IL6R (P08887) variants and mutations
IL6R (also known as P08887) is a human protein-coding gene encoding an interleukin-6 receptor subunit alpha protein. It binds IL-6 and signals through gp130 either from the cell surface or as a soluble receptor, allowing both classical and trans-signaling. Genetic and pharmacologic reduction of IL-6 receptor signaling lowers inflammatory activity and is therapeutically useful in several immune-mediated diseases. This analysis covers 759 IL6R variants and mutations. Of these, 82% have computational variant effect predictions. Disease context includes rheumatoid arthritis, Eczematoid dermatitis, and COVID-19. Example IL6R variants include L2M, L2L, and L2Q.
Variant analysis overview
- Gene: IL6R
- Protein: P08887
- UniProt accession: P08887
- Organism: Homo sapiens
- Variants analyzed: 759
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 523 unspecified-consequence records; 83 synonymous variants; 17 frameshift variants; 124 missense variants; 9 stop-gained variants; 1 in-frame deletions; 2 splice-region variants
- Prediction scores: 624 variants have prediction scores (82% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: rheumatoid arthritis, Eczematoid dermatitis, COVID-19, juvenile idiopathic arthritis, neuromyelitis optica, coronary artery disorder, temporal arteritis, hyper-IgE recurrent infection syndrome 5, autosomal recessive, asthma, atopic eczema, dermatitis, abdominal aortic aneurysm.
Protein structure and variant hotspots
- Protein features: 1 transmembrane segments; 3 domains; 6 post-translational modification sites.
- Structural context: 485 variants have structural context.
- PTM context: 10 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 IL6R variants
Examples include L2M, L2L, L2Q, L2P, A3S, A3T, A3P, A3D. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- L2M (p.Leu2Met), TOPMed rs962968046, gnomAD rs962968046, REVEL 0.06, CADD 23.60
- L2L (p.Leu2Leu), gnomAD 1-154405633-C-T, CADD 14.60
- L2Q (p.Leu2Gln), gnomAD 1-154405634-T-A, REVEL 0.09, CADD 24.50
- L2P (p.Leu2Pro), gnomAD 1-154405634-T-C, REVEL 0.14, CADD 26.60
- A3S (p.Ala3Ser), rs894754581, ClinGen CA342595309, ClinVar RCV002690479, ClinVar RCV004758237, REVEL 0.08, CADD 22.50, Uncertain significance, not provided
- A3T (p.Ala3Thr), TOPMed rs894754581, gnomAD rs894754581, REVEL 0.06, CADD 21.40, Uncertain significance
- A3P (p.Ala3Pro), gnomAD 1-154405634-TG-T, CADD 24.70
- A3D (p.Ala3Asp), gnomAD 1-154405637-C-A, REVEL 0.11, CADD 22.80
- A3G (p.Ala3Gly), gnomAD 1-154405637-C-G, REVEL 0.09, CADD 23.10
- A3V (p.Ala3Val), gnomAD 1-154405637-C-T, REVEL 0.12, CADD 23.90
- A3A (p.Ala3Ala), rs1392390296, gnomAD 1-154405638-C-T, CADD 11.60
- V4F (p.Val4Phe), rs867881689, ClinGen CA30783874, ClinVar RCV001938262, 1000Genomes rs867881689, REVEL 0.06, CADD 23.40, Uncertain significance, not provided
- V4I (p.Val4Ile), 1000Genomes rs867881689, TOPMed rs867881689, gnomAD rs867881689, REVEL 0.02, CADD 16.40, Uncertain significance
- V4A (p.Val4Ala), rs1687658446, gnomAD 1-154405634-TGGCC, CADD 25.60
- V4L (p.Val4Leu), gnomAD 1-154405639-G-C, REVEL 0.02, CADD 17.60
- V4V (p.Val4Val), rs1413222090, gnomAD 1-154405641-C-A, CADD 8.48
- G5R (p.Gly5Arg), TOPMed rs1315405835, gnomAD rs1315405835, REVEL 0.22, CADD 5.03
- G5V (p.Gly5Val), TOPMed rs1687659801, gnomAD rs1687659801, REVEL 0.14, CADD 13.80
- G5C (p.Gly5Cys), gnomAD 1-154405642-G-T, REVEL 0.13, CADD 10.30
- G5S (p.Gly5Ser), gnomAD 1-154405642-G-A, REVEL 0.12, CADD 5.13
- G5D (p.Gly5Asp), gnomAD 1-154405643-G-A, REVEL 0.20, CADD 12.90
- G5G (p.Gly5Gly), rs1376117788, gnomAD 1-154405644-C-T, CADD 10.70
- C6S (p.Cys6Ser), gnomAD 1-154405645-T-A, REVEL 0.19, CADD 16.30
- C6R (p.Cys6Arg), gnomAD 1-154405645-T-C, REVEL 0.12, CADD 20.40
- C6F (p.Cys6Phe), gnomAD 1-154405646-G-T, REVEL 0.25, CADD 23.40
- C6Y (p.Cys6Tyr), gnomAD 1-154405646-G-A, REVEL 0.26, CADD 23.40
- C6C (p.Cys6Cys), rs1687660121, gnomAD 1-154405647-C-T, CADD 9.28
- C6* (p.Cys6Ter), gnomAD 1-154405647-C-A, CADD 33.00
- A7T (p.Ala7Thr), TOPMed rs1687660276, REVEL 0.11, CADD 12.90
- A7V (p.Ala7Val), gnomAD rs1409349805, REVEL 0.08, CADD 14.60
- A7S (p.Ala7Ser), gnomAD 1-154405648-G-T, REVEL 0.09, CADD 16.40
- A7E (p.Ala7Glu), gnomAD 1-154405649-C-A, REVEL 0.19, CADD 22.60
- A7A (p.Ala7Ala), rs777001411, gnomAD 1-154405650-G-T, CADD 7.45
- L8V (p.Leu8Val), gnomAD 1-154405651-C-G, REVEL 0.09, MetaLR 0.04
- L8L (p.Leu8Leu), gnomAD 1-154405651-C-T, CADD 8.26
- L8M (p.Leu8Met), gnomAD 1-154405651-C-A, REVEL 0.10, MetaLR 0.05
- L8P (p.Leu8Pro), gnomAD 1-154405652-T-C, REVEL 0.24, MetaLR 0.06
- L8Q (p.Leu8Gln), gnomAD 1-154405652-T-A, REVEL 0.17, MetaLR 0.06
- L9L (p.Leu9Leu), rs567699349, gnomAD 1-154405654-C-T, CADD 8.50
- L9M (p.Leu9Met), gnomAD 1-154405654-C-A, REVEL 0.16, MetaLR 0.08
- L9P (p.Leu9Pro), gnomAD 1-154405655-T-C, REVEL 0.30, MetaLR 0.11
- L9Q (p.Leu9Gln), gnomAD 1-154405655-T-A, REVEL 0.20, MetaLR 0.10
- A10T (p.Ala10Thr), gnomAD 1-154405657-G-A, REVEL 0.07, MetaLR 0.00
- A10S (p.Ala10Ser), gnomAD 1-154405657-G-T, REVEL 0.07, MetaLR 0.01
- A10P (p.Ala10Pro), gnomAD 1-154405657-G-C, REVEL 0.12, MetaLR 0.01
- A10G (p.Ala10Gly), gnomAD 1-154405658-C-G, REVEL 0.05, MetaLR 0.01
- A10D (p.Ala10Asp), gnomAD 1-154405658-C-A, REVEL 0.10, MetaLR 0.02
- A10V (p.Ala10Val), gnomAD 1-154405658-C-T, REVEL 0.04, MetaLR 0.01
- A10A (p.Ala10Ala), gnomAD 1-154405659-T-C, CADD 10.00
- A11S (p.Ala11Ser), TOPMed rs1240042661, gnomAD rs1240042661, REVEL 0.05, CADD 11.30
- A11T (p.Ala11Thr), TOPMed rs1240042661, gnomAD rs1240042661, REVEL 0.09, CADD 14.40
- A11V (p.Ala11Val), gnomAD rs1273991580, REVEL 0.05, CADD 16.10
- A11D (p.Ala11Asp), gnomAD 1-154405661-C-A, REVEL 0.14, MetaLR 0.06
- A11A (p.Ala11Ala), rs762073642, gnomAD 1-154405662-C-T, CADD 10.30
- L12M (p.Leu12Met), gnomAD 1-154405663-C-A, REVEL 0.10, MetaLR 0.05
- L12L (p.Leu12Leu), rs1212907967, gnomAD 1-154405663-C-T, CADD 7.65
- L12P (p.Leu12Pro), gnomAD 1-154405664-T-C, REVEL 0.21, MetaLR 0.07
- L13R (p.Leu13Arg), gnomAD 1-154405656-GGCTG, CADD 24.50
- L13W (p.Leu13Trp), gnomAD 1-154405664-TG-T, CADD 22.80
- L13L (p.Leu13Leu), gnomAD 1-154405666-C-T, CADD 9.64
- L13M (p.Leu13Met), gnomAD 1-154405666-C-A, REVEL 0.11, MetaLR 0.07
- L13P (p.Leu13Pro), gnomAD 1-154405667-T-C, REVEL 0.23, MetaLR 0.08
- A14T (p.Ala14Thr), gnomAD 1-154405669-G-A, REVEL 0.05, MetaLR 0.02
- A14S (p.Ala14Ser), gnomAD 1-154405669-G-T, REVEL 0.04, MetaLR 0.02
- A14D (p.Ala14Asp), gnomAD 1-154405670-C-A, REVEL 0.10, MetaLR 0.05
- A14V (p.Ala14Val), gnomAD 1-154405670-C-T, REVEL 0.05, MetaLR 0.03
- A14A (p.Ala14Ala), gnomAD 1-154405671-C-T, CADD 9.56
- A15T (p.Ala15Thr), gnomAD 1-154405672-G-A, REVEL 0.01, MetaLR 0.02
- A15S (p.Ala15Ser), gnomAD 1-154405672-G-T, REVEL 0.03, MetaLR 0.01
- A15V (p.Ala15Val), gnomAD 1-154405673-C-T, REVEL 0.03, MetaLR 0.02
- A15E (p.Ala15Glu), gnomAD 1-154405673-C-A, REVEL 0.06, MetaLR 0.03
- A15A (p.Ala15Ala), gnomAD 1-154405674-G-T, CADD 7.10
- P16L (p.Pro16Leu), rs2149196136, ClinGen CA342595522, ClinVar RCV002011772, Ensembl rs2149196136, REVEL 0.02, CADD 5.53, Uncertain significance, not provided
- P16S (p.Pro16Ser), gnomAD 1-154405675-C-T, REVEL 0.03, MetaLR 0.01
- P16T (p.Pro16Thr), gnomAD 1-154405675-C-A, REVEL 0.05, MetaLR 0.01
- P16R (p.Pro16Arg), gnomAD 1-154405676-C-G, REVEL 0.05, MetaLR 0.02
- P16Q (p.Pro16Gln), gnomAD 1-154405676-C-A, REVEL 0.05, MetaLR 0.02
- P16P (p.Pro16Pro), gnomAD 1-154405677-G-C, CADD 8.63
- G17A (p.Gly17Ala), rs1438000486, ClinGen CA342595536, ClinVar RCV002026925, TOPMed rs1438000486, REVEL 0.02, CADD 9.31, Uncertain significance, not provided
- G17R (p.Gly17Arg), gnomAD rs1253366021, REVEL 0.06, CADD 18.90
- G17* (p.Gly17Ter), gnomAD 1-154405678-G-T, CADD 33.00
- G17V (p.Gly17Val), gnomAD 1-154405679-G-T, REVEL 0.06, MetaLR 0.02
- G17E (p.Gly17Glu), gnomAD 1-154405679-G-A, REVEL 0.02, MetaLR 0.02
- G17G (p.Gly17Gly), rs528464156, gnomAD 1-154405680-A-G, CADD 8.98
- A18E (p.Ala18Glu), gnomAD rs1377391987, REVEL 0.06, CADD 0.21
- A18R (p.Ala18Arg), gnomAD 1-154405679-GA-G, CADD 16.00
- A18T (p.Ala18Thr), gnomAD 1-154405681-G-A, REVEL 0.02, MetaLR 0.01
- A18S (p.Ala18Ser), gnomAD 1-154405681-G-T, REVEL 0.02, MetaLR 0.02
- A18V (p.Ala18Val), gnomAD 1-154405682-C-T, REVEL 0.02, MetaLR 0.01
- A18A (p.Ala18Ala), gnomAD 1-154405683-G-A, CADD 9.03
- A19T (p.Ala19Thr), rs758469371, ClinGen CA1128902, ClinVar RCV001882942, ClinVar RCV004927734, REVEL 0.04, CADD 10.40, Uncertain significance, not specified; not provided
- A19V (p.Ala19Val), Ensembl rs1687663717, REVEL 0.04, CADD 18.30
- A19E (p.Ala19Glu), gnomAD 1-154405685-C-A, REVEL 0.04, MetaLR 0.02
- A19A (p.Ala19Ala), rs1396279859, gnomAD 1-154405686-G-A, CADD 6.45
- L20M (p.Leu20Met), gnomAD 1-154405687-C-A, REVEL 0.08, MetaLR 0.04
- L20L (p.Leu20Leu), rs767401791, gnomAD 1-154405689-G-A, CADD 9.31
- A21P (p.Ala21Pro), Ensembl rs1558292924, REVEL 0.07, CADD 18.50
- A21T (p.Ala21Thr), gnomAD 1-154405690-G-A, REVEL 0.01, MetaLR 0.02
- A21S (p.Ala21Ser), gnomAD 1-154405690-G-T, REVEL 0.02, MetaLR 0.01
- A21D (p.Ala21Asp), gnomAD 1-154405691-C-A, REVEL 0.05, MetaLR 0.03
- A21V (p.Ala21Val), gnomAD 1-154405691-C-T, REVEL 0.02, MetaLR 0.01
- A21A (p.Ala21Ala), gnomAD 1-154405692-C-T, CADD 8.11
- P22Q (p.Pro22Gln), gnomAD 1-154405690-GC-G, CADD 13.20
- P22T (p.Pro22Thr), gnomAD 1-154405693-C-A, REVEL 0.07, MetaLR 0.01
- P22S (p.Pro22Ser), gnomAD 1-154405693-C-T, REVEL 0.04, MetaLR 0.01
- P22R (p.Pro22Arg), gnomAD 1-154405694-C-G, REVEL 0.06, MetaLR 0.01
- P22P (p.Pro22Pro), gnomAD 1-154405695-A-G, CADD 3.56
- R23K (p.Arg23Lys), gnomAD rs1306195163, REVEL 0.01, CADD 5.79
- R23G (p.Arg23Gly), gnomAD 1-154405696-A-G, REVEL 0.03, MetaLR 0.01
- R23T (p.Arg23Thr), gnomAD 1-154405697-G-C, REVEL 0.02, MetaLR 0.01
- R23M (p.Arg23Met), gnomAD 1-154405697-G-T, REVEL 0.03, MetaLR 0.01
- R23S (p.Arg23Ser), gnomAD 1-154405698-G-T, REVEL 0.04, MetaLR 0.01
- R24C (p.Arg24Cys), gnomAD rs1398752017, REVEL 0.04, CADD 14.00
- R24H (p.Arg24His), TOPMed rs1309026478, REVEL 0.01, CADD 8.37
- R24S (p.Arg24Ser), gnomAD rs1398752017, REVEL 0.01, CADD 1.88
- R24P (p.Arg24Pro), gnomAD 1-154405700-G-C, REVEL 0.09, MetaLR 0.01
- R24L (p.Arg24Leu), gnomAD 1-154405700-G-T, REVEL 0.01, MetaLR 0.01
- R24R (p.Arg24Arg), gnomAD 1-154405701-C-G, CADD 8.97
- C25* (p.Cys25Ter), TOPMed rs1287550693, gnomAD rs1287550693, CADD 32.00
- p.Cys25 Gln28del, gnomAD 1-154405701-CTGCC, CADD 16.00
- C25F (p.Cys25Phe), gnomAD 1-154405703-G-T, REVEL 0.08, MetaLR 0.06
- C25C (p.Cys25Cys), gnomAD 1-154405704-C-T, CADD 8.22
- P26L (p.Pro26Leu), rs1392150709, ClinGen CA342595705, ClinVar RCV002017911, gnomAD rs1392150709, REVEL 0.02, CADD 13.10, Uncertain significance, not provided
- P26S (p.Pro26Ser), gnomAD 1-154405705-C-T, REVEL 0.03, MetaLR 0.01
- P26R (p.Pro26Arg), gnomAD 1-154405706-C-G, REVEL 0.02, MetaLR 0.01
- P26H (p.Pro26His), gnomAD 1-154405706-C-A, REVEL 0.04, MetaLR 0.02
- P26P (p.Pro26Pro), gnomAD 1-154405707-T-G, CADD 9.44
- A27S (p.Ala27Ser), gnomAD 1-154405708-G-T, REVEL 0.01, MetaLR 0.01
- A27G (p.Ala27Gly), gnomAD 1-154405709-C-G, REVEL 0.01, MetaLR 0.01
- A27V (p.Ala27Val), gnomAD 1-154405709-C-T, REVEL 0.01, MetaLR 0.01
- A27E (p.Ala27Glu), gnomAD 1-154405709-C-A, REVEL 0.03, MetaLR 0.01
- A27A (p.Ala27Ala), rs1323201526, gnomAD 1-154405710-G-T, CADD 9.47
- Q28G (p.Gln28Gly), gnomAD 1-154405656-G-GGC, CADD 22.80
- Q28K (p.Gln28Lys), gnomAD 1-154405711-C-A, REVEL 0.09, MetaLR 0.01
- Q28* (p.Gln28Ter), gnomAD 1-154405711-C-T, CADD 34.00
- Q28L (p.Gln28Leu), gnomAD 1-154405712-A-T, REVEL 0.09, MetaLR 0.00
- Q28R (p.Gln28Arg), gnomAD 1-154405712-A-G, REVEL 0.04, MetaLR 0.00
- Q28Q (p.Gln28Gln), gnomAD 1-154405713-G-A, CADD 5.41
- E29V (p.Glu29Val), TOPMed rs1044860196
- E29* (p.Glu29Ter), gnomAD 1-154405714-G-T, CADD 43.00
- E29K (p.Glu29Lys), gnomAD 1-154405714-G-A, REVEL 0.07, MetaLR 0.02
- A31V (p.Ala31Val), rs868345266, NCI-TCGA Cosmic COSV5981, cosmic curated COSV59815, gnomAD rs868345266, REVEL 0.03, CADD 1.08, Variant assessed as somatic; moderate impact.
- A31A (p.Ala31Ala), rs2228144, gnomAD 1-154429203-G-A, CADD 0.78
- R32K (p.Arg32Lys), Ensembl rs1689150816, REVEL 0.04, CADD 0.25
- R32T (p.Arg32Thr), Ensembl rs1689150816, REVEL 0.02, CADD 0.50
- G33S (p.Gly33Ser), Ensembl rs1570950659
- G33G (p.Gly33Gly), rs538533109, gnomAD 1-154429209-C-T, CADD 0.12
- V34G (p.Val34Gly), 1000Genomes rs2149235303, REVEL 0.10, CADD 15.50
- V34M (p.Val34Met), rs762153528, ClinGen CA1128917, ClinVar RCV002575827, ExAC rs762153528, REVEL 0.07, CADD 12.20, Uncertain significance, not provided
- V34L (p.Val34Leu), gnomAD 1-154429210-G-T, REVEL 0.06, MetaLR 0.02
- V34V (p.Val34Val), rs765593427, gnomAD 1-154429212-G-A, CADD 2.59
- L35Q (p.Leu35Gln), ExAC rs773458420, TOPMed rs773458420, gnomAD rs773458420, REVEL 0.12, CADD 17.00
- L35P (p.Leu35Pro), gnomAD 1-154429211-TGCTG, CADD 23.50
- L35L (p.Leu35Leu), gnomAD 1-154429215-G-A, CADD 4.32
- T36A (p.Thr36Ala), rs766474176, ClinGen CA1128921, ClinVar RCV002041243, ExAC rs766474176, REVEL 0.10, CADD 8.57, Uncertain significance, not provided
- T36P (p.Thr36Pro), gnomAD 1-154429216-A-C, REVEL 0.19, MetaLR 0.05
- S37G (p.Ser37Gly), TOPMed rs994608378, gnomAD rs994608378, REVEL 0.04, CADD 7.48
- S37I (p.Ser37Ile), gnomAD 1-154429220-G-T, REVEL 0.11, MetaLR 0.06
- L38V (p.Leu38Val), ExAC rs752579637, TOPMed rs752579637, gnomAD rs752579637, REVEL 0.08, CADD 1.07
- L38L (p.Leu38Leu), rs752579637, gnomAD 1-154429222-C-T, CADD 1.96
- P39A (p.Pro39Ala), gnomAD rs1274153124, REVEL 0.16, CADD 20.40
- P39S (p.Pro39Ser), gnomAD rs1274153124
- P39L (p.Pro39Leu), gnomAD 1-154429226-C-T, REVEL 0.20, MetaLR 0.04
- G40V (p.Gly40Val), TOPMed rs1165971497, gnomAD rs1165971497, REVEL 0.41, CADD 24.00
- G40R (p.Gly40Arg), gnomAD 1-154429228-G-A, REVEL 0.35, MetaLR 0.14
- G40E (p.Gly40Glu), gnomAD 1-154429229-G-A, REVEL 0.35, MetaLR 0.12
- D41E (p.Asp41Glu), rs1393806703, TOPMed rs1393806703, gnomAD rs1393806703, ClinGen CA342602649, REVEL 0.01, CADD 16.70, Uncertain significance, not provided
- S42G (p.Ser42Gly), Ensembl rs1689155397
- S42N (p.Ser42Asn), ExAC rs763907785, TOPMed rs763907785, gnomAD rs763907785, REVEL 0.01, CADD 0.02
- S42R (p.Ser42Arg), 1000Genomes rs34099703, ESP rs34099703, ExAC rs34099703, TOPMed rs34099703, Benign
- S42T (p.Ser42Thr), ExAC rs763907785, TOPMed rs763907785, gnomAD rs763907785, REVEL 0.02, CADD 0.10
- S42S (p.Ser42Ser), rs34099703, gnomAD 1-154429236-C-T, CADD 0.08
- V43M (p.Val43Met), rs757025871, ClinGen CA1128926, cosmic curated COSV59816, ClinVar RCV001869978, REVEL 0.23, CADD 22.80, Uncertain significance, Hyper-IgE recurrent infection syndrome 5, autosomal recessive; not specified; no
- T44S (p.Thr44Ser), gnomAD rs1429634359, REVEL 0.06, CADD 8.19
- T44T (p.Thr44Thr), rs778489682, gnomAD 1-154429242-T-C, CADD 4.71
- L45L (p.Leu45Leu), gnomAD 1-154429245-G-T, CADD 4.35
- T46S (p.Thr46Ser), NCI-TCGA Cosmic COSV1006, cosmic curated COSV10069, Variant assessed as somatic; moderate impact.
- T46I (p.Thr46Ile), gnomAD 1-154429247-C-T, REVEL 0.04, MetaLR 0.01
- T46T (p.Thr46Thr), gnomAD 1-154429248-C-T, CADD 6.31
- C47G (p.Cys47Gly), gnomAD 1-154429249-T-G, REVEL 0.81, MetaLR 0.89
Public IL6R analysis runs
- IL6R analysis run — IL6R (759 variants) — completed 2026-08-19