IL6 (Interleukin-6) variants and mutations
IL6 (also known as Interleukin-6) is a human protein-coding gene encoding an interleukin-6 protein. It coordinates acute-phase responses, fever, B-cell differentiation, and inflammatory signaling through JAK-STAT and related pathways. Excessive production contributes to autoimmune disease and cytokine-release syndromes, making IL-6 pathway blockade an important therapy. This analysis covers 525 IL6 variants and mutations. Of these, 76% have computational variant effect predictions. Disease context includes asthma, rheumatoid arthritis, and immune system disorder. Example IL6 variants include N2I, S3F, and S3P.
Variant analysis overview
- Gene: IL6
- Protein: Interleukin-6
- UniProt accession: P05231
- Organism: Homo sapiens
- Variants analyzed: 525
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 305 unspecified-consequence records; 118 missense variants; 5 in-frame deletions; 78 synonymous variants; 5 splice-region variants; 1 in-frame insertions; 4 stop-gained variants; 4 frameshift variants; 3 stop lost; 1 stop retained variant; 1 substitution
- Prediction scores: 401 variants have prediction scores (76% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: asthma, rheumatoid arthritis, immune system disorder, aortic stenosis, atherosclerosis, aortic valve calcification, Giant Lymph Node Hyperplasia, Kaposi sarcoma, susceptibility to, COVID-19, atrial fibrillation, hair color, Kaposi's sarcoma.
Protein structure and variant hotspots
- Protein features: 2 post-translational modification sites.
- PTM context: 6 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 IL6 variants
Examples include N2I, S3F, S3P, S3S, F4L, F4V, p.Phe4del, F4S. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- N2I (p.Asn2Ile), 1000Genomes rs200700194, ExAC rs200700194, gnomAD rs200700194, REVEL 0.22, MetaLR 0.41
- S3F (p.Ser3Phe), cosmic curated COSV51732
- S3P (p.Ser3Pro), gnomAD 7-22727269-T-C, REVEL 0.19, MetaLR 0.58
- S3S (p.Ser3Ser), gnomAD 7-22727271-C-G, CADD 5.95
- F4L (p.Phe4Leu), cosmic curated COSV51732
- F4V (p.Phe4Val), rs958965295, NCI-TCGA Cosmic COSV5173, cosmic curated COSV51732, gnomAD rs958965295, REVEL 0.13, MetaLR 0.15, Variant assessed as somatic; moderate impact.
- F4del (p.Phe4del), rs1034241131, gnomAD 7-22727270-CCTT-C, CADD 16.00
- F4S (p.Phe4Ser), gnomAD 7-22727273-T-C, REVEL 0.18, MetaLR 0.22
- F4F (p.Phe4Phe), rs1375185255, gnomAD 7-22727274-C-T, CADD 13.00
- S5F (p.Ser5Phe), TOPMed rs1224052258, gnomAD rs1224052258, REVEL 0.14, MetaLR 0.22
- S5del (p.Ser5del), gnomAD 7-22727273-TCTC-T, CADD 18.00
- T6A (p.Thr6Ala), 1000Genomes rs569143621, TOPMed rs569143621, gnomAD rs569143621, REVEL 0.15, MetaLR 0.42
- T6I (p.Thr6Ile), ExAC rs774003579, TOPMed rs774003579, gnomAD rs774003579, REVEL 0.19, MetaLR 0.55
- T6S (p.Thr6Ser), cosmic curated COSV51732
- T6K (p.Thr6Lys), gnomAD 7-22727279-C-A, REVEL 0.23, MetaLR 0.59
- S7G (p.Ser7Gly), gnomAD rs1212373109, REVEL 0.27, MetaLR 0.58
- S7R (p.Ser7Arg), 1000Genomes rs199941251, ExAC rs199941251, TOPMed rs199941251, gnomAD rs199941251, REVEL 0.34, MetaLR 0.46
- S7T (p.Ser7Thr), gnomAD rs1415468375, REVEL 0.30, MetaLR 0.44
- S7S (p.Ser7Ser), rs199941251, gnomAD 7-22727445-C-T, CADD 17.00
- A8T (p.Ala8Thr), cosmic curated COSV51732
- A8V (p.Ala8Val), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- A8A (p.Ala8Ala), rs200637969, gnomAD 7-22727448-C-A, CADD 11.40
- F9S (p.Phe9Ser), gnomAD rs1383764310, REVEL 0.33, MetaLR 0.47
- F9L (p.Phe9Leu), gnomAD 7-22727449-T-C, REVEL 0.18, MetaLR 0.26
- F9F (p.Phe9Phe), rs2128174056, gnomAD 7-22727451-C-T, CADD 13.40
- G10A (p.Gly10Ala), ExAC rs762283178, gnomAD rs762283178, REVEL 0.17, MetaLR 0.20
- G10C (p.Gly10Cys), cosmic curated COSV99331
- G10R (p.Gly10Arg), Ensembl rs937615940, REVEL 0.34, AlphaMissense 0.12
- G10S (p.Gly10Ser), rs937615940, NCI-TCGA Cosmic COSV9933, cosmic curated COSV99331, AlphaMissense 0.12, MetaLR 0.11, Variant assessed as somatic; moderate impact.
- P11L (p.Pro11Leu), Ensembl rs2128174058
- P11T (p.Pro11Thr), TOPMed rs1784030174
- P11R (p.Pro11Arg), gnomAD 7-22727456-C-G, REVEL 0.37, MetaLR 0.50
- V12L (p.Val12Leu), gnomAD rs1784030327, REVEL 0.23, MetaLR 0.28
- V12V (p.Val12Val), rs1217156737, gnomAD 7-22727460-T-C, CADD 4.25
- A13S (p.Ala13Ser), ExAC rs767924065, gnomAD rs767924065, REVEL 0.29, MetaLR 0.58
- A13V (p.Ala13Val), ExAC rs750778143, gnomAD rs750778143
- F14C (p.Phe14Cys), TOPMed rs986803797, REVEL 0.40, MetaLR 0.58
- F14L (p.Phe14Leu), ExAC rs760962452, gnomAD rs760962452, REVEL 0.27, MetaLR 0.37
- S15C (p.Ser15Cys), gnomAD rs1337461123, REVEL 0.34, MetaLR 0.50
- S15T (p.Ser15Thr), gnomAD rs1291977570, REVEL 0.23, MetaLR 0.46
- S15F (p.Ser15Phe), gnomAD 7-22727468-C-T, REVEL 0.37, MetaLR 0.50
- L16V (p.Leu16Val), gnomAD 7-22727470-C-G, REVEL 0.33, MetaLR 0.51
- L16M (p.Leu16Met), gnomAD 7-22727470-C-A, REVEL 0.35, MetaLR 0.56
- L16L (p.Leu16Leu), rs766033770, gnomAD 7-22727472-G-T, CADD 12.30
- G17R (p.Gly17Arg), Ensembl rs2128174068, REVEL 0.54, MetaLR 0.51
- G17V (p.Gly17Val), TOPMed rs1282201857, REVEL 0.54, MetaLR 0.50
- G17G (p.Gly17Gly), gnomAD 7-22727475-G-C, CADD 12.70
- L18L (p.Leu18Leu), rs753479461, gnomAD 7-22727476-C-T, CADD 13.90
- L19V (p.Leu19Val), Ensembl rs2128174072
- L19L (p.Leu19Leu), gnomAD 7-22727481-C-T, CADD 11.20
- L20M (p.Leu20Met), TOPMed rs1784031375
- L20L (p.Leu20Leu), gnomAD 7-22727482-C-T, CADD 12.60
- V21G (p.Val21Gly), Ensembl rs1583431936
- V21L (p.Val21Leu), Ensembl rs1583431931, REVEL 0.24, MetaLR 0.45
- V21M (p.Val21Met), cosmic curated COSV99331
- V21V (p.Val21Val), rs1348845707, gnomAD 7-22727487-G-A, CADD 8.95
- L22F (p.Leu22Phe), TOPMed rs1207045699, gnomAD rs1207045699, REVEL 0.15, MetaLR 0.21
- L22L (p.Leu22Leu), rs1207045699, gnomAD 7-22727490-G-A, CADD 10.80
- P23S (p.Pro23Ser), TOPMed rs1335707674, REVEL 0.09, MetaLR 0.17
- P23T (p.Pro23Thr), TOPMed rs1335707674
- A24P (p.Ala24Pro), TOPMed rs746848366, gnomAD rs746848366, REVEL 0.32, MetaLR 0.22
- A24S (p.Ala24Ser), TOPMed rs746848366, gnomAD rs746848366, REVEL 0.13, MetaLR 0.13
- A24T (p.Ala24Thr), TOPMed rs746848366, gnomAD rs746848366, REVEL 0.14, MetaLR 0.08
- A24V (p.Ala24Val), Ensembl rs2128174082
- A25T (p.Ala25Thr), gnomAD 7-22727497-G-A, REVEL 0.40, CADD 25.40
- F26L (p.Phe26Leu), gnomAD rs1784032100, REVEL 0.11, MetaLR 0.22
- P27P (p.Pro27Pro), gnomAD 7-22727505-T-A, CADD 10.90
- A28S (p.Ala28Ser), NCI-TCGA Cosmic COSV5173, cosmic curated COSV51732, Variant assessed as somatic; moderate impact.
- A28V (p.Ala28Val), NCI-TCGA Cosmic COSV5173, cosmic curated COSV51733, Variant assessed as somatic; moderate impact.
- A28D (p.Ala28Asp), gnomAD 7-22727507-C-A, REVEL 0.23, CADD 16.10
- P29R (p.Pro29Arg), gnomAD 7-22727510-C-G, REVEL 0.26, CADD 22.30
- V30I (p.Val30Ile), gnomAD rs1485376559
- V30E (p.Val30Glu), gnomAD 7-22727513-T-A, REVEL 0.25, CADD 0.05
- V30A (p.Val30Ala), gnomAD 7-22727513-T-C, REVEL 0.17, CADD 0.06
- P31H (p.Pro31His), ExAC rs778465778, TOPMed rs778465778, gnomAD rs778465778, REVEL 0.10, MetaLR 0.42
- P31R (p.Pro31Arg), ExAC rs778465778, TOPMed rs778465778, gnomAD rs778465778, REVEL 0.17, MetaLR 0.34
- P31S (p.Pro31Ser), 1000Genomes rs142759801, ESP rs142759801, ExAC rs142759801, TOPMed rs142759801, REVEL 0.09, MetaLR 0.24, Benign
- P31T (p.Pro31Thr), rs142759801, ClinGen CA4185309, ClinVar RCV000880472, ClinVar RCV003930512, REVEL 0.08, MetaLR 0.14, Benign, not provided
- P31A (p.Pro31Ala), gnomAD 7-22727515-C-G, REVEL 0.12, CADD 3.73
- P31L (p.Pro31Leu), gnomAD 7-22727516-C-T, REVEL 0.11, CADD 0.69
- P31P (p.Pro31Pro), rs1376742674, gnomAD 7-22727517-C-A, CADD 3.29
- P32Q (p.Pro32Gln), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- P32S (p.Pro32Ser), rs2069830, ClinGen CA4185311, ClinVar RCV000947003, UniProt VAR 013075, REVEL 0.17, MetaLR 0.01, Benign, not provided
- P32T (p.Pro32Thr), gnomAD 7-22727518-C-A, REVEL 0.16, CADD 5.13
- P32P (p.Pro32Pro), rs758406611, gnomAD 7-22727520-A-G, CADD 8.28
- G33A (p.Gly33Ala), gnomAD rs1362940639, REVEL 0.12, MetaLR 0.22
- G33R (p.Gly33Arg), Ensembl rs2128174095
- G33V (p.Gly33Val), gnomAD rs1362940639, REVEL 0.20, MetaLR 0.39
- G33E (p.Gly33Glu), gnomAD 7-22727522-G-A, REVEL 0.09, CADD 6.17
- E34* (p.Glu34Ter), NCI-TCGA Cosmic COSV5173, cosmic curated COSV51732, Variant assessed as somatic; high impact.
- E34A (p.Glu34Ala), gnomAD rs1784032955, REVEL 0.21, MetaLR 0.32
- E34K (p.Glu34Lys), cosmic curated COSV10635
- D35N (p.Asp35Asn), cosmic curated COSV10608
- D35V (p.Asp35Val), ExAC rs201787553, TOPMed rs201787553, gnomAD rs201787553, REVEL 0.25, MetaLR 0.49
- S36F (p.Ser36Phe), NCI-TCGA Cosmic COSV5173, cosmic curated COSV51734, Variant assessed as somatic; moderate impact.
- S36Y (p.Ser36Tyr), cosmic curated COSV51733
- S36P (p.Ser36Pro), gnomAD 7-22727530-T-C, REVEL 0.22, CADD 14.90
- K37N (p.Lys37Asn), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- K37E (p.Lys37Glu), gnomAD 7-22727533-A-G, REVEL 0.17, CADD 14.70
- K37R (p.Lys37Arg), gnomAD 7-22727534-A-G, REVEL 0.12, CADD 17.20
- D38V (p.Asp38Val), gnomAD 7-22727537-A-T, REVEL 0.16, CADD 14.50
- V39A (p.Val39Ala), gnomAD rs769904935, REVEL 0.25, MetaLR 0.14
- V39G (p.Val39Gly), gnomAD 7-22727540-T-G, REVEL 0.21, CADD 6.83
- A40D (p.Ala40Asp), rs1360685977, ClinGen CA366971860, ClinVar RCV004104204, TOPMed rs1360685977, REVEL 0.23, MetaLR 0.42, Uncertain significance, not specified
- A40G (p.Ala40Gly), TOPMed rs1360685977, gnomAD rs1360685977, Uncertain significance
- A40P (p.Ala40Pro), Ensembl rs2128174100
- A40S (p.Ala40Ser), Ensembl rs2128174100
- A40T (p.Ala40Thr), Ensembl rs2128174100
- A40V (p.Ala40Val), TOPMed rs1360685977, gnomAD rs1360685977, REVEL 0.23, MetaLR 0.39, Uncertain significance
- A40A (p.Ala40Ala), gnomAD 7-22727544-C-A, CADD 5.30
- A41T (p.Ala41Thr), ExAC rs746818346, TOPMed rs746818346, gnomAD rs746818346, REVEL 0.10, MetaLR 0.10
- A41P (p.Ala41Pro), gnomAD 7-22727545-G-C, REVEL 0.19, CADD 16.10
- A41V (p.Ala41Val), gnomAD 7-22727546-C-T, REVEL 0.11, CADD 14.30
- P42A (p.Pro42Ala), ExAC rs770802865, TOPMed rs770802865, gnomAD rs770802865, REVEL 0.11, MetaLR 0.28
- P42Q (p.Pro42Gln), Ensembl rs2128174104
- P42T (p.Pro42Thr), ExAC rs770802865, TOPMed rs770802865, gnomAD rs770802865
- P42L (p.Pro42Leu), gnomAD 7-22727549-C-T, REVEL 0.12, CADD 21.10
- H43R (p.His43Arg), ExAC rs780174319, REVEL 0.06, MetaLR 0.17
- H43Y (p.His43Tyr), Ensembl rs2128174106
- H43N (p.His43Asn), gnomAD 7-22727551-C-A, REVEL 0.13, CADD 0.13
- H43H (p.His43His), rs2128174110, gnomAD 7-22727553-C-T, CADD 0.84
- R44K (p.Arg44Lys), cosmic curated COSV10725
- R44S (p.Arg44Ser), gnomAD rs1397087240, REVEL 0.25, MetaLR 0.25
- R44T (p.Arg44Thr), Ensembl rs2128174113, REVEL 0.21, MetaLR 0.40
- R44R (p.Arg44Arg), rs199957016, gnomAD 7-22727554-A-C, CADD 7.58
- Q45* (p.Gln45Ter), Ensembl rs2128174115
- Q45K (p.Gln45Lys), NCI-TCGA Cosmic COSV5173, cosmic curated COSV51732, REVEL 0.05, MetaLR 0.16, Variant assessed as somatic; moderate impact.
- p.Gln45dup, gnomAD 7-22727555-G-GACA, CADD 6.36
- Q45Q (p.Gln45Gln), rs1306736896, gnomAD 7-22727559-G-A, CADD 2.10
- P46Q (p.Pro46Gln), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- P46S (p.Pro46Ser), Ensembl rs2128174116
- P46P (p.Pro46Pro), rs1784034202, gnomAD 7-22727562-A-G, CADD 4.65
- L47F (p.Leu47Phe), gnomAD 7-22727563-C-T, REVEL 0.26, CADD 6.49
- L47I (p.Leu47Ile), gnomAD 7-22727563-C-A, REVEL 0.22, CADD 6.37
- T48A (p.Thr48Ala), gnomAD rs1334287578, REVEL 0.19, MetaLR 0.31
- T48I (p.Thr48Ile), ExAC rs768665469, gnomAD rs768665469, REVEL 0.23, MetaLR 0.36
- T48S (p.Thr48Ser), gnomAD 7-22727567-C-G, REVEL 0.11, CADD 19.50
- T48T (p.Thr48Thr), gnomAD 7-22727568-C-T, CADD 13.50
- S49C (p.Ser49Cys), NCI-TCGA Cosmic COSV9933, cosmic curated COSV99331, Variant assessed as somatic; moderate impact.
- S49F (p.Ser49Phe), gnomAD 7-22727570-C-T, REVEL 0.16, CADD 22.80
- S50L (p.Ser50Leu), Ensembl rs2128174122
- S50S (p.Ser50Ser), gnomAD 7-22727574-A-G, CADD 8.48
- E51Q (p.Glu51Gln), NCI-TCGA Cosmic COSV5173, cosmic curated COSV51732, Ensembl rs2128174124, Variant assessed as somatic; moderate impact.
- R52* (p.Arg52Ter), NCI-TCGA Cosmic COSV5173, cosmic curated COSV51733, CADD 33.00, Variant assessed as somatic; high impact.
- R52L (p.Arg52Leu), cosmic curated COSV51734
- R52Q (p.Arg52Gln), cosmic curated COSV51733, TOPMed rs907057477, REVEL 0.02, MetaLR 0.02
- R52R (p.Arg52Arg), rs774472593, gnomAD 7-22727578-C-A, CADD 12.30
- I53T (p.Ile53Thr), rs762371056, NCI-TCGA Cosmic COSV5173, cosmic curated COSV51733, ExAC rs762371056, REVEL 0.07, MetaLR 0.03, Variant assessed as somatic; moderate impact.
- I53S (p.Ile53Ser), gnomAD 7-22727582-T-G, REVEL 0.19, CADD 8.75
- D54G (p.Asp54Gly), cosmic curated COSV51733
- D54Y (p.Asp54Tyr), cosmic curated COSV10877
- D54E (p.Asp54Glu), gnomAD 7-22727586-C-G, REVEL 0.05, CADD 7.14
- K55E (p.Lys55Glu), 1000Genomes rs202138427, ExAC rs202138427, TOPMed rs202138427, gnomAD rs202138427, REVEL 0.12, MetaLR 0.01, Likely benign, not specified
- K55R (p.Lys55Arg), 1000Genomes rs541074925, ExAC rs541074925, TOPMed rs541074925, gnomAD rs541074925, REVEL 0.02, MetaLR 0.03
- Q56E (p.Gln56Glu), Ensembl rs1562645299, REVEL 0.03, MetaLR 0.04
- Q56H (p.Gln56His), rs199925567, ClinGen CA4185323, ClinVar RCV004283203, ExAC rs199925567, REVEL 0.05, MetaLR 0.02, Likely benign, not specified
- Q56P (p.Gln56Pro), Ensembl rs1784035226
- Q56* (p.Gln56Ter), gnomAD 7-22727590-C-T, CADD 33.00
- Q56Q (p.Gln56Gln), gnomAD 7-22727592-A-G, CADD 3.42
- I57L (p.Ile57Leu), TOPMed rs1187509514, gnomAD rs1187509514, REVEL 0.14, MetaLR 0.11
- I57V (p.Ile57Val), TOPMed rs1187509514, gnomAD rs1187509514
- I57I (p.Ile57Ile), gnomAD 7-22727595-T-C, CADD 5.77
- R58Q (p.Arg58Gln), NCI-TCGA Cosmic COSV5173, cosmic curated COSV51732, Ensembl rs2128174136, Variant assessed as somatic; moderate impact.
- R58W (p.Arg58Trp), NCI-TCGA Cosmic COSV5173, cosmic curated COSV51732, REVEL 0.08, MetaLR 0.03, Variant assessed as somatic; moderate impact.
- R58R (p.Arg58Arg), rs200999878, gnomAD 7-22727598-G-A, CADD 4.66
- Y59H (p.Tyr59His), rs201822486, NCI-TCGA Cosmic COSV9933, cosmic curated COSV99331, TOPMed rs201822486, REVEL 0.04, MetaLR 0.03, Uncertain significance, not specified
- Y59F (p.Tyr59Phe), gnomAD 7-22727600-A-T, REVEL 0.12, CADD 2.16
- I60F (p.Ile60Phe), TOPMed rs1275239114, gnomAD rs1275239114, REVEL 0.30, MetaLR 0.12
- I60N (p.Ile60Asn), NCI-TCGA Cosmic COSV5173, cosmic curated COSV51733, Variant assessed as somatic; moderate impact.
- I60T (p.Ile60Thr), cosmic curated COSV51733, TOPMed rs1002676051, gnomAD rs1002676051, REVEL 0.33, MetaLR 0.15
- I60L (p.Ile60Leu), gnomAD 7-22727602-A-C, REVEL 0.11, CADD 14.10
- I60M (p.Ile60Met), gnomAD 7-22727604-C-G, REVEL 0.25, CADD 19.30
- I60I (p.Ile60Ile), rs753484746, gnomAD 7-22727604-C-A, CADD 14.50
- L61I (p.Leu61Ile), TOPMed rs1034683280
- L61L (p.Leu61Leu), rs140764737, gnomAD 7-22727607-C-T, CADD 10.60
- D62N (p.Asp62Asn), NCI-TCGA Cosmic COSV5173, cosmic curated COSV51732, TOPMed rs1784036209, REVEL 0.05, MetaLR 0.03, Variant assessed as somatic; moderate impact.
- D62Y (p.Asp62Tyr), gnomAD 7-22727608-G-T, REVEL 0.23, CADD 9.81
- D62D (p.Asp62Asp), rs764720869, gnomAD 7-22727610-C-T, CADD 8.31
- G63C (p.Gly63Cys), rs752257060, NCI-TCGA Cosmic COSV9933, cosmic curated COSV99331, REVEL 0.22, AlphaMissense 0.12, Variant assessed as somatic; moderate impact.
- G63D (p.Gly63Asp), Ensembl rs2128174148, REVEL 0.14, MetaLR 0.04
Public IL6 analysis runs
- IL6 analysis run — IL6 (525 variants) — completed 2026-08-19