IL6

Chr 7MultiSomaticADAR

interleukin 6

Also known as: BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2, IFNB2, IL-6

NCBI Gene: 3569 ENSG00000136244 UniProt: P05231

This gene encodes a cytokine that functions in inflammation and the maturation of B cells. In addition, the encoded protein has been shown to be an endogenous pyrogen capable of inducing fever in people with autoimmune diseases or infections. The protein is primarily produced at sites of acute and chronic inflammation, where it is secreted into the serum and induces a transcriptional inflammatory response through interleukin 6 receptor, alpha. The functioning of this gene is implicated in a wide variety of inflammation-associated disease states, including suspectibility to diabetes mellitus and systemic juvenile rheumatoid arthritis. Elevated levels of the encoded protein have been found in virus infections, including COVID-19 (disease caused by SARS-CoV-2). [provided by RefSeq, Aug 2020]

Primary Disease Associations & Inheritance

{Crohn disease-associated growth failure}MIM #266600

Multi

{Intracranial hemorrhage in brain cerebrovascular malformations, susceptibility to}MIM #108010

Somatic

{Kaposi sarcoma in HIV+, susceptibility to}MIM #148000

{Rheumatoid arthritis, systemic juvenile}MIM #604302

{Type 1 diabetes mellitus}MIM #222100

{Type 2 diabetes mellitus}MIM #125853

ClinVar variants

Pathogenic / LP

0.32

pLI score

Active trials

Clinical Summary— IL6

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

30 Pathogenic / Likely Pathogenic· 21 VUS of 60 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

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.

0.75LOEUF

pLI 0.315

Z-score 2.04

OE 0.24 (0.10–0.75)

Tolerant

Typical tolerance to LoF variation

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.

0.00Z-score

OE missense 1.00 (0.86–1.17)

112 obs / 112.1 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.0.24 (0.10–0.75)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.00 (0.86–1.17)

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.0.99

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	28	0	28
Likely Pathogenic	0	2	0	2
VUS	12	9	0	21
Likely Benign	2	0	2	4
Benign	3	1	1	5
Total	17	40	3	60

IL6

Primary Disease Associations & Inheritance

Population Genetics & Constraint

ClinVar Variant Classifications

Classification Summary

Curated Variants Distribution

Protein Context — Lollipop Plot

DECIPHER · Gene2Phenotype

Gene2Phenotype Curations

OMIM — Genotype-Phenotype Relationships

Gene Overview

ClinGen Curation

Disease Associations

External Resources

Variant Interpretation

Population Databases

Gene Resources