IL6ST

Chr 5ADAR

interleukin 6 cytokine family signal transducer

NCBI Gene: 3572ENSG00000134352UniProt: P40189

Signal-transducing molecule (PubMed:2261637). The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize IL6ST for initiating signal transmission. Binding of IL6 to IL6R induces IL6ST homodimerization and formation of a high-affinity receptor complex, which activates the intracellular JAK-MAPK and JAK-STAT3 signaling pathways (PubMed:19915009, PubMed:2261637, PubMed:23294003). That causes phosphorylation of IL6ST tyrosine residues which in turn activates STAT3 (PubMed:19915009, PubMed:23294003, PubMed:25731159). In parallel, the IL6 signaling pathway induces the expression of two cytokine receptor signaling inhibitors, SOCS1 and SOCS3, which inhibit JAK and terminate the activity of the IL6 signaling pathway as a negative feedback loop (By similarity). Also activates the yes-associated protein 1 (YAP) and NOTCH pathways to control inflammation-induced epithelial regeneration, independently of STAT3 (By similarity). Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL27RA/WSX1 and CNTFR (PubMed:19386761). Mediates signals which regulate immune response, hematopoiesis, pain control and bone metabolism (By similarity). Has a role in embryonic development (By similarity). Essential for survival of motor and sensory neurons and for differentiation of astrocytes (By similarity). Required for expression of TRPA1 in nociceptive neurons (By similarity). Required for the maintenance of PTH1R expression in the osteoblast lineage and for the stimulation of PTH-induced osteoblast differentiation (By similarity). Required for normal trabecular bone mass and cortical bone composition (By similarity)

Primary Disease Associations & Inheritance

?Immunodeficiency 94 with autoinflammation and dysmorphic faciesMIM #619750
AD
Hyper-IgE syndrome 4A, autosomal dominant, with recurrent infectionsMIM #619752
AD
Hyper-IgE syndrome 4B, autosomal recessive, with recurrent infectionsMIM #618523
AR
Stuve-Wiedemann syndrome 2MIM #619751
AR
585
ClinVar variants
16
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— IL6ST
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
16 Pathogenic / Likely Pathogenic· 367 VUS of 585 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.23LOEUF
pLI 1.000
Z-score 5.61
OE 0.11 (0.06–0.23)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.06Z-score
OE missense 0.86 (0.80–0.94)
408 obs / 472.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.11 (0.06–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.80–0.94)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 5 / 46.2Missense obs/exp: 408 / 472.8Syn Z: -0.09

ClinVar Variant Classifications

585 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic7
VUS367
Likely Benign193
Benign6
Conflicting3
9
Pathogenic
7
Likely Pathogenic
367
VUS
193
Likely Benign
6
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
4
0
9
Likely Pathogenic
5
0
2
0
7
VUS
6
337
20
4
367
Likely Benign
0
4
74
115
193
Benign
0
1
4
1
6
Conflicting
—3
Total16342104120585

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

IL6ST · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Immunodeficiency 94 with autoinflammation and dysmorphic facies

MIM #619750

Molecular basis of disorder known

Autosomal dominant

Hyper-IgE syndrome 4A, autosomal dominant, with recurrent infections

MIM #619752

Molecular basis of disorder known

Autosomal dominant

Hyper-IgE syndrome 4B, autosomal recessive, with recurrent infections

MIM #618523

Molecular basis of disorder known

Autosomal recessive

Stuve-Wiedemann syndrome 2

MIM #619751

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Integrated analysis of single-cell RNA-seq, bulk RNA-seq, Mendelian randomization, and eQTL reveals T cell-related nomogram model and subtype classification in rheumatoid arthritis.
Ding Q et al.·Front Immunol
2024Functional
STAT3 Hyper-IgE Syndrome-an Update and Unanswered Questions.
Tsilifis C et al.·J Clin Immunol
2021Review
Hyper IgE Syndromes.
Gracci S et al.·Curr Pediatr Rev
2024
Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting.
Zanders L et al.·J Cachexia Sarcopenia Muscle
2022
Single-Cell Sequencing of Peripheral Mononuclear Cells Reveals Distinct Immune Response Landscapes of COVID-19 and Influenza Patients.
Zhu L et al.·Immunity
2020Cohort
Inherited human ZNF341 deficiency.
Béziat V et al.·Curr Opin Immunol
2023Review
Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment.
Sternberg C et al.·Mol Cancer
2024
Microglia toxicology in α-synuclein pathology.
Zhang H et al.·Biochim Biophys Acta Mol Basis Dis
2025
New Dominant-Negative IL6ST Variants Expand the Immunological and Clinical Spectrum of GP130-Dependent Hyper-IgE Syndrome.
Arlabosse T et al.·J Clin Immunol
2023
Leveraging large-scale multi-omics evidences to identify therapeutic targets from genome-wide association studies.
Lessard S et al.·BMC Genomics
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Esophageal AdenocarcinomaOesophageal AdenocarcinomaResectable Carcinoma

Blood-borne Assessment of Stromal Activation in Esophageal Adenocarcinoma to Guide Tocilizumab Therapy

ACTIVE NOT RECRUITING
NCT04554771Phase PHASE2Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)Started 2021-01-27
Tocilizumab 20 Mg/mL Intravenous SolutionPaclitaxelCarboplatin
Knee Osteoarthritis

Dietary Supplementation With Blueberry in OA

ACTIVE NOT RECRUITING
NCT05784545Phase NAUniversity of ExeterStarted 2023-05-22
Blueberry powder supplementMaltodextrin supplementation

External Resources

Links to major genomics databases and tools