IL6ST

Chr 5ADAR

interleukin 6 cytokine family signal transducer

Also known as: CD130, CDW130, GP130, HIES4, HIES4A, HIES4B, IL-6RB, IMD94

NCBI Gene: 3572 ENSG00000134352 UniProt: P40189 OMIM: 600694

The protein functions as a shared signal transducer for multiple cytokines including interleukin-6, forming receptor complexes that activate JAK-STAT3 signaling pathways critical for immune response, hematopoiesis, and neuronal survival. Mutations cause hyper-IgE syndromes with recurrent infections (both autosomal dominant and recessive forms), Stüve-Wiedemann syndrome 2, and immunodeficiency with autoinflammation and dysmorphic features. This gene is highly constrained against loss-of-function variants, reflecting its essential role in cytokine signaling and development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a signal transducer shared by many cytokines, including interleukin 6 (IL6), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and oncostatin M (OSM). This protein functions as a part of the cytokine receptor complex. The activation of this protein is dependent upon the binding of cytokines to their receptors. vIL6, a protein related to IL6 and encoded by the Kaposi sarcoma-associated herpesvirus, can bypass the interleukin 6 receptor (IL6R) and directly activate this protein. Knockout studies in mice suggest that this gene plays a critical role in regulating myocyte apoptosis. Alternatively spliced transcript variants have been described. A related pseudogene has been identified on chromosome 17. [provided by RefSeq, May 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.234 OMIM phenotypes

Clinical Summary— IL6ST

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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.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

1.06Z-score

OE missense 0.86 (0.80–0.94)

408 obs / 472.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.23)

0≤0.351.4

Missense OE?0.86 (0.80–0.94)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 5 / 46.2Missense obs/exp: 408 / 472.8Syn Z: -0.09

This gene — mechanism propensity

0.5378th %ile

GOF

0.6344th %ile

LOF

0.54top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOFLOEUF 0.23

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNDominant-negative mutations in human IL6ST underlie hyper-IgE syndrome1

GOFSomatic gain-of-function IL6ST mutations, in particular, small monoallelic in-frame deletions of which the most prevalent is the IL6ST Ser187_Tyr190del, are an established cause of inflammatory hepatocellular tumors, but so far, no disease caused by such mutations present constitutively has been des2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References