TLR2

Chr 4ADSomatic

toll like receptor 2

Also known as: CD282, TIL4

NCBI Gene: 7097 ENSG00000137462 UniProt: O60603

TLR2 encodes a Toll-like receptor that recognizes bacterial lipoproteins and other microbial cell wall components, cooperating with TLR1 or TLR6 to activate innate immune responses through NF-kappa-B signaling and cytokine secretion. Mutations cause increased susceptibility to infections including leprosy and tuberculosis, as well as predisposition to colorectal cancer. The gene shows autosomal dominant inheritance with low constraint against loss-of-function variants (pLI near 0).

Summary from RefSeq, OMIM, UniProt

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Primary Disease Associations & Inheritance

{Colorectal cancer, susceptibility to}MIM #114500

ADSomatic

{Leprosy, susceptibility to}MIM #246300

{Mycobacterium tuberculosis, susceptibility to}MIM #607948

Active trials

913

Pubs (1 yr)

P/LP submissions

P/LP missense

0.93

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— TLR2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 89 VUS of 153 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — TLR2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.93LOEUF

pLI 0.000

Z-score 1.80

OE 0.59 (0.38–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

0.41Z-score

OE missense 0.94 (0.87–1.03)

380 obs / 403.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.59 (0.38–0.93)

0≤0.351.4

Missense OE0.94 (0.87–1.03)

0≤0.61.4

Synonymous OE0.91

0≤1.21.6

LoF obs/exp: 13 / 22.1Missense obs/exp: 380 / 403.0Syn Z: 0.94

0.75top 25%

GOF

0.75top 25%

LOF

0.2092th %ile

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.

DNprediction above median · 1 literature citation

GOFprediction 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.

Literature Evidence

DNThe TLR2-P631H mutant has a dominant negative effect on the wild type TLR2 signalling in transfected HEK293 kidney cells using the NF-kappaB-driven luciferase as a reporter gene with ligands like M. avium extracts, Pam3CysSK4 or FSL-1 that bind TLR2/TLR1 or TLR2/TLR6 heterodimers, respectively.PMID:20500688

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.