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

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 OE0.11 (0.06–0.23)

0≤0.351.4

Missense OE0.86 (0.80–0.94)

0≤0.61.4

Synonymous OE1.01

0≤1.21.6

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

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 syndromePMID:32207811

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 desPMID:33517393

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