TLR8

Chr XSomaticX-linked

toll like receptor 8

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

NCBI Gene: 51311 ENSG00000101916 UniProt: Q9NR97 OMIM: 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).

OMIM ResearchSummary from RefSeq, UniProt

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 (PAMPs) 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. This gene is predominantly expressed in lung and peripheral blood leukocytes, and lies in close proximity to another family member, TLR7, on chromosome X. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

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

5 unique Pathogenic / Likely Pathogenic· 68 VUS of 138 total submissions

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Clinical Trials

2 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 OE?0.23 (0.12–0.49)

0≤0.351.4

Missense OE?0.56 (0.50–0.63)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 5 / 21.6Missense obs/exp: 218 / 389.2Syn Z: -0.02

This gene — mechanism propensity

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

138 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS68

Likely Benign9

Benign9

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	1	1	0	0	2
VUS	0	68	0	0	68
Likely Benign	0	5	0	4	9
Benign	0	2	0	7	9
Conflicting	—				2
Total	1	79	0	11	93

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

View in ClinVar →

71 pathogenic / likely-pathogenic (of 75) ClinVar copy-number / structural variants overlap TLR8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →