TLR4
Chr 9toll like receptor 4
Also known as: ARMD10, CD284, TLR-4, TOLL
The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. In silico studies have found a particularly strong binding of surface TLR4 with the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease-2019 (COVID-19). This receptor has also been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness, and with susceptibility to age-related macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2020]
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
163 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 22 | 0 | 22 |
Likely Pathogenic | 0 | 0 | 3 | 0 | 3 |
VUS | 0 | 84 | 22 | 0 | 106 |
Likely Benign | 0 | 13 | 3 | 8 | 24 |
Benign | 0 | 4 | 1 | 2 | 7 |
Conflicting | — | 1 | |||
| Total | 0 | 101 | 51 | 10 | 163 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TLR4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
The Effect of Quadratus Lumborum (QL) Block on the Incidence of Chronic Neuropathic Pain After Retroperitoneal Laparoscopic Donor Nephrectomy: A Study on Neuroinflammation and Neurophysiology
NOT YET RECRUITINGAssessing Gut Microbiota Mediated Health Outcomes of Whole Wheat and Its Major Bioactive Components
ACTIVE NOT RECRUITINGStudy of the Effect of Innate on the Inflammatory Response to Endotoxin
RECRUITINGAdipose Tissue and Inflammation in Coronary Heart Disease
ACTIVE NOT RECRUITINGThe Role of Toll-like Receptor-4 in Periodontitis Patients With End-stage Renal Disease in a Sample of Egyptian Population
RECRUITINGEffects of Propolis Flavonoids on TLR4 Signaling and Inflammation in Human PDLSCs In Vitro
NOT YET RECRUITINGGenomic Approaches to Dissect Human Host-pathogen Interactions in the Amazonian Rainforest
NOT YET RECRUITINGThe Developmental Origins of Obesity
RECRUITINGTributyrin Treatment in Mild Alzheimer Disease: Assessment of Butyrate Effects Via the Gut-Brain
NOT YET RECRUITINGExternal Resources
Links to major genomics databases and tools