TLR8

Chr XSomaticX-linked

toll like receptor 8

Also known as: CD288, IMD98, TLR-8, hTLR8

NCBI Gene: 51311ENSG00000101916UniProt: Q9NR97OMIM: 300366

TLR8 encodes an endosomal Toll-like receptor that recognizes single-stranded RNA from pathogens and activates innate immune responses through cytokine and interferon production. Mutations cause X-linked intellectual disability with autistic features, seizures, and recurrent infections, typically manifesting in early childhood. The gene shows X-linked inheritance and is moderately constrained against loss-of-function variants (LOEUF 0.486).

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismSomatic/X-linkedLOEUF 0.491 OMIM phenotype
Clinical Summary— TLR8
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Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
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ClinVar Variants
74 unique Pathogenic / Likely Pathogenic· 72 VUS of 211 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.49LOEUF
pLI 0.324
Z-score 3.31
OE 0.23 (0.12–0.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
3.08Z-score
OE missense 0.56 (0.50–0.63)
218 obs / 389.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.23 (0.12–0.49)
0≤0.351.4
Missense OE0.56 (0.50–0.63)
0≤0.61.4
Synonymous OE1.00
0≤1.21.6
LoF obs/exp: 5 / 21.6Missense obs/exp: 218 / 389.2Syn Z: -0.02
DN
0.6648th %ile
GOF
0.7029th %ile
LOF
0.3164th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-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
DNprediction above median

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

211 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic70
Likely Pathogenic4
VUS72
Likely Benign9
Benign9
Conflicting2
70
Pathogenic
4
Likely Pathogenic
72
VUS
9
Likely Benign
9
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
67
0
70
Likely Pathogenic
1
1
2
0
4
VUS
0
68
4
0
72
Likely Benign
0
5
0
4
9
Benign
0
2
0
7
9
Conflicting
—2
Total1797311166

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

View in ClinVar →

Protein Context — Lollipop Plot

TLR8 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Structure-guided approaches to modulate endosomal toll-like receptors TLR7, TLR8 and TLR9: advances, challenges and therapeutic promise.
Matziol T et al.·Drug Discov Today
2025Review
TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy.
Rodell CB et al.·Nat Biomed Eng
2018
TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis.
Kong X et al.·Rheumatology (Oxford)
2024
Discovery of M5049: A Novel Selective Toll-Like Receptor 7/8 Inhibitor for Treatment of Autoimmunity.
Vlach J et al.·J Pharmacol Exp Ther
2021
Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade.
Ruiz-Torres DA et al.·Front Immunol
2024Clinical trial
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients