TIRAP

Chr 11

TIR domain containing adaptor protein

Also known as: BACTS1, Mal, MyD88-2, wyatt

NCBI Gene: 114609ENSG00000150455UniProt: P58753

The TIRAP protein functions as an adapter in TLR2, TLR4, and RAGE signaling pathways, activating NF-kappa-B and MAPK pathways to trigger cytokine secretion and inflammatory responses in innate immunity. Mutations in this gene are associated with protection against bacteremia, malaria, and tuberculosis rather than causing disease. The gene shows low constraint to loss-of-function variation (pLI = 0.0008, LOEUF = 1.66), consistent with its role in protective immunity rather than essential cellular function.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

{Bacteremia, protection against}MIM #614382
{Malaria, protection against}MIM #611162
{Tuberculosis, protection against}MIM #607948
1
Active trials
26
Pubs (1 yr)
59
P/LP submissions
0%
P/LP missense
1.66
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— TIRAP
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
59 unique Pathogenic / Likely Pathogenic· 23 VUS of 100 total submissions
💊
Clinical Trials
1 active or recruiting trial — 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
Tolerant — LoF & missense variants common in population
LoF Constraint
1.66LOEUF
pLI 0.001
Z-score 0.38
OE 0.83 (0.43–1.66)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.27Z-score
OE missense 1.07 (0.93–1.22)
149 obs / 139.9 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.83 (0.43–1.66)
0≤0.351.4
Missense OE1.07 (0.93–1.22)
0≤0.61.4
Synonymous OE1.05
0≤1.21.6
LoF obs/exp: 5 / 6.0Missense obs/exp: 149 / 139.9Syn Z: -0.31
DN
0.6841th %ile
GOF
0.75top 25%
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

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic57
Likely Pathogenic2
VUS23
Likely Benign6
Benign9
57
Pathogenic
2
Likely Pathogenic
23
VUS
6
Likely Benign
9
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
57
0
57
Likely Pathogenic
0
0
2
0
2
VUS
0
17
6
0
23
Likely Benign
0
3
1
2
6
Benign
0
1
5
3
9
Total02171597

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

View in ClinVar →

Protein Context — Lollipop Plot

TIRAP · 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
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