TRAF6 (TNF receptor-associated factor 6) variants and mutations
TRAF6 (also known as TNF receptor-associated factor 6) is a human protein-coding gene encoding a TNF receptor-associated factor 6 protein. It functions as a signaling adaptor and ubiquitin ligase downstream of Toll-like, IL-1, and several TNF-family receptors, activating NF-kappaB and MAPK pathways. Dysregulation can disturb immunity, bone remodeling, and inflammatory signaling and contributes to selected cancers. This analysis covers 793 TRAF6 variants and mutations. Of these, 74% have computational variant effect predictions. Disease context includes autosomal dominant hypohidrotic ectodermal dysplasia, severe acute respiratory syndrome, and vertebral column disorder. Example TRAF6 variants include L3M, L3R, and L4P.
Variant analysis overview
- Gene: TRAF6
- Protein: TNF receptor-associated factor 6
- UniProt accession: Q9Y4K3
- Organism: Homo sapiens
- Variants analyzed: 793
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 484 unspecified-consequence records; 8 frameshift variants; 147 missense variants; 142 synonymous variants; 6 stop-gained variants; 3 in-frame deletions; 3 splice-region variants
- Prediction scores: 584 variants have prediction scores (74% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: autosomal dominant hypohidrotic ectodermal dysplasia, severe acute respiratory syndrome, vertebral column disorder, ovarian neoplasm, renal osteodystrophy, neoplasm, gastric cancer, pachyonychia congenita, colorectal carcinoma, hepatocellular carcinoma, rheumatoid arthritis, glioblastoma.
Protein structure and variant hotspots
- Protein features: 1 domains.
- Structural context: 218 variants have structural context.
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, MaveDB, LitVar.
Notable TRAF6 variants
Examples include L3M, L3R, L4P, L4Q, E7K, G11E, G11V, S12F. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- L3M (p.Leu3Met), cosmic curated COSV61923
- L3R (p.Leu3Arg), TOPMed rs1859715946
- L4P (p.Leu4Pro), cosmic curated COSV10466
- L4Q (p.Leu4Gln), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- E7K (p.Glu7Lys), NCI-TCGA Cosmic COSV6192, cosmic curated COSV61922, Variant assessed as somatic; moderate impact.
- G11E (p.Gly11Glu), 1000Genomes rs547082469, ExAC rs547082469, gnomAD rs547082469
- G11V (p.Gly11Val), 1000Genomes rs547082469, ExAC rs547082469, gnomAD rs547082469, REVEL 0.21, MetaLR 0.42
- S12F (p.Ser12Phe), Ensembl rs17852887, REVEL 0.28, MetaLR 0.41
- S12P (p.Ser12Pro), ExAC rs748986045, TOPMed rs748986045, gnomAD rs748986045, REVEL 0.27, MetaLR 0.33
- S13R (p.Ser13Arg), gnomAD rs1418472079, REVEL 0.23, MetaLR 0.35
- S17N (p.Ser17Asn), ExAC rs769322740, gnomAD rs769322740
- D18E (p.Asp18Glu), TOPMed rs1453088768, REVEL 0.25, MetaLR 0.35
- D18G (p.Asp18Gly), gnomAD rs1859715043, REVEL 0.18, MetaLR 0.23
- D18H (p.Asp18His), gnomAD rs1859715084, REVEL 0.26, MetaLR 0.57
- D18N (p.Asp18Asn), gnomAD rs1859715084, REVEL 0.30, MetaLR 0.37
- C20Y (p.Cys20Tyr), rs1314159296, ClinGen CA380149049, ClinVar RCV004321734, TOPMed rs1314159296, REVEL 0.56, MetaLR 0.72, Uncertain significance, not specified
- A22S (p.Ala22Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- A22T (p.Ala22Thr), Ensembl rs2133675416
- M23T (p.Met23Thr), TOPMed rs1859714782
- M23V (p.Met23Val), rs747559755, ExAC rs747559755, gnomAD rs747559755, REVEL 0.21, MetaLR 0.33, Variant assessed as somatic; moderate impact.
- S28R (p.Ser28Arg), ExAC rs765097739, TOPMed rs765097739, gnomAD rs765097739, REVEL 0.31, MetaLR 0.35
- A29P (p.Ala29Pro), ESP rs370057355, ExAC rs370057355, TOPMed rs370057355, gnomAD rs370057355, REVEL 0.26, MetaLR 0.35
- A29T (p.Ala29Thr), ESP rs370057355, ExAC rs370057355, TOPMed rs370057355, gnomAD rs370057355, REVEL 0.11, MetaLR 0.25
- A29V (p.Ala29Val), cosmic curated COSV10742, Ensembl rs1357823611
- V30A (p.Val30Ala), gnomAD rs1379813834, REVEL 0.16, MetaLR 0.15
- V30I (p.Val30Ile), cosmic curated COSV61923, TOPMed rs1418393714, gnomAD rs1418393714, REVEL 0.08, MetaLR 0.20, Uncertain significance, not specified
- V30L (p.Val30Leu), TOPMed rs1418393714, gnomAD rs1418393714, REVEL 0.10, MetaLR 0.19, Uncertain significance
- T31I (p.Thr31Ile), ExAC rs780618300, TOPMed rs780618300, gnomAD rs780618300, REVEL 0.16, MetaLR 0.35
- K32E (p.Lys32Glu), gnomAD rs1421138534, REVEL 0.41, MetaLR 0.51
- D33A (p.Asp33Ala), TOPMed rs76605445, gnomAD rs76605445
- D33G (p.Asp33Gly), TOPMed rs76605445, gnomAD rs76605445, REVEL 0.26, MetaLR 0.45
- D34G (p.Asp34Gly), TOPMed rs1859714097, gnomAD rs1859714097, REVEL 0.44, MetaLR 0.49
- S35N (p.Ser35Asn), ExAC rs758804620, TOPMed rs758804620, gnomAD rs758804620, REVEL 0.42, MetaLR 0.54, Uncertain significance, not specified
- V36M (p.Val36Met), ExAC rs750708011, TOPMed rs750708011, gnomAD rs750708011, REVEL 0.32, MetaLR 0.50
- G37C (p.Gly37Cys), cosmic curated COSV61923
- G38R (p.Gly38Arg), gnomAD rs1259355702, REVEL 0.28, MetaLR 0.34, Uncertain significance, not specified
- T39A (p.Thr39Ala), Ensembl rs1859713797, REVEL 0.17, MetaLR 0.28
- T39I (p.Thr39Ile), TOPMed rs1859713750
- S41N (p.Ser41Asn), ExAC rs779230479, gnomAD rs779230479, REVEL 0.23, MetaLR 0.28
- T42M (p.Thr42Met), TOPMed rs759328711, gnomAD rs759328711, REVEL 0.17, MetaLR 0.45
- G43E (p.Gly43Glu), TOPMed rs1859713476, REVEL 0.39, MetaLR 0.41
- G43R (p.Gly43Arg), ExAC rs753791639, TOPMed rs753791639, gnomAD rs753791639, REVEL 0.39, MetaLR 0.54
- N44K (p.Asn44Lys), Ensembl rs1859713330
- N44S (p.Asn44Ser), rs1031359230, ClinGen CA220595386, ClinVar RCV004099960, TOPMed rs1031359230, REVEL 0.20, MetaLR 0.32, Uncertain significance, not specified
- L45F (p.Leu45Phe), ExAC rs759449231, gnomAD rs759449231, REVEL 0.25, MetaLR 0.37
- S46A (p.Ser46Ala), ExAC rs751488547, TOPMed rs751488547, REVEL 0.15, MetaLR 0.32
- S46C (p.Ser46Cys), TOPMed rs1294385877, gnomAD rs1294385877, REVEL 0.27, MetaLR 0.51
- S46F (p.Ser46Phe), TOPMed rs1294385877, gnomAD rs1294385877
- S46P (p.Ser46Pro), ExAC rs751488547, TOPMed rs751488547
- S48L (p.Ser48Leu), NCI-TCGA TCGA novel, REVEL 0.23, MetaLR 0.37, Variant assessed as somatic; moderate impact.
- F49L (p.Phe49Leu), gnomAD rs1311497253, REVEL 0.18, MetaLR 0.32
- M50I (p.Met50Ile), TOPMed rs1373018587
- M50T (p.Met50Thr), ExAC rs766198008, TOPMed rs766198008, gnomAD rs766198008, REVEL 0.17, MetaLR 0.26, Uncertain significance, not specified
- E51G (p.Glu51Gly), Ensembl rs1590642478, REVEL 0.36, MetaLR 0.46
- E52D (p.Glu52Asp), TOPMed rs998647138, gnomAD rs998647138, REVEL 0.16, MetaLR 0.32
- E52Q (p.Glu52Gln), Ensembl rs1859712914, REVEL 0.21, MetaLR 0.48
- I53N (p.Ile53Asn), TOPMed rs904321355, gnomAD rs904321355, REVEL 0.23, MetaLR 0.34
- V58A (p.Val58Ala), ExAC rs772870667, gnomAD rs772870667, REVEL 0.42, MetaLR 0.50
- V58I (p.Val58Ile), gnomAD rs1179758607, REVEL 0.41, MetaLR 0.43
- E59* (p.Glu59Ter), cosmic curated COSV10077
- E59D (p.Glu59Asp), cosmic curated COSV61923
- E59G (p.Glu59Gly), cosmic curated COSV10967
- D61E (p.Asp61Glu), TOPMed rs1859712412, REVEL 0.32, MetaLR 0.38, Uncertain significance, not specified
- D61G (p.Asp61Gly), Ensembl rs1353605695
- P62L (p.Pro62Leu), TOPMed rs1859712360, REVEL 0.62, MetaLR 0.49
- C70S (p.Cys70Ser), cosmic curated COSV10466
- P71A (p.Pro71Ala), gnomAD rs1455356924, REVEL 0.72, MetaLR 0.57
- P71L (p.Pro71Leu), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- R78* (p.Arg78Ter), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- R78L (p.Arg78Leu), cosmic curated COSV10077
- R78Q (p.Arg78Gln), rs1859711944, ClinGen CA380148270, NCI-TCGA Cosmic COSV1007, ClinVar RCV004471137, REVEL 0.74, MetaLR 0.68, Uncertain significance, not specified
- E79D (p.Glu79Asp), Ensembl rs1859711893, REVEL 0.25, MetaLR 0.24
- A80V (p.Ala80Val), cosmic curated COSV61923, REVEL 0.67, MetaLR 0.64
- T83M (p.Thr83Met), cosmic curated COSV61923, 1000Genomes rs199552714, ExAC rs199552714, REVEL 0.80, MetaLR 0.76
- P84L (p.Pro84Leu), Ensembl rs1564968169, REVEL 0.69, MetaLR 0.67
- P84Q (p.Pro84Gln), cosmic curated COSV10077
- G86S (p.Gly86Ser), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10077, Variant assessed as somatic; moderate impact.
- C90F (p.Cys90Phe), cosmic curated COSV10077, REVEL 0.95, MetaLR 0.98
- K91N (p.Lys91Asn), Ensembl rs2133675193
- K91R (p.Lys91Arg), gnomAD rs1263751287
- C93Y (p.Cys93Tyr), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10077, Variant assessed as somatic; moderate impact.
- I94V (p.Ile94Val), Ensembl rs1590642358
- I95L (p.Ile95Leu), ExAC rs34320471, TOPMed rs34320471, gnomAD rs34320471, REVEL 0.21, MetaLR 0.21
- S97* (p.Ser97Ter), TOPMed rs1019670034, CADD 38.00
- S97L (p.Ser97Leu), NCI-TCGA Cosmic COSV6192, cosmic curated COSV61922, Variant assessed as somatic; moderate impact.
- I98V (p.Ile98Val), TOPMed rs1859711039, REVEL 0.32, MetaLR 0.41
- R99K (p.Arg99Lys), TOPMed rs1325843053, gnomAD rs1325843053, REVEL 0.57, MetaLR 0.37
- D100E (p.Asp100Glu), 1000Genomes rs2133673051, REVEL 0.43, MetaLR 0.20
- D100N (p.Asp100Asn), Ensembl rs1859672400, REVEL 0.38, MetaLR 0.28
- A101S (p.Ala101Ser), gnomAD rs1169399583, REVEL 0.35, MetaLR 0.22
- A101T (p.Ala101Thr), NCI-TCGA Cosmic COSV6192, cosmic curated COSV61923, REVEL 0.36, MetaLR 0.27, Variant assessed as somatic; moderate impact.
- K104T (p.Lys104Thr), Ensembl rs1859672190
- C105Y (p.Cys105Tyr), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10077, Variant assessed as somatic; moderate impact.
- P106S (p.Pro106Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- N109H (p.Asn109His), cosmic curated COSV61923, REVEL 0.65, MetaLR 0.61
- N109S (p.Asn109Ser), rs368077395, cosmic curated COSV10077, ESP rs368077395, ExAC rs368077395, REVEL 0.42, MetaLR 0.41, Variant assessed as somatic; moderate impact.
- E110K (p.Glu110Lys), NCI-TCGA TCGA novel, REVEL 0.48, MetaLR 0.37, Variant assessed as somatic; moderate impact.
- L112V (p.Leu112Val), ExAC rs774914488, gnomAD rs774914488
- E114D (p.Glu114Asp), rs2494644491, ClinGen CA380147947, ClinVar RCV004471138, Uncertain significance, not specified
- E114K (p.Glu114Lys), NCI-TCGA Cosmic COSV6192, cosmic curated COSV61922, Variant assessed as somatic; moderate impact.
- N115K (p.Asn115Lys), cosmic curated COSV61921
- N115Y (p.Asn115Tyr), Ensembl rs1859671847, REVEL 0.49, MetaLR 0.50
- Q116H (p.Gln116His), 1000Genomes rs552722556, ExAC rs552722556, TOPMed rs552722556, gnomAD rs552722556, REVEL 0.67, MetaLR 0.55
- Q116K (p.Gln116Lys), ExAC rs771304757, TOPMed rs771304757, gnomAD rs771304757, REVEL 0.43, MetaLR 0.36
- Q116R (p.Gln116Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- P119R (p.Pro119Arg), Ensembl rs1564967420
- P119T (p.Pro119Thr), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10077, Variant assessed as somatic; moderate impact.
- D120N (p.Asp120Asn), NCI-TCGA Cosmic COSV6192, cosmic curated COSV61923, Variant assessed as somatic; moderate impact.
- N121S (p.Asn121Ser), cosmic curated COSV61922, ExAC rs748164490, TOPMed rs748164490, gnomAD rs748164490, REVEL 0.41, MetaLR 0.50
- A123V (p.Ala123Val), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10077, REVEL 0.54, MetaLR 0.47, Variant assessed as somatic; moderate impact.
- R125C (p.Arg125Cys), cosmic curated COSV61922, gnomAD rs945331121, REVEL 0.81, MetaLR 0.81
- E126G (p.Glu126Gly), cosmic curated COSV61922
- I127V (p.Ile127Val), ExAC rs781247915, gnomAD rs781247915, REVEL 0.32, MetaLR 0.45
- S129C (p.Ser129Cys), gnomAD rs1255863441, REVEL 0.34, MetaLR 0.22
- S129F (p.Ser129Phe), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10077, Variant assessed as somatic; moderate impact.
- M131L (p.Met131Leu), ExAC rs758390119, gnomAD rs758390119, REVEL 0.09, MetaLR 0.03
- M131V (p.Met131Val), ExAC rs758390119, gnomAD rs758390119, REVEL 0.09, MetaLR 0.04
- K133I (p.Lys133Ile), ExAC rs750341857, gnomAD rs750341857, REVEL 0.18, MetaLR 0.08
- P135A (p.Pro135Ala), ExAC rs764984865, gnomAD rs764984865, REVEL 0.13, MetaLR 0.11
- E137K (p.Glu137Lys), NCI-TCGA TCGA novel, REVEL 0.04, MetaLR 0.03, Variant assessed as somatic; moderate impact.
- L140F (p.Leu140Phe), ExAC rs757037041, gnomAD rs757037041, REVEL 0.02, MetaLR 0.05
- L140S (p.Leu140Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- H141Q (p.His141Gln), TOPMed rs1448050815, REVEL 0.02, MetaLR 0.04
- K142N (p.Lys142Asn), cosmic curated COSV10742
- K142R (p.Lys142Arg), Ensembl rs1859670719
- E144K (p.Glu144Lys), rs915337241, ClinGen CA220594191, NCI-TCGA Cosmic COSV1007, cosmic curated COSV10077, REVEL 0.13, MetaLR 0.07, Uncertain significance, not specified
- E149G (p.Glu149Gly), Ensembl rs2133672900
- D150H (p.Asp150His), gnomAD rs1859651419, REVEL 0.02, MetaLR 0.04
- D150G (p.Asp150Gly), gnomAD 11-36497265-T-C, REVEL 0.03, MetaLR 0.05
- D150Y (p.Asp150Tyr), gnomAD 11-36497266-C-A, REVEL 0.04, MetaLR 0.06
- H151N (p.His151Asn), gnomAD 11-36497263-G-T, REVEL 0.76, MetaLR 0.58
- Q152E (p.Gln152Glu), ExAC rs763790387, gnomAD rs763790387, REVEL 0.09, MetaLR 0.03
- Q152K (p.Gln152Lys), ExAC rs763790387, gnomAD rs763790387, REVEL 0.11, MetaLR 0.05
- Q152Q (p.Gln152Gln), rs755887374, gnomAD 11-36497258-T-C, CADD 10.30
- A153S (p.Ala153Ser), NCI-TCGA Cosmic COSV6192, cosmic curated COSV61921, Variant assessed as somatic; moderate impact.
- A153T (p.Ala153Thr), Ensembl rs963936751
- H154Y (p.His154Tyr), TOPMed rs1479680091
- H154R (p.His154Arg), gnomAD 11-36497253-T-C, REVEL 0.03, MetaLR 0.05
- C155F (p.Cys155Phe), cosmic curated COSV61923
- C155S (p.Cys155Ser), 1000Genomes rs184872313, ExAC rs184872313, gnomAD rs184872313, REVEL 0.81, MetaLR 0.50
- E156G (p.Glu156Gly), ExAC rs767175873, gnomAD rs767175873, REVEL 0.08, MetaLR 0.07
- F157S (p.Phe157Ser), TOPMed rs1859650985
- A158V (p.Ala158Val), gnomAD rs1293716205, REVEL 0.13, MetaLR 0.09
- A158A (p.Ala158Ala), rs1355372419, gnomAD 11-36497240-A-G, CADD 13.10
- A158G (p.Ala158Gly), gnomAD 11-36497241-G-C, REVEL 0.12, MetaLR 0.10
- A158T (p.Ala158Thr), gnomAD 11-36497242-C-T, REVEL 0.07, MetaLR 0.06
- L159F (p.Leu159Phe), ExAC rs759073172, TOPMed rs759073172, gnomAD rs759073172, REVEL 0.12, MetaLR 0.07, Uncertain significance, not specified
- M160T (p.Met160Thr), rs145863131, ClinGen CA5949781, cosmic curated COSV10526, ClinVar RCV003949230, REVEL 0.09, MetaLR 0.05, Likely benign, TRAF6-related disorder
- M160I (p.Met160Ile), gnomAD 11-36497234-C-T, REVEL 0.04, MetaLR 0.03
- M160R (p.Met160Arg), gnomAD 11-36497235-A-C, REVEL 0.08, MetaLR 0.07
- D161N (p.Asp161Asn), rs950811873, ClinGen CA220593563, ClinVar RCV004471139, TOPMed rs950811873, REVEL 0.05, MetaLR 0.02, Likely benign, not specified
- C162Y (p.Cys162Tyr), cosmic curated COSV61921
- P163L (p.Pro163Leu), TOPMed rs1186118901, gnomAD rs1186118901, REVEL 0.16, MetaLR 0.11
- P163S (p.Pro163Ser), Ensembl rs1564966938, REVEL 0.09, MetaLR 0.09
- P163P (p.Pro163Pro), gnomAD 11-36497225-G-A, CADD 5.47
- Q164Q (p.Gln164Gln), rs367735194, gnomAD 11-36497222-T-C, CADD 2.95
- C165Y (p.Cys165Tyr), cosmic curated COSV10742
- C165C (p.Cys165Cys), rs370101151, gnomAD 11-36497219-G-A, CADD 8.45
- C165A (p.Cys165Ala), gnomAD 11-36497220-CA-C, CADD 28.20
- Q166R (p.Gln166Arg), TOPMed rs1429532893, gnomAD rs1429532893, REVEL 0.09, MetaLR 0.08
- R167C (p.Arg167Cys), ESP rs374431321, ExAC rs374431321, TOPMed rs374431321, gnomAD rs374431321, REVEL 0.05, MetaLR 0.05
- R167H (p.Arg167His), cosmic curated COSV61922, TOPMed rs577802750, gnomAD rs577802750, REVEL 0.07, MetaLR 0.03, Uncertain significance, not specified
- R167R (p.Arg167Arg), rs770034805, gnomAD 11-36497213-A-G, CADD 6.33
- R167G (p.Arg167Gly), gnomAD 11-36497215-G-C, REVEL 0.08, MetaLR 0.03
- P168H (p.Pro168His), gnomAD 11-36497211-G-T, REVEL 0.03, MetaLR 0.07
- P168A (p.Pro168Ala), gnomAD 11-36497212-G-C, REVEL 0.08, MetaLR 0.03
- F169L (p.Phe169Leu), Ensembl rs75433098
- Q170P (p.Gln170Pro), Ensembl rs74830764
- K171E (p.Lys171Glu), NCI-TCGA Cosmic COSV6192, cosmic curated COSV61923, Variant assessed as somatic; moderate impact.
- K171T (p.Lys171Thr), Ensembl rs1859649844
- F172L (p.Phe172Leu), NCI-TCGA TCGA novel, REVEL 0.02, MetaLR 0.02, Variant assessed as somatic; moderate impact.
- F172S (p.Phe172Ser), TOPMed rs1859649786
- H173R (p.His173Arg), gnomAD rs1394703667, REVEL 0.16, MetaLR 0.04
- H173Y (p.His173Tyr), NCI-TCGA Cosmic COSV6192, cosmic curated COSV61923, Variant assessed as somatic; moderate impact.
- I174V (p.Ile174Val), rs762066204, ClinGen CA5949776, ClinVar RCV004471140, ExAC rs762066204, REVEL 0.10, MetaLR 0.02, Uncertain significance, not specified
- I174T (p.Ile174Thr), gnomAD 11-36497193-A-G, REVEL 0.13, MetaLR 0.05
- N175D (p.Asn175Asp), cosmic curated COSV61923
- N175S (p.Asn175Ser), Ensembl rs1859649636
- N175N (p.Asn175Asn), rs776797727, gnomAD 11-36497189-A-G, CADD 3.42
- N175I (p.Asn175Ile), gnomAD 11-36497190-T-A, REVEL 0.07, MetaLR 0.08
Public TRAF6 analysis runs
- TRAF6 analysis run — TRAF6 (793 variants) — completed 2026-08-20