.0.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable BTK variants
Examples include M1I, M1T, A2G, A2S, A2V, A3Q, A3S, A3T. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1I (p.Met1Ile), rs1927172387, ClinGen CA413939883, ClinVar RCV001070338, AlphaMissense 0.40, MetaLR 0.64, Pathogenic
- M1T (p.Met1Thr), rs128620186, ClinGen CA255796, ClinVar RCV000012102, ClinVar RCV003511976, AlphaMissense 0.14, MetaLR 0.61, Pathogenic
- A2G (p.Ala2Gly), cosmic curated COSV10516
- A2S (p.Ala2Ser), Ensembl rs2147448394
- A2V (p.Ala2Val), Ensembl rs2147448389
- A3Q (p.Ala3Gln), NCI-TCGA Cosmic COSV5811, Variant assessed as somatic; high impact.
- A3S (p.Ala3Ser), NCI-TCGA Cosmic COSV5811, NCI-TCGA Cosmic COSV5812, cosmic curated COSV58121, ESP rs368549990, REVEL 0.14, CADD 0.79, Uncertain significance
- A3T (p.Ala3Thr), rs368549990, ClinGen CA10473242, NCI-TCGA Cosmic COSV5811, cosmic curated COSV58117, REVEL 0.14, CADD 2.73, Uncertain significance, not provided; X-linked agammaglobulinemia with growth hormone deficiency
- I5N (p.Ile5Asn), Ensembl rs2147448370
- L6M (p.Leu6Met), gnomAD rs1320514510, REVEL 0.45, CADD 23.80
- S8T (p.Ser8Thr), Ensembl rs1927171844
- I9N (p.Ile9Asn), rs2520695586, ClinGen CA413939800, ClinVar RCV003626049, Uncertain significance
- L11P (p.Leu11Pro), rs1603020228, ClinGen CA413939777, ClinVar RCV000806755, UniProt VAR 006216, AlphaMissense 1.00, MetaLR 0.85, Pathogenic, in XLA
- L11V (p.Leu11Val), NCI-TCGA Cosmic COSV5812, cosmic curated COSV58120, Variant assessed as somatic; moderate impact., in XLA
- K12N (p.Lys12Asn), rs782519139, ClinGen CA413939762, ClinVar RCV000990919, ExAC rs782519139, AlphaMissense 1.00, MetaLR 0.93, Likely pathogenic, in XLA
- K12R (p.Lys12Arg), UniProt VAR 006217, Pathogenic, in XLA
- R13* (p.Arg13Ter), rs128620187, ClinGen CA255788, NCI-TCGA Cosmic COSV5811, cosmic curated COSV58118, Pathogenic
- R13L (p.Arg13Leu), TOPMed rs868924845
- R13Q (p.Arg13Gln), rs868924845, NCI-TCGA Cosmic COSV1004, cosmic curated COSV10043, TOPMed rs868924845, REVEL 0.65, CADD 26.70, Variant assessed as somatic; moderate impact.
- S14C (p.Ser14Cys), gnomAD rs1057520682, REVEL 0.86, AlphaMissense 0.99, Pathogenic, in XLA
- S14F (p.Ser14Phe), rs1057520682, ClinGen CA413939745, cosmic curated COSV10043, ClinVar RCV000795113, AlphaMissense 0.99, MetaLR 0.66, Pathogenic, in XLA
- S14P (p.Ser14Pro), cosmic curated COSV58117
- S14T (p.Ser14Thr), NCI-TCGA Cosmic COSV1004, cosmic curated COSV10043, NCI-TCGA Cosmic COSV5811, Variant assessed as somatic; moderate impact., in XLA
- S14Y (p.Ser14Tyr), rs1057520682, ClinGen CA16608230, NCI-TCGA Cosmic COSV1004, NCI-TCGA Cosmic COSV5811, AlphaMissense 0.99, MetaLR 0.66, Pathogenic, in XLA
- Q15* (p.Gln15Ter), rs128620188, ClinGen CA255791, ClinVar RCV000012098, ClinVar RCV001027550, Pathogenic
- Q15N (p.Gln15Asn), rs2520695220, ClinGen CA2580100087, ClinVar RCV003066347, Pathogenic
- Q16* (p.Gln16Ter), rs1555980888, ClinGen CA413939723, ClinVar RCV000627328, Ensembl rs1555980888, Pathogenic
- Q16H (p.Gln16His), cosmic curated COSV58122
- Q16K (p.Gln16Lys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- K17T (p.Lys17Thr), cosmic curated COSV58119
- K18E (p.Lys18Glu), rs2520695124, ClinGen CA413939688, ClinVar RCV003625818, Uncertain significance
- K18N (p.Lys18Asn), Ensembl rs2147448296
- K19E (p.Lys19Glu), UniProt VAR 008291, Pathogenic, in XLA
- T20R (p.Thr20Arg), Ensembl rs2147448294
- S21* (p.Ser21Ter), rs2147448284, ClinGen CA413939630, cosmic curated COSV58117, ClinVar RCV001381525, Pathogenic
- S21L (p.Ser21Leu), cosmic curated COSV10461
- P22H (p.Pro22His), NCI-TCGA Cosmic COSV5811, cosmic curated COSV58117, Variant assessed as somatic; moderate impact.
- P22L (p.Pro22Leu), NCI-TCGA Cosmic COSV5811, Variant assessed as somatic; moderate impact.
- F25I (p.Phe25Ile), Ensembl rs2147448268
- F25L (p.Phe25Leu), NCI-TCGA Cosmic COSV1004, cosmic curated COSV10043, Variant assessed as somatic; moderate impact., in XLA
- F25S (p.Phe25Ser), UniProt VAR 006219, Pathogenic, in XLA
- K26N (p.Lys26Asn), NCI-TCGA Cosmic COSV1004, NCI-TCGA Cosmic COSV5812, cosmic curated COSV58122, Variant assessed as somatic; moderate impact.
- K26R (p.Lys26Arg), rs2147448262, ClinGen CA413939551, ClinVar RCV001374321, Ensembl rs2147448262, AlphaMissense 0.51, MetaLR 0.90, Uncertain significance
- K27R (p.Lys27Arg), UniProt VAR 008292, Pathogenic, in XLA
- R28C (p.Arg28Cys), rs1927168815, ClinGen CA413939518, NCI-TCGA Cosmic COSV5811, cosmic curated COSV58117, AlphaMissense 1.00, MetaLR 0.94, Pathogenic, in XLA
- R28H (p.Arg28His), rs128620185, ClinGen CA255794, cosmic curated COSV10589, ClinVar RCV000012101, REVEL 0.93, AlphaMissense 1.00, Pathogenic, in XLA
- R28L (p.Arg28Leu), rs128620185, ClinGen CA413939515, ClinVar RCV001389176, ClinVar RCV006557424, AlphaMissense 1.00, MetaLR 0.95, Pathogenic, in XLA
- R28P (p.Arg28Pro), UniProt VAR 006221, Pathogenic, in XLA
- L29M (p.Leu29Met), NCI-TCGA Cosmic COSV5811, cosmic curated COSV58119, Ensembl rs2147448236, Variant assessed as somatic; moderate impact.
- F30L (p.Phe30Leu), cosmic curated COSV58124
- L31I (p.Leu31Ile), cosmic curated COSV58124
- L32F (p.Leu32Phe), Ensembl rs2147448228
- L32V (p.Leu32Val), cosmic curated COSV58121
- T33P (p.Thr33Pro), rs128620189, ClinGen CA255799, ClinVar RCV000012104, UniProt VAR 006222, AlphaMissense 0.94, MetaLR 0.63, Pathogenic, in XLA
- T33S (p.Thr33Ser), Ensembl rs128620189, Pathogenic, in XLA
- V34L (p.Val34Leu), rs141488935, ClinGen CA413939433, ClinVar RCV003046447, REVEL 0.21, CADD 7.34, Uncertain significance
- V34M (p.Val34Met), rs141488935, ClinGen CA10473233, ClinVar RCV001169612, ClinVar RCV001169613, REVEL 0.10, CADD 13.70, Uncertain significance
- H35N (p.His35Asn), NCI-TCGA Cosmic COSV5812, cosmic curated COSV58122, Ensembl rs2147448202, Variant assessed as somatic; moderate impact.
- H35R (p.His35Arg), TOPMed rs1927167257, REVEL 0.23, CADD 14.90
- H35Y (p.His35Tyr), Ensembl rs2147448202
- Y39C (p.Tyr39Cys), cosmic curated COSV10516
- Y39S (p.Tyr39Ser), UniProt VAR 008960, Pathogenic, in XLA
- Y40C (p.Tyr40Cys), rs1555980875, ClinGen CA413939330, ClinVar RCV000521066, ClinVar RCV000707368, AlphaMissense 0.89, MetaLR 0.66, Pathogenic, in XLA
- Y40N (p.Tyr40Asn), UniProt VAR 008295, Pathogenic, in XLA
- E41K (p.Glu41Lys), Ensembl rs1057520045, REVEL 0.83, CADD 26.60
- Y42* (p.Tyr42Ter), rs2147448164, ClinGen CA413939289, ClinVar RCV002243536, Ensembl rs2147448164, Pathogenic
- Y42N (p.Tyr42Asn), cosmic curated COSV10461
- D43H (p.Asp43His), cosmic curated COSV10962
- D43N (p.Asp43Asn), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- D43V (p.Asp43Val), cosmic curated COSV10516
- E45* (p.Glu45Ter), cosmic curated COSV58123
- E45D (p.Glu45Asp), Ensembl rs2147448158
- E45K (p.Glu45Lys), cosmic curated COSV58119
- R46C (p.Arg46Cys), NCI-TCGA Cosmic COSV5811, cosmic curated COSV58117, Ensembl rs2147448151, Variant assessed as somatic; moderate impact.
- R46H (p.Arg46His), cosmic curated COSV58123, gnomAD rs1555980871, REVEL 0.47, CADD 24.20
- G47R (p.Gly47Arg), cosmic curated COSV58125
- G47V (p.Gly47Val), Ensembl rs2147448130
- R48G (p.Arg48Gly), cosmic curated COSV10461, REVEL 0.49, CADD 23.10
- R48S (p.Arg48Ser), Ensembl rs1927147937
- G50D (p.Gly50Asp), cosmic curated COSV10516, Ensembl rs2147447625
- S51N (p.Ser51Asn), NCI-TCGA Cosmic COSV5812, cosmic curated COSV58124, REVEL 0.28, CADD 19.90, Variant assessed as somatic; moderate impact.
- S51R (p.Ser51Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- S51T (p.Ser51Thr), gnomAD rs1555980800, REVEL 0.26, CADD 18.20
- K52N (p.Lys52Asn), cosmic curated COSV10962
- K53T (p.Lys53Thr), cosmic curated COSV10043
- K53R (p.Lys53Arg), rs782556598, []
- S55* (p.Ser55Ter), rs1555980796, ClinGen CA413939060, cosmic curated COSV58121, ClinVar RCV000589435, Likely pathogenic
- S55A (p.Ser55Ala), cosmic curated COSV58123
- S55P (p.Ser55Pro), rs1603019607, ClinGen CA413939064, ClinVar RCV000809057, Ensembl rs1603019607, AlphaMissense 1.00, MetaLR 0.57, Uncertain significance
- I56T (p.Ile56Thr), rs1927146374, ClinGen CA413939045, ClinVar RCV001235566, Ensembl rs1927146374, AlphaMissense 0.91, MetaLR 0.93, Likely pathogenic
- I56V (p.Ile56Val), cosmic curated COSV10043, REVEL 0.25, CADD 14.50
- D57H (p.Asp57His), gnomAD rs1555980795, REVEL 0.73, CADD 24.70
- D57N (p.Asp57Asn), cosmic curated COSV58117
- V58I (p.Val58Ile), Ensembl rs1927145834, REVEL 0.19, CADD 14.80
- K60N (p.Lys60Asn), cosmic curated COSV10735
- K60E (p.Lys60Glu), NCI-TCGA Cosmic COSV5812, cosmic curated COSV58124, Variant assessed as somatic; moderate impact.
- K60M (p.Lys60Met), cosmic curated COSV99079
- I61N (p.Ile61Asn), NCI-TCGA Cosmic COSV1004, cosmic curated COSV10043, UniProt VAR 008296, Pathogenic, in XLA
- T62I (p.Thr62Ile), NCI-TCGA Cosmic COSV1004, cosmic curated COSV10043, TOPMed rs1927145073, Variant assessed as somatic; moderate impact.
- C63S (p.Cys63Ser), rs2520688614, ClinGen CA413938919, ClinVar RCV003027209, Uncertain significance
- V64D (p.Val64Asp), UniProt VAR 008297, Pathogenic, in XLA
- V64F (p.Val64Phe), UniProt VAR 006223, Pathogenic, in XLA
- V64I (p.Val64Ile), ExAC rs782007035
- E65A (p.Glu65Ala), gnomAD rs1555980793, REVEL 0.69, CADD 25.30
- E65D (p.Glu65Asp), cosmic curated COSV10461
- E65K (p.Glu65Lys), Ensembl rs1603019578
- V68F (p.Val68Phe), Ensembl rs1346397922
- N72K (p.Asn72Lys), rs1555980789, ClinGen CA413938762, ClinVar RCV001203879, gnomAD rs1555980789, REVEL 0.27, CADD 22.00, Likely benign
- P73L (p.Pro73Leu), cosmic curated COSV58118
- P74S (p.Pro74Ser), cosmic curated COSV10516
- P75A (p.Pro75Ala), rs930891306, NCI-TCGA Cosmic COSV5811, cosmic curated COSV58118, NCI-TCGA Cosmic COSV5812, AlphaMissense 0.06, MetaLR 0.60, Variant assessed as somatic; moderate impact.
- P75L (p.Pro75Leu), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- P75T (p.Pro75Thr), cosmic curated COSV58122
- Q78* (p.Gln78Ter), rs1603019535, ClinGen CA413938666, ClinVar RCV000814965, Ensembl rs1603019535, Pathogenic
- I79T (p.Ile79Thr), gnomAD rs1555980788, REVEL 0.36, CADD 21.20
- P80L (p.Pro80Leu), rs1400251682, ClinGen CA413938618, ClinVar RCV003511478, TOPMed rs1400251682, REVEL 0.21, CADD 23.00, Uncertain significance
- P80Q (p.Pro80Gln), cosmic curated COSV58119
- P80S (p.Pro80Ser), cosmic curated COSV58118, ExAC rs782406513, gnomAD rs782406513, REVEL 0.20, CADD 23.10
- P80T (p.Pro80Thr), NCI-TCGA Cosmic COSV5811, REVEL 0.37, CADD 20.30, Variant assessed as somatic; moderate impact.
- R81K (p.Arg81Lys), NCI-TCGA Cosmic COSV5812, cosmic curated COSV58120, Variant assessed as somatic; moderate impact.
- R82I (p.Arg82Ile), cosmic curated COSV58123, ExAC rs56035945, TOPMed rs56035945, gnomAD rs56035945, REVEL 0.30, CADD 23.20
- R82K (p.Arg82Lys), rs56035945, cosmic curated COSV58123, UniProt VAR 041676, ExAC rs56035945, REVEL 0.18, CADD 19.80
- G83C (p.Gly83Cys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- G83S (p.Gly83Ser), Ensembl rs2147444949
- E85* (p.Glu85Ter), NCI-TCGA Cosmic COSV5811, cosmic curated COSV58119, Variant assessed as somatic; high impact.
- S86A (p.Ser86Ala), gnomAD rs1927038069, REVEL 0.18, CADD 13.00
- S86C (p.Ser86Cys), TOPMed rs1927037919, REVEL 0.23, CADD 16.00
- E88D (p.Glu88Asp), NCI-TCGA Cosmic COSV5812, cosmic curated COSV58123, Variant assessed as somatic; moderate impact.
- E88K (p.Glu88Lys), NCI-TCGA Cosmic COSV5812, cosmic curated COSV58122, Variant assessed as somatic; moderate impact.
- M89I (p.Met89Ile), Ensembl rs2147444939
- E90Q (p.Glu90Gln), cosmic curated COSV10962
- Q91* (p.Gln91Ter), rs2520668410, ClinGen CA413938121, ClinVar RCV003140473, Pathogenic
- Q91H (p.Gln91His), NCI-TCGA Cosmic COSV1004, cosmic curated COSV10043, Variant assessed as somatic; moderate impact.
- Q91K (p.Gln91Lys), NCI-TCGA Cosmic COSV5811, cosmic curated COSV58118, Variant assessed as somatic; moderate impact.
- S93* (p.Ser93Ter), rs1569295678, ClinGen CA413938098, cosmic curated COSV58123, ClinVar RCV000703916, Pathogenic
- S93L (p.Ser93Leu), cosmic curated COSV58117
- I94M (p.Ile94Met), rs2147444915, ClinGen CA413938089, ClinVar RCV001886862, Ensembl rs2147444915, AlphaMissense 0.38, MetaLR 0.45, Uncertain significance
- I94V (p.Ile94Val), TOPMed rs1450054904, gnomAD rs1450054904, REVEL 0.28, CADD 19.20
- I95F (p.Ile95Phe), Ensembl rs2147444907, REVEL 0.34, CADD 20.90
- E96* (p.Glu96Ter), rs2520668139, ClinGen CA413938079, ClinVar RCV003625831, Pathogenic
- E96K (p.Glu96Lys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- E96V (p.Glu96Val), TOPMed rs1317277241, gnomAD rs1317277241, REVEL 0.43, CADD 23.00
- R97K (p.Arg97Lys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- R97M (p.Arg97Met), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- R97T (p.Arg97Thr), cosmic curated COSV10642
- F98L (p.Phe98Leu), rs1927036921, ClinGen CA413938060, ClinVar RCV001175466, Ensembl rs1927036921, AlphaMissense 1.00, MetaLR 0.38, Uncertain significance
- F98S (p.Phe98Ser), cosmic curated COSV10881
- P99H (p.Pro99His), NCI-TCGA Cosmic COSV1004, cosmic curated COSV10043, Variant assessed as somatic; moderate impact.
- P99L (p.Pro99Leu), gnomAD rs1555980318
- P99S (p.Pro99Ser), cosmic curated COSV10516
- P99T (p.Pro99Thr), cosmic curated COSV58120
- Y100* (p.Tyr100Ter), rs1927036604, ClinGen CA413938046, ClinVar RCV001250190, Ensembl rs1927036604, Pathogenic
- Y100F (p.Tyr100Phe), cosmic curated COSV58121
- P101H (p.Pro101His), cosmic curated COSV58123
- P101L (p.Pro101Leu), rs2520667901, ClinGen CA413938041, ClinVar RCV003054790, Uncertain significance
- P101S (p.Pro101Ser), cosmic curated COSV10516
- F102L (p.Phe102Leu), TOPMed rs1927036285
- F102S (p.Phe102Ser), rs2147444867, ClinGen CA413938034, ClinVar RCV001910950, Ensembl rs2147444867, AlphaMissense 1.00, MetaLR 0.97, Likely pathogenic
- Q103* (p.Gln103Ter), rs886039657, ClinGen CA10588733, ClinVar RCV000255735, Ensembl rs886039657, Pathogenic, in XLA
- Q103P (p.Gln103Pro), rs2520667717, ClinGen CA413938023, ClinVar RCV003513696, Uncertain significance, in XLA
- Q103X, rs886039657, Pathogenic
- V104L (p.Val104Leu), Ensembl rs1926977834
- V105A (p.Val105Ala), 1000Genomes rs782626687, ExAC rs782626687, REVEL 0.79, CADD 22.50
- V105I (p.Val105Ile), Ensembl rs1603016483
- D107Y (p.Asp107Tyr), rs1926977202, ClinGen CA413937345, ClinVar RCV001218381, ClinVar RCV004526816, AlphaMissense 0.92, MetaLR 0.89, Uncertain significance
- E108K (p.Glu108Lys), NCI-TCGA Cosmic COSV5811, cosmic curated COSV58118, Variant assessed as somatic; moderate impact.
- P110S (p.Pro110Ser), Ensembl rs2147443484
- L111R (p.Leu111Arg), cosmic curated COSV10962
- Y112* (p.Tyr112Ter), rs1409835623, ClinGen CA413937218, ClinVar RCV001870380, TOPMed rs1409835623, Pathogenic
- Y112F (p.Tyr112Phe), Ensembl rs2147443468
- Y112H (p.Tyr112His), rs1926977049, ClinGen CA413937245, ClinVar RCV001041939, Ensembl rs1926977049, AlphaMissense 1.00, MetaLR 0.90, Pathogenic
- Y112S (p.Tyr112Ser), Ensembl rs2147443468
- V113D (p.Val113Asp), rs128621190, ClinGen CA255801, ClinVar RCV000012109, UniProt VAR 006225, AlphaMissense 1.00, MetaLR 0.89, Pathogenic, in XLA
- V113I (p.Val113Ile), rs2147443453, ClinGen CA413937212, cosmic curated COSV58119, ClinVar RCV002022737, REVEL 0.39, CADD 17.10, Uncertain significance, in XLA
- F114S (p.Phe114Ser), cosmic curated COSV58120, Ensembl rs868960790
- S115F (p.Ser115Phe), rs2520657546, ClinGen CA413937160, ClinVar RCV003513695, UniProt VAR 008298, Pathogenic, in XLA
- S115Y (p.Ser115Tyr), cosmic curated COSV58123
- P116L (p.Pro116Leu), cosmic curated COSV58117
- P116T (p.Pro116Thr), cosmic curated COSV10516, Ensembl rs2147443430
- T117I (p.Thr117Ile), NCI-TCGA Cosmic COSV1004, cosmic curated COSV10043, Variant assessed as somatic; moderate impact., in XLA
Public BTK analysis runs
- BTK analysis run — BTK (1,261 variants) — completed 2026-08-18