TLR4 (Toll-like receptor 4) variants and mutations
TLR4 (also known as Toll-like receptor 4) is a human protein-coding gene encoding a toll-like receptor 4 protein. It detects bacterial lipopolysaccharide with accessory proteins and activates NF-kappaB and interferon signaling during innate immune responses. Excessive activation contributes to septic inflammation and chronic inflammatory disease, while common variants can modify responses to microbial stimuli. This analysis covers 1,745 TLR4 variants and mutations. Of these, 59% have computational variant effect predictions. Disease context includes major depressive disorder, type 2 diabetes mellitus, and Sepsis. Example TLR4 variants include M1?, M2I, and S3T.
Variant analysis overview
- Gene: TLR4
- Protein: Toll-like receptor 4
- UniProt accession: O00206
- Organism: Homo sapiens
- Variants analyzed: 1745
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 1,434 unspecified-consequence records; 131 missense variants; 147 synonymous variants; 4 in-frame deletions; 16 frameshift variants; 2 splice-region variants; 5 stop-gained variants; 1 stop lost; 5 substitution
- Prediction scores: 1,023 variants have prediction scores (59% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: major depressive disorder, type 2 diabetes mellitus, Sepsis, dengue disease, ulcerative colitis, inborn error of immunity, psoriasis, sclerosing cholangitis, Crohn disease, ankylosing spondylitis, adolescent idiopathic scoliosis, obesity disorder.
Protein structure and variant hotspots
- Protein features: 1 transmembrane segments; 2 domains; 10 post-translational modification sites.
- Structural context: 375 variants have structural context.
- 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, MaveDB, LitVar.
Notable TLR4 variants
Examples include M1?, M2I, S3T, A4V, A4S, A4A, S5L, S5S. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, NCI-TCGA Cosmic COSV6292, cosmic curated COSV62922, Variant assessed as somatic; high impact.
- M2I (p.Met2Ile), rs1005484206, Ensembl rs1005484206, ClinGen CA374652837, ClinVar RCV003129691, AlphaMissense 0.15, MetaLR 0.05, Uncertain significance, Lung adenocarcinoma
- S3T (p.Ser3Thr), gnomAD 9-117704479-T-A, REVEL 0.00, CADD 8.04
- A4V (p.Ala4Val), TOPMed rs540134484, gnomAD rs540134484, REVEL 0.02, CADD 0.15
- A4S (p.Ala4Ser), gnomAD 9-117704482-G-T, REVEL 0.01, CADD 0.48
- A4A (p.Ala4Ala), rs1389577268, gnomAD 9-117704484-C-T, CADD 3.96
- S5L (p.Ser5Leu), cosmic curated COSV10467, TOPMed rs1588091037, REVEL 0.01, CADD 1.06
- S5S (p.Ser5Ser), rs199500883, gnomAD 9-117704487-G-A, CADD 2.42
- S5C (p.Ser5Cys), rs897794510, []
- R6C (p.Arg6Cys), ExAC rs763056825, TOPMed rs763056825, gnomAD rs763056825, REVEL 0.02, CADD 8.98
- R6H (p.Arg6His), ExAC rs770810237, gnomAD rs770810237, REVEL 0.03, CADD 17.40
- R6R (p.Arg6Arg), rs1404952872, gnomAD 9-117704490-C-G, CADD 11.50
- A8G (p.Ala8Gly), ExAC rs774003809, TOPMed rs774003809, gnomAD rs774003809, REVEL 0.06, CADD 24.60
- A8S (p.Ala8Ser), rs200829864, ClinGen CA198754304, ClinVar RCV004354519, TOPMed rs200829864, REVEL 0.09, CADD 23.80, Uncertain significance, not specified
- A8T (p.Ala8Thr), cosmic curated COSV10467, TOPMed rs200829864, gnomAD rs200829864, REVEL 0.07, CADD 24.10, Uncertain significance
- A8V (p.Ala8Val), ExAC rs774003809, TOPMed rs774003809, gnomAD rs774003809, REVEL 0.03, CADD 22.90
- G9E (p.Gly9Glu), rs537921979, NCI-TCGA Cosmic COSV1007, cosmic curated COSV10079, 1000Genomes rs537921979, REVEL 0.17, CADD 23.50, Variant assessed as somatic; moderate impact.
- G9W (p.Gly9Trp), cosmic curated COSV10079
- G9G (p.Gly9Gly), rs1234105417, gnomAD 9-117704499-G-T, CADD 11.60
- T10I (p.Thr10Ile), TOPMed rs1829102136, gnomAD rs1829102136, REVEL 0.02, CADD 4.84
- T10P (p.Thr10Pro), gnomAD rs1829102018, REVEL 0.12, CADD 16.30
- T10S (p.Thr10Ser), TOPMed rs1829102136, gnomAD rs1829102136, REVEL 0.03, CADD 3.56
- p.Thr10 Leu11del, rs1829101953, gnomAD 9-117704498-GGACT, CADD 18.20
- T10T (p.Thr10Thr), rs1173018059, gnomAD 9-117704502-T-C, CADD 5.22
- L11V (p.Leu11Val), gnomAD 9-117704503-C-G, REVEL 0.13, CADD 22.00
- I12M (p.Ile12Met), ExAC rs767566477, TOPMed rs767566477, gnomAD rs767566477
- I12I (p.Ile12Ile), rs767566477, gnomAD 9-117704508-C-T, CADD 12.00
- P13L (p.Pro13Leu), ExAC rs775509862, gnomAD rs775509862, REVEL 0.06, CADD 20.70
- P13T (p.Pro13Thr), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10079, Ensembl rs2131159976, Variant assessed as somatic; moderate impact.
- A14S (p.Ala14Ser), NCI-TCGA TCGA novel, REVEL 0.06, CADD 23.50, Variant assessed as somatic; moderate impact.
- A14V (p.Ala14Val), NCI-TCGA Cosmic COSV6292, cosmic curated COSV62924, Variant assessed as somatic; moderate impact.
- M15I (p.Met15Ile), TOPMed rs1443971167
- M15L (p.Met15Leu), ExAC rs202028525, TOPMed rs202028525, gnomAD rs202028525, REVEL 0.13, CADD 22.70
- M15V (p.Met15Val), ExAC rs202028525, TOPMed rs202028525, gnomAD rs202028525, REVEL 0.04, CADD 22.20
- M15R (p.Met15Arg), gnomAD 9-117704512-GCCAT, CADD 32.00
- A16S (p.Ala16Ser), cosmic curated COSV10079, gnomAD rs796659471, REVEL 0.03, CADD 23.20
- A16V (p.Ala16Val), cosmic curated COSV10649, NCI-TCGA TCGA novel, REVEL 0.09, CADD 23.90, Variant assessed as somatic; moderate impact.
- A16A (p.Ala16Ala), gnomAD 9-117704520-C-T, CADD 12.00
- F17L (p.Phe17Leu), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L18F (p.Leu18Phe), cosmic curated COSV62922
- L18I (p.Leu18Ile), NCI-TCGA Cosmic COSV6292, Variant assessed as somatic; moderate impact.
- S19F (p.Ser19Phe), TOPMed rs963130464
- C20S (p.Cys20Ser), ExAC rs763655001, gnomAD rs763655001, REVEL 0.21, CADD 23.80
- C20Y (p.Cys20Tyr), cosmic curated COSV10079
- C20P (p.Cys20Pro), rs1564261927, gnomAD 9-117704523-C-CCT, CADD 24.50
- C20C (p.Cys20Cys), rs374086120, gnomAD 9-117704532-C-T, CADD 14.40
- C20W (p.Cys20Trp), gnomAD 9-117704532-C-G, REVEL 0.31, CADD 26.80
- V21L (p.Val21Leu), 1000Genomes rs112840323, ESP rs112840323, ExAC rs112840323, TOPMed rs112840323, REVEL 0.01, CADD 10.60, Uncertain significance
- V21M (p.Val21Met), rs112840323, ClinGen CA5212137, ClinVar RCV004242324, 1000Genomes rs112840323, REVEL 0.15, CADD 20.60, Uncertain significance, not specified
- V21G (p.Val21Gly), gnomAD 9-117704532-C-CG, CADD 27.50
- R22G (p.Arg22Gly), rs141676121, ClinGen CA5212140, cosmic curated COSV10591, ClinVar RCV004190535, REVEL 0.11, CADD 22.90, Uncertain significance, not specified
- P23A (p.Pro23Ala), TOPMed rs1191926239, gnomAD rs1191926239, REVEL 0.06, CADD 15.00, Uncertain significance, not specified
- P23Q (p.Pro23Gln), cosmic curated COSV10591
- P23T (p.Pro23Thr), TOPMed rs1191926239, gnomAD rs1191926239, REVEL 0.05, CADD 15.80
- P23R (p.Pro23Arg), gnomAD 9-117704540-C-G, REVEL 0.16, CADD 23.50
- P23L (p.Pro23Leu), rs868087145, []
- E24D (p.Glu24Asp), Ensembl rs1829103238, REVEL 0.03, CADD 21.60
- E24K (p.Glu24Lys), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10079, Variant assessed as somatic; moderate impact.
- S25N (p.Ser25Asn), cosmic curated COSV10591
- S25R (p.Ser25Arg), cosmic curated COSV62922
- S25T (p.Ser25Thr), Ensembl rs201601258
- W26C (p.Trp26Cys), NCI-TCGA Cosmic COSV6292, cosmic curated COSV62923, Variant assessed as somatic; moderate impact.
- W26L (p.Trp26Leu), cosmic curated COSV62924
- W26R (p.Trp26Arg), 1000Genomes rs199712595, ExAC rs199712595, TOPMed rs199712595, gnomAD rs199712595
- E27D (p.Glu27Asp), cosmic curated COSV62923, REVEL 0.13, CADD 0.10
- E27Q (p.Glu27Gln), TOPMed rs200144068, gnomAD rs200144068, REVEL 0.03, CADD 22.50
- E27V (p.Glu27Val), gnomAD rs1186652911, REVEL 0.13, CADD 29.80
- E27E (p.Glu27Glu), rs200889734, gnomAD 9-117704553-G-A, CADD 2.04
- P28H (p.Pro28His), cosmic curated COSV62922, Uncertain significance, not specified
- P28T (p.Pro28Thr), gnomAD 9-117704554-C-A, REVEL 0.15, CADD 25.30
- P28S (p.Pro28Ser), gnomAD 9-117704554-C-T, REVEL 0.02, CADD 23.80
- C29* (p.Cys29Ter), cosmic curated COSV62922, CADD 34.00
- C29Y (p.Cys29Tyr), TOPMed rs1829103501, REVEL 0.44, CADD 28.40
- C29R (p.Cys29Arg), gnomAD 9-117704557-T-C, REVEL 0.56, CADD 29.90
- C29C (p.Cys29Cys), rs202003047, gnomAD 9-117704559-C-T, CADD 6.78
- V30A (p.Val30Ala), gnomAD rs1829103734, REVEL 0.08, CADD 16.30
- V30L (p.Val30Leu), ExAC rs756229233, TOPMed rs756229233, gnomAD rs756229233, REVEL 0.02, CADD 18.80
- V30M (p.Val30Met), rs756229233, NCI-TCGA Cosmic COSV6292, cosmic curated COSV62923, ExAC rs756229233, REVEL 0.02, CADD 19.70, Variant assessed as somatic; moderate impact.
- E31D (p.Glu31Asp), gnomAD rs1347844721, REVEL 0.10, CADD 33.00
- E31V (p.Glu31Val), rs1163840909, gnomAD rs1163840909, REVEL 0.24, CADD 33.00, Variant assessed as somatic; moderate impact.
- E31E (p.Glu31Glu), rs1347844721, gnomAD 9-117704565-G-A, CADD 23.40
- V32L (p.Val32Leu), cosmic curated COSV10744, gnomAD rs1301599599, REVEL 0.09, CADD 31.00
- V32M (p.Val32Met), gnomAD rs1301599599, CADD 15.20
- V32E (p.Val32Glu), gnomAD 9-117708564-T-A, REVEL 0.25, CADD 33.00
- V33F (p.Val33Phe), NCI-TCGA Cosmic COSV6292, cosmic curated COSV62922, Variant assessed as somatic; moderate impact.
- V33I (p.Val33Ile), cosmic curated COSV10744, ExAC rs200405562, TOPMed rs200405562, gnomAD rs200405562, REVEL 0.08, CADD 14.00
- V33L (p.Val33Leu), ExAC rs200405562, TOPMed rs200405562, gnomAD rs200405562, REVEL 0.04, CADD 17.00
- P34H (p.Pro34His), cosmic curated COSV62924
- P34L (p.Pro34Leu), rs1480703575, NCI-TCGA Cosmic COSV1007, cosmic curated COSV10079, NCI-TCGA Cosmic COSV6292, AlphaMissense 0.22, MetaLR 0.13, Variant assessed as somatic; moderate impact.
- P34S (p.Pro34Ser), NCI-TCGA Cosmic COSV6292, cosmic curated COSV62923, Ensembl rs1829176200, REVEL 0.13, CADD 22.30, Variant assessed as somatic; moderate impact.
- P34T (p.Pro34Thr), gnomAD 9-117708569-C-A, REVEL 0.14, CADD 22.50
- N35D (p.Asn35Asp), TOPMed rs1431441433, gnomAD rs1431441433, REVEL 0.05, CADD 18.20, Uncertain significance, not specified
- N35H (p.Asn35His), TOPMed rs1431441433, gnomAD rs1431441433
- N35S (p.Asn35Ser), gnomAD rs1829176377, REVEL 0.09, CADD 18.40, Likely benign, not specified
- N35K (p.Asn35Lys), gnomAD 9-117708573-AT-A, CADD 16.80
- I36N (p.Ile36Asn), cosmic curated COSV62924
- I36V (p.Ile36Val), ExAC rs749333850, TOPMed rs749333850, gnomAD rs749333850, REVEL 0.06, CADD 5.50
- I36S (p.Ile36Ser), gnomAD 9-117708576-T-G, REVEL 0.07, CADD 15.80
- T37I (p.Thr37Ile), gnomAD 9-117708579-C-T, REVEL 0.09, CADD 16.10
- T37T (p.Thr37Thr), gnomAD 9-117708580-T-C, CADD 4.86
- Y38* (p.Tyr38Ter), gnomAD rs1288074882, CADD 33.00
- Q39H (p.Gln39His), 1000Genomes rs201589239, ExAC rs201589239, TOPMed rs201589239, gnomAD rs201589239, REVEL 0.15, CADD 18.30
- Q39L (p.Gln39Leu), gnomAD 9-117708585-A-T, REVEL 0.20, CADD 21.90
- Q39Q (p.Gln39Gln), gnomAD 9-117708586-A-G, CADD 3.89
- C40F (p.Cys40Phe), NCI-TCGA Cosmic COSV6292, cosmic curated COSV62923, ExAC rs779025130, TOPMed rs779025130, REVEL 0.62, CADD 26.70, Variant assessed as somatic; moderate impact.
- C40G (p.Cys40Gly), Ensembl rs1829176668
- C40Y (p.Cys40Tyr), ExAC rs779025130, TOPMed rs779025130, gnomAD rs779025130, REVEL 0.62, CADD 26.60
- M41I (p.Met41Ile), cosmic curated COSV10079, Ensembl rs2131165029
- M41L (p.Met41Leu), gnomAD rs199632734
- M41V (p.Met41Val), gnomAD rs199632734, Uncertain significance, not specified
- E42K (p.Glu42Lys), cosmic curated COSV10527
- E42Q (p.Glu42Gln), ExAC rs746061968, TOPMed rs746061968, gnomAD rs746061968, REVEL 0.12, CADD 23.80
- E42E (p.Glu42Glu), rs1209407592, gnomAD 9-117708595-G-A, CADD 5.46
- L43L (p.Leu43Leu), rs1242267931, gnomAD 9-117708598-G-A, CADD 14.10
- N44H (p.Asn44His), TOPMed rs1235644534, gnomAD rs1235644534, REVEL 0.20, CADD 24.60
- N44K (p.Asn44Lys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- Y46* (p.Tyr46Ter), NCI-TCGA Cosmic COSV6292, cosmic curated COSV62922, Ensembl rs1829177303, CADD 38.00, Variant assessed as somatic; high impact.
- Y46C (p.Tyr46Cys), rs78848399, ClinVar RCV004585277, 1000Genomes rs78848399, ESP rs78848399, REVEL 0.12, CADD 22.70, Likely benign, not provided
- Y46Y (p.Tyr46Tyr), gnomAD 9-117708607-C-T, CADD 13.40
- K47R (p.Lys47Arg), Ensembl rs1829177362, REVEL 0.02, CADD 15.60
- K47I (p.Lys47Ile), gnomAD 9-117708609-A-T, REVEL 0.06, CADD 20.50
- K47K (p.Lys47Lys), rs1410888763, gnomAD 9-117708610-A-G, CADD 10.30
- I48M (p.Ile48Met), cosmic curated COSV10887
- I48I (p.Ile48Ile), gnomAD 9-117708613-C-T, CADD 5.44
- P49A (p.Pro49Ala), ExAC rs775401427, gnomAD rs775401427, REVEL 0.49, CADD 23.50, Uncertain significance, not specified
- P49H (p.Pro49His), cosmic curated COSV10527
- P49R (p.Pro49Arg), TOPMed rs1829177552
- P49S (p.Pro49Ser), rs775401427, NCI-TCGA Cosmic COSV6292, cosmic curated COSV62923, ExAC rs775401427, REVEL 0.52, CADD 24.00, Variant assessed as somatic; moderate impact.
- P49P (p.Pro49Pro), rs375037549, gnomAD 9-117708616-C-T, CADD 0.48
- D50A (p.Asp50Ala), cosmic curated COSV10527
- D50E (p.Asp50Glu), Ensembl rs1829177679
- D50N (p.Asp50Asn), rs776561489, NCI-TCGA Cosmic COSV6292, cosmic curated COSV62924, ExAC rs776561489, REVEL 0.08, CADD 7.14, Variant assessed as somatic; moderate impact.
- N51K (p.Asn51Lys), ESP rs148151027, ExAC rs148151027, TOPMed rs148151027, gnomAD rs148151027, REVEL 0.04, CADD 15.00
- N51S (p.Asn51Ser), gnomAD 9-117708621-A-G, REVEL 0.02, CADD 13.50
- N51N (p.Asn51Asn), rs148151027, gnomAD 9-117708622-C-T, CADD 6.78
- L52I (p.Leu52Ile), gnomAD 9-117708623-C-A, REVEL 0.05, CADD 4.67
- P53H (p.Pro53His), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10079, NCI-TCGA Cosmic COSV6292, Variant assessed as somatic; moderate impact.
- P53L (p.Pro53Leu), cosmic curated COSV62924
- P53S (p.Pro53Ser), NCI-TCGA Cosmic COSV6292, cosmic curated COSV62924, Variant assessed as somatic; moderate impact.
- P53P (p.Pro53Pro), gnomAD 9-117708628-C-G, CADD 4.42
- F54C (p.Phe54Cys), NCI-TCGA Cosmic COSV6292, cosmic curated COSV62923, Variant assessed as somatic; moderate impact.
- F54L (p.Phe54Leu), cosmic curated COSV62922, NCI-TCGA Cosmic COSV6292, TOPMed rs1829177984, Variant assessed as somatic; moderate impact.
- S55* (p.Ser55Ter), NCI-TCGA Cosmic COSV6292, Variant assessed as somatic; high impact.
- S55L (p.Ser55Leu), cosmic curated COSV62922, gnomAD rs1829178045, REVEL 0.29, CADD 25.00
- S55A (p.Ser55Ala), gnomAD 9-117708632-T-G, REVEL 0.13, CADD 23.20
- T56A (p.Thr56Ala), ESP rs369153844, TOPMed rs369153844, gnomAD rs369153844, REVEL 0.06, CADD 6.43, Uncertain significance, not specified
- T56T (p.Thr56Thr), gnomAD 9-117708637-C-T, CADD 5.96
- K57N (p.Lys57Asn), cosmic curated COSV10968
- K57R (p.Lys57Arg), gnomAD rs981483029, REVEL 0.07, CADD 23.00
- N58K (p.Asn58Lys), Ensembl rs1052101073
- N58N (p.Asn58Asn), gnomAD 9-117708643-C-T, CADD 1.33
- L59M (p.Leu59Met), TOPMed rs892362464, gnomAD rs892362464, REVEL 0.29, AlphaMissense 0.25
- L59V (p.Leu59Val), rs892362464, ClinGen CA374653207, ClinVar RCV004237422, AlphaMissense 0.25, MetaLR 0.66, Uncertain significance, not specified
- L59P (p.Leu59Pro), gnomAD 9-117708642-A-ACC, CADD 23.40
- D60E (p.Asp60Glu), NCI-TCGA Cosmic COSV6292, cosmic curated COSV62924, Variant assessed as somatic; moderate impact.
- D60N (p.Asp60Asn), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10079, cosmic curated COSV10467, Variant assessed as somatic; moderate impact.
- D60G (p.Asp60Gly), gnomAD 9-117708648-A-G, REVEL 0.49, CADD 27.00
- L61R (p.Leu61Arg), rs2490687062, ClinGen CA374653223, ClinVar RCV003993339, Uncertain significance, not provided
- L61L (p.Leu61Leu), rs1437519237, gnomAD 9-117708650-C-T, CADD 7.87
- L61P (p.Leu61Pro), gnomAD 9-117708651-T-C, REVEL 0.65, CADD 27.40
- S62I (p.Ser62Ile), cosmic curated COSV10744
- S62N (p.Ser62Asn), cosmic curated COSV62923
- S62R (p.Ser62Arg), cosmic curated COSV62923
- P65A (p.Pro65Ala), cosmic curated COSV10591, ExAC rs772783306, TOPMed rs772783306, gnomAD rs772783306, REVEL 0.13, CADD 7.67
- P65L (p.Pro65Leu), cosmic curated COSV62924, gnomAD rs868087145, REVEL 0.05, CADD 10.90
- P65S (p.Pro65Ser), rs772783306, NCI-TCGA Cosmic COSV1007, cosmic curated COSV10079, NCI-TCGA Cosmic COSV6292, REVEL 0.17, CADD 9.83, Variant assessed as somatic; moderate impact.
- P65T (p.Pro65Thr), cosmic curated COSV62922
- P65P (p.Pro65Pro), rs927300950, gnomAD 9-117708664-C-A, CADD 7.25
- L66M (p.Leu66Met), cosmic curated COSV62923
- R67K (p.Arg67Lys), TOPMed rs1280345843, gnomAD rs1280345843, REVEL 0.10, CADD 1.40
- R67M (p.Arg67Met), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- R67S (p.Arg67Ser), Ensembl rs1829178970
- R67G (p.Arg67Gly), gnomAD 9-117708668-A-G, REVEL 0.02, CADD 18.60
- R67R (p.Arg67Arg), gnomAD 9-117708670-G-A, CADD 6.90
- H68D (p.His68Asp), ExAC rs762574594, gnomAD rs762574594, REVEL 0.11, CADD 9.95
- H68Y (p.His68Tyr), gnomAD 9-117708671-C-T, REVEL 0.12, CADD 3.88
- H68P (p.His68Pro), gnomAD 9-117708672-A-C, REVEL 0.20, CADD 9.51
- G70S (p.Gly70Ser), TOPMed rs1217519172, gnomAD rs1217519172, REVEL 0.04, CADD 10.90
- G70G (p.Gly70Gly), rs958681405, gnomAD 9-117708679-C-A, CADD 6.23
- S71N (p.Ser71Asn), gnomAD rs200606970, REVEL 0.07, CADD 17.90
Public TLR4 analysis runs
- TLR4 analysis run — TLR4 (1,745 variants) — completed 2026-08-19