PHF6 (PHD finger protein 6) variants and mutations
PHF6 (also known as PHD finger protein 6) is a human protein-coding gene encoding a PHD finger protein 6 protein. It participates in chromatin regulation, transcription, and ribosome biogenesis during development and hematopoiesis. Germline loss-of-function variants cause Borjeson-Forssman-Lehmann syndrome, while somatic mutations occur recurrently in T-cell leukemia and myeloid malignancies. This analysis covers 632 PHF6 variants and mutations. Of these, 51% have computational variant effect predictions. Disease context includes Borjeson-Forssman-Lehmann syndrome, neurodegenerative disease, and hereditary disease. Example PHF6 variants include M1?, M1I, and M1T.
Variant analysis overview
- Gene: PHF6
- Protein: PHD finger protein 6
- UniProt accession: Q8IWS0
- Organism: Homo sapiens
- Variants analyzed: 632
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 458 unspecified-consequence records; 74 synonymous variants; 73 missense variants; 10 frameshift variants; 6 stop-gained variants; 4 splice-region variants; 2 in-frame deletions; 3 stop lost; 1 splice acceptor variant; 1 substitution
- Prediction scores: 320 variants have prediction scores (51% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Borjeson-Forssman-Lehmann syndrome, neurodegenerative disease, hereditary disease, acute myeloid leukemia, Intellectual disability, T-cell acute lymphoblastic leukemia, lymphoid neoplasm, carcinoma of liver and intrahepatic biliary tract, ovarian endometrioid adenocarcinoma with squamous differentiation, endometrial endometrioid adenocarcinoma, breast ductal adenocarcinoma, acute lymphoblastic leukemia.
Protein structure and variant hotspots
- Protein features: 8 post-translational modification sites.
- PTM context: 23 variants overlap post-translational modification sites.
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 PHF6 variants
Examples include M1?, M1I, M1T, S2*, S3S, S4*, S4A, V5A. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, NCI-TCGA Cosmic COSV5970, Variant assessed as somatic; high impact.
- M1I (p.Met1Ile), rs398124428, ClinGen CA223837, ClinVar RCV000082301, MetaLR 0.84, MetaSVM 0.81, Pathogenic, not provided
- M1T (p.Met1Thr), rs132630300, ClinGen CA121334, ClinVar RCV000011817, ClinVar RCV002286694, MetaLR 0.82, MetaSVM 0.81, Pathogenic, not provided; Borjeson-Forssman-Lehmann syndrome; Hereditary spastic paraplegia
- S2* (p.Ser2Ter), NCI-TCGA Cosmic COSV5970, cosmic curated COSV59703, Variant assessed as somatic; high impact.
- S3S (p.Ser3Ser), rs779548130, gnomAD X-134377626-C-T, CADD 12.10
- S4* (p.Ser4Ter), Ensembl rs2077283490
- S4A (p.Ser4Ala), gnomAD X-134377627-T-G, REVEL 0.39, CADD 23.50
- V5A (p.Val5Ala), cosmic curated COSV10610, ExAC rs748760985, TOPMed rs748760985, gnomAD rs748760985, REVEL 0.16, CADD 16.90
- V5I (p.Val5Ile), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- V5L (p.Val5Leu), TOPMed rs1214861271
- E6A (p.Glu6Ala), cosmic curated COSV59701
- E6E (p.Glu6Glu), gnomAD X-134377635-A-G, CADD 12.10
- Q7K (p.Gln7Lys), Ensembl rs2077283604
- Q7E (p.Gln7Glu), gnomAD X-134377636-C-G, REVEL 0.43, CADD 24.00
- Q7R (p.Gln7Arg), gnomAD X-134377637-A-G, REVEL 0.53, CADD 23.30
- K8* (p.Lys8Ter), rs132630301, ClinGen CA121344, ClinVar RCV000011819, Ensembl rs132630301, Pathogenic
- K8R (p.Lys8Arg), gnomAD X-134377640-A-G, REVEL 0.27, CADD 20.70
- K8K (p.Lys8Lys), rs769068524, gnomAD X-134377641-A-G, CADD 12.50
- G10E (p.Gly10Glu), gnomAD rs1368145485, REVEL 0.46, CADD 23.30
- G10R (p.Gly10Arg), rs758791658, gnomAD X-134377638-G-GA, CADD 27.40
- P11A (p.Pro11Ala), TOPMed rs2077283804, Uncertain significance
- P11S (p.Pro11Ser), TOPMed rs2077283804, REVEL 0.18, CADD 16.00, Uncertain significance, Inborn genetic diseases; Borjeson-Forssman-Lehmann syndrome
- P11L (p.Pro11Leu), gnomAD X-134377649-C-T, REVEL 0.29, CADD 22.10
- P11P (p.Pro11Pro), rs774974810, gnomAD X-134377650-T-C, CADD 13.10
- T12A (p.Thr12Ala), ESP rs371190526, TOPMed rs371190526, gnomAD rs371190526, REVEL 0.26, CADD 16.90
- T12K (p.Thr12Lys), rs1569334235, Ensembl rs1569334235, REVEL 0.24, CADD 18.10, Variant assessed as somatic; moderate impact.
- T12I (p.Thr12Ile), gnomAD X-134377652-C-T, REVEL 0.22, CADD 20.80
- R13K (p.Arg13Lys), NCI-TCGA TCGA novel, REVEL 0.42, CADD 24.00, Variant assessed as somatic; moderate impact.
- R13S (p.Arg13Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- R13R (p.Arg13Arg), rs1259223307, gnomAD X-134377656-A-G, CADD 13.80
- Q14* (p.Gln14Ter), cosmic curated COSV10524
- Q14R (p.Gln14Arg), TOPMed rs2077283978
- Q14H (p.Gln14His), gnomAD X-134377659-G-T, REVEL 0.38, CADD 19.80
- R15C (p.Arg15Cys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- R15H (p.Arg15His), rs1302895379, NCI-TCGA Cosmic COSV1001, cosmic curated COSV10013, TOPMed rs1302895379, REVEL 0.45, CADD 22.90, Uncertain significance, Borjeson-Forssman-Lehmann syndrome
- K16Q (p.Lys16Gln), cosmic curated COSV99045
- K16R (p.Lys16Arg), ESP rs376022686, ExAC rs376022686, gnomAD rs376022686, REVEL 0.44, CADD 22.40
- K16K (p.Lys16Lys), rs2077284056, gnomAD X-134377665-A-G, CADD 10.50
- C17* (p.Cys17Ter), cosmic curated COSV10013
- C17S (p.Cys17Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- G18K (p.Gly18Lys), gnomAD X-134377668-T-TAA, CADD 29.00
- C20* (p.Cys20Ter), cosmic curated COSV10013, cosmic curated COSV10942
- C20F (p.Cys20Phe), cosmic curated COSV59699
- C20W (p.Cys20Trp), cosmic curated COSV10610
- K21E (p.Lys21Glu), ESP rs367754027, TOPMed rs367754027
- K21T (p.Lys21Thr), gnomAD rs1434235024, Uncertain significance, not provided
- S22* (p.Ser22Ter), rs1569334260, ClinGen CA414710724, ClinVar RCV000761327, Ensembl rs1569334260, CADD 35.00, Likely pathogenic
- S22S (p.Ser22Ser), rs758842701, gnomAD X-134377683-A-G, CADD 11.40
- N23S (p.Asn23Ser), cosmic curated COSV59706
- N23N (p.Asn23Asn), rs1231826518, gnomAD X-134377686-T-C, CADD 11.90
- R24G (p.Arg24Gly), cosmic curated COSV59706, REVEL 0.44, CADD 23.20
- R24K (p.Arg24Lys), rs1372900096, NCI-TCGA Cosmic COSV9904, cosmic curated COSV10645, Variant assessed as somatic; high impact.
- R24T (p.Arg24Thr), rs1556013227, ClinGen CA414710738, ClinVar RCV000585570, ClinVar RCV004024664, REVEL 0.35, CADD 23.20, Uncertain significance, Inborn genetic diseases; not provided
- D25N (p.Asp25Asn), gnomAD X-134377690-G-A, REVEL 0.41, CADD 22.60
- K26M (p.Lys26Met), rs2077284287, ClinGen CA414710755, ClinVar RCV002473394, TOPMed rs2077284287, AlphaMissense 0.23, MetaLR 0.50, Uncertain significance, not provided
- E27* (p.Glu27Ter), gnomAD X-134377696-G-T, CADD 36.00
- E27E (p.Glu27Glu), rs1304142291, gnomAD X-134377698-A-G, CADD 11.40
- C28Y (p.Cys28Tyr), TOPMed rs1390727815, gnomAD rs1390727815, REVEL 0.51, CADD 24.30
- C28C (p.Cys28Cys), rs140590075, gnomAD X-134377701-T-C, CADD 12.90
- G29* (p.Gly29Ter), rs2124198253, ClinGen CA414710776, ClinVar RCV003238668, Ensembl rs2124198253, Pathogenic
- G29A (p.Gly29Ala), rs2077284343, ClinGen CA414710779, ClinVar RCV001307926, Ensembl rs2077284343, AlphaMissense 0.94, MetaLR 0.79, Uncertain significance, Borjeson-Forssman-Lehmann syndrome
- Q30* (p.Gln30Ter), cosmic curated COSV10942
- Q30R (p.Gln30Arg), rs2077284380, ClinGen CA414710784, ClinVar RCV002711681, Ensembl rs2077284380, AlphaMissense 0.23, MetaLR 0.47, Uncertain significance, Borjeson-Forssman-Lehmann syndrome
- Q30V (p.Gln30Val), rs2077284360, gnomAD X-134377703-GAC-G, CADD 27.60
- L31* (p.Leu31Ter), cosmic curated COSV59701, cosmic curated COSV59706
- I33V (p.Ile33Val), TOPMed rs2077284425
- I33M (p.Ile33Met), gnomAD X-134377716-A-G, REVEL 0.22, CADD 17.40
- S34* (p.Ser34Ter), cosmic curated COSV10610
- S34L (p.Ser34Leu), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- S34P (p.Ser34Pro), gnomAD X-134377717-T-C, REVEL 0.66, CADD 25.60
- E35* (p.Glu35Ter), cosmic curated COSV10884
- Q37Q (p.Gln37Gln), rs2077284436, gnomAD X-134377728-G-A, CADD 11.90
- K38* (p.Lys38Ter), cosmic curated COSV10964
- K38N (p.Lys38Asn), rs2520468088, ClinGen CA414710844, ClinVar RCV003887392, Uncertain significance, not provided
- K38T (p.Lys38Thr), gnomAD X-134377730-A-C, REVEL 0.58, CADD 23.90
- A40E (p.Ala40Glu), rs1556013242, ClinGen CA414710854, cosmic curated COSV59704, ClinVar RCV000505651, AlphaMissense 0.96, MetaLR 0.75, other, Neuroblastoma
- A40V (p.Ala40Val), NCI-TCGA Cosmic COSV1001, cosmic curated COSV10013, NCI-TCGA Cosmic COSV5970, Variant assessed as somatic; moderate impact.
- A40A (p.Ala40Ala), gnomAD X-134377737-A-C, CADD 14.10
- A41G (p.Ala41Gly), NCI-TCGA Cosmic COSV5970, cosmic curated COSV59706, Variant assessed as somatic; moderate impact.
- A41V (p.Ala41Val), rs760978695, ClinGen CA10521138, ClinVar RCV001978793, ExAC rs760978695, REVEL 0.71, CADD 26.70, Uncertain significance, Borjeson-Forssman-Lehmann syndrome
- A41A (p.Ala41Ala), rs573685409, gnomAD X-134377740-G-A, CADD 11.90
- H42G (p.His42Gly), NCI-TCGA Cosmic COSV5969, NCI-TCGA Cosmic COSV5970, Variant assessed as somatic; high impact.
- H42Y (p.His42Tyr), gnomAD X-134377741-C-T, REVEL 0.95, CADD 25.50
- H42H (p.His42His), rs776870994, gnomAD X-134377743-C-T, CADD 8.52
- H43N (p.His43Asn), cosmic curated COSV10013
- H43P (p.His43Pro), rs1273843884, ClinGen CA414710875, ClinVar RCV003887401, AlphaMissense 0.50, MetaLR 0.30, Uncertain significance, not provided
- H43Q (p.His43Gln), cosmic curated COSV59699, cosmic curated COSV59701
- H43R (p.His43Arg), rs1273843884, TOPMed rs1273843884, gnomAD rs1273843884, REVEL 0.51, AlphaMissense 0.50, Uncertain significance, Inborn genetic diseases; Borjeson-Forssman-Lehmann syndrome
- H43H (p.His43His), rs1352544862, gnomAD X-134377746-T-C, CADD 10.20
- K44* (p.Lys44Ter), cosmic curated COSV59699, cosmic curated COSV59703, NCI-TCGA Cosmic COSV5969, Variant assessed as somatic; high impact.
- K44A (p.Lys44Ala), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- K44R (p.Lys44Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- K44S (p.Lys44Ser), NCI-TCGA Cosmic COSV5969, NCI-TCGA Cosmic COSV5970, Variant assessed as somatic; high impact.
- K44K (p.Lys44Lys), rs759708359, gnomAD X-134377749-G-A, CADD 10.00
- C45* (p.Cys45Ter), NCI-TCGA Cosmic COSV5970, cosmic curated COSV59705, Variant assessed as somatic; high impact., in BFLS
- C45Y (p.Cys45Tyr), rs132630299, ClinGen CA121326, ClinVar RCV000011815, ClinVar RCV004700218, AlphaMissense 1.00, MetaLR 0.84, Pathogenic, Borjeson-Forssman-Lehmann syndrome; not provided
- M46L (p.Met46Leu), NCI-TCGA TCGA novel, Ensembl rs2077284601, Variant assessed as somatic; moderate impact.
- M46V (p.Met46Val), gnomAD X-134377753-A-G, REVEL 0.52, CADD 25.20
- L47H (p.Leu47His), cosmic curated COSV10964
- L47F (p.Leu47Phe), gnomAD X-134378005-C-T, REVEL 0.71, CADD 30.00
- L47I (p.Leu47Ile), gnomAD X-134378005-C-A, REVEL 0.46, CADD 24.10
- L47L (p.Leu47Leu), gnomAD X-134378007-C-A, CADD 6.16
- F48F (p.Phe48Phe), gnomAD X-134378010-T-C, CADD 11.00
- S49L (p.Ser49Leu), rs2520470317, cosmic curated COSV10524, NCI-TCGA TCGA novel, ClinGen CA414710931, Likely pathogenic, Borjeson-Forssman-Lehmann syndrome
- S49S (p.Ser49Ser), rs143039976, gnomAD X-134378013-A-G, CADD 12.20
- A51D (p.Ala51Asp), rs778511523, ClinGen CA336026598, ClinVar RCV001800019, TOPMed rs778511523, REVEL 0.51, CADD 23.50, Uncertain significance, not provided
- A51A (p.Ala51Ala), rs759675921, gnomAD X-134378019-T-G, CADD 11.90
- L52F (p.Leu52Phe), cosmic curated COSV10013, REVEL 0.68, CADD 26.60
- L52W (p.Leu52Trp), gnomAD X-134378018-CT-C, CADD 24.70
- V53L (p.Val53Leu), rs2520470391, ClinGen CA414710954, ClinVar RCV002304902, Uncertain significance, Borjeson-Forssman-Lehmann syndrome
- V53V (p.Val53Val), rs769976257, gnomAD X-134378025-A-G, CADD 6.47
- S54S (p.Ser54Ser), gnomAD X-134378028-A-G, CADD 9.39
- S55del (p.Ser55del), gnomAD X-134378024-TATC-, CADD 18.70
- S55L (p.Ser55Leu), gnomAD X-134378030-C-T, REVEL 0.39, CADD 27.30
- H56P (p.His56Pro), TOPMed rs1418409325, gnomAD rs1418409325, REVEL 0.10, CADD 20.50
- S57S (p.Ser57Ser), gnomAD X-134378037-T-C, CADD 9.69
- D58E (p.Asp58Glu), cosmic curated COSV10964
- N59H (p.Asn59His), gnomAD rs1462978695, REVEL 0.12, CADD 18.90
- N59S (p.Asn59Ser), rs202007952, ClinGen CA10521163, ClinVar RCV000497949, ClinVar RCV003766791, REVEL 0.15, CADD 19.30, Uncertain significance
- E60G (p.Glu60Gly), ExAC rs761815168, gnomAD rs761815168, Uncertain significance, not provided
- E60K (p.Glu60Lys), cosmic curated COSV59704
- E60* (p.Glu60Ter), gnomAD X-134378044-G-T, CADD 36.00
- E60Q (p.Glu60Gln), gnomAD X-134378044-G-C, REVEL 0.59, CADD 25.80
- E60E (p.Glu60Glu), gnomAD X-134378046-A-G, CADD 9.54
- L62F (p.Leu62Phe), Ensembl rs2077286763, REVEL 0.13, CADD 19.40
- L62I (p.Leu62Ile), NCI-TCGA TCGA novel, REVEL 0.11, CADD 17.50, Variant assessed as somatic; moderate impact.
- G63C (p.Gly63Cys), cosmic curated COSV59704, REVEL 0.60, CADD 29.40
- G64* (p.Gly64Ter), cosmic curated COSV59705, CADD 37.00
- G64del (p.Gly64del), gnomAD X-134378051-TTGG-, CADD 20.20
- G64E (p.Gly64Glu), gnomAD X-134378057-G-A, REVEL 0.72, CADD 26.50
- F65F (p.Phe65Phe), gnomAD X-134378061-T-C, CADD 12.80
- S66Y (p.Ser66Tyr), gnomAD X-134378063-C-A, REVEL 0.53, CADD 24.60
- I67V (p.Ile67Val), TOPMed rs1381833110, gnomAD rs1381833110, REVEL 0.28, CADD 22.40
- I67I (p.Ile67Ile), gnomAD X-134378067-T-C, CADD 12.50
- E68G (p.Glu68Gly), gnomAD X-134378069-A-G, REVEL 0.72, CADD 26.60
- D69G (p.Asp69Gly), gnomAD rs1319295097, REVEL 0.67, CADD 29.70
- D69D (p.Asp69Asp), gnomAD X-134378073-T-C, CADD 11.70
- V70I (p.Val70Ile), TOPMed rs1179202301, gnomAD rs1179202301, REVEL 0.11, CADD 18.80
- V70V (p.Val70Val), rs1328440396, gnomAD X-134378076-C-A, CADD 8.92
- Q71* (p.Gln71Ter), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- Q71R (p.Gln71Arg), 1000Genomes rs200498373, REVEL 0.13, CADD 18.60
- Q71K (p.Gln71Lys), gnomAD X-134378077-C-A, REVEL 0.12, CADD 15.60
- K72R (p.Lys72Arg), TOPMed rs1382016457, REVEL 0.49, CADD 25.90
- K72K (p.Lys72Lys), gnomAD X-134378082-G-A, CADD 9.95
- E73D (p.Glu73Asp), cosmic curated COSV10884
- I74S (p.Ile74Ser), gnomAD X-134378087-T-G, REVEL 0.78, CADD 27.20
- K75L (p.Lys75Leu), NCI-TCGA Cosmic COSV5970, Variant assessed as somatic; high impact.
- K75R (p.Lys75Arg), gnomAD rs1365245358, REVEL 0.34, CADD 24.30
- K75K (p.Lys75Lys), gnomAD X-134378091-A-G, CADD 11.40
- R76K (p.Arg76Lys), cosmic curated COSV10524
- R76S (p.Arg76Ser), Ensembl rs2124198840
- G77D (p.Gly77Asp), cosmic curated COSV59701, REVEL 0.85, CADD 26.30
- T78M (p.Thr78Met), rs767406620, ClinGen CA10521165, NCI-TCGA Cosmic COSV1001, cosmic curated COSV10013, REVEL 0.21, CADD 22.60, Uncertain significance, Borjeson-Forssman-Lehmann syndrome
- T78R (p.Thr78Arg), ExAC rs767406620, TOPMed rs767406620, gnomAD rs767406620, Uncertain significance
- T78A (p.Thr78Ala), gnomAD X-134378098-A-G, REVEL 0.24, CADD 20.90
- T78K (p.Thr78Lys), gnomAD X-134378099-C-A, REVEL 0.30, CADD 14.10
- T78T (p.Thr78Thr), rs1160852520, gnomAD X-134378100-G-A, CADD 5.84
- K79K (p.Lys79Lys), rs2077287012, gnomAD X-134378103-G-A, CADD 9.97
- L80M (p.Leu80Met), gnomAD X-134378104-C-A, REVEL 0.39, CADD 23.50
- L80L (p.Leu80Leu), gnomAD X-134378104-C-T, CADD 16.70
- L80P (p.Leu80Pro), gnomAD X-134378105-T-C, REVEL 0.85, CADD 32.00
- M81L (p.Met81Leu), gnomAD X-134393501-A-T, REVEL 0.35, CADD 22.80
- M81I (p.Met81Ile), gnomAD X-134393503-G-A, REVEL 0.36, CADD 22.70
- S83A (p.Ser83Ala), rs762897039, ClinGen CA10521186, ClinVar RCV001785996, ClinVar RCV003512136, REVEL 0.24, CADD 23.30, Uncertain significance, not provided; Borjeson-Forssman-Lehmann syndrome
- S83F (p.Ser83Phe), NCI-TCGA Cosmic COSV5970, cosmic curated COSV59704, Variant assessed as somatic; moderate impact.
- S83Y (p.Ser83Tyr), NCI-TCGA Cosmic COSV5970, Variant assessed as somatic; moderate impact.
- C85* (p.Cys85Ter), rs1114167289, ClinGen CA414711526, ClinVar RCV000491322, Ensembl rs1114167289, Pathogenic
- C85S (p.Cys85Ser), gnomAD X-134377755-G-GCT, CADD 28.00
- H86Y (p.His86Tyr), cosmic curated COSV59701
- C87* (p.Cys87Ter), cosmic curated COSV59706
- C87Y (p.Cys87Tyr), TOPMed rs1002049485, gnomAD rs1002049485, REVEL 0.42, CADD 23.50, Uncertain significance, PHF6-related disorder
- G89E (p.Gly89Glu), ExAC rs768703341
- G89V (p.Gly89Val), gnomAD X-134393526-G-T, REVEL 0.93, CADD 28.90
- T91A (p.Thr91Ala), cosmic curated COSV10524, Uncertain significance, Borjeson-Forssman-Lehmann syndrome
- I92V (p.Ile92Val), rs773176481, ClinGen CA10521188, ClinVar RCV002865351, ClinVar RCV003621674, REVEL 0.38, CADD 23.20, Benign/Likely benign, Borjeson-Forssman-Lehmann syndrome; Inborn genetic diseases
- G93C (p.Gly93Cys), NCI-TCGA Cosmic COSV5970, cosmic curated COSV59705, Variant assessed as somatic; moderate impact.
- G93G (p.Gly93Gly), gnomAD X-134393539-T-A, CADD 10.80
- C94C (p.Cys94Cys), rs760590183, gnomAD X-134393542-T-C, CADD 13.70
- D95D (p.Asp95Asp), gnomAD X-134393545-T-C, CADD 10.40
- K97* (p.Lys97Ter), cosmic curated COSV59700
Public PHF6 analysis runs
- PHF6 analysis run — PHF6 (632 variants) — completed 2026-08-20