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…

Primary Disease Associations & Inheritance

Immunodeficiency 98 with autoinflammation, X-linkedMIM #301078

SomaticX-linked

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Immunodeficiency 98 with autoinflammation, X-linked; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

231

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.49

LOEUF

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in TLR8?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

601 rare PASS variants

Rare truncating (LoF)

1 in 6,200

36 rare PASS variants

Rare synonymous (reference)

1 in 180

337 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TLR8. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 160	1 in 8,800
South Asian	~36k	1 in 100	≈ 1 in 36,000
Remaining (unassigned)	~31k	1 in 94	≈ 1 in 31,000
European (Finnish)	~27k	1 in 380	≈ 1 in 14,000
Admixed American	~23k	1 in 130	none seen
African / African American	~21k	1 in 110	1 in 3,300
East Asian	~20k	1 in 110	none seen
Ashkenazi Jewish	~13k	1 in 920	1 in 2,600
Middle Eastern	~2,758	1 in 110	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 1 of 2 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 2.? see exons ↓