NLRP3
Chr 1ADNLR family pyrin domain containing 3
Also known as: AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1, DFNA34, FCAS
This protein functions as a sensor component of the NLRP3 inflammasome complex, which detects membrane integrity defects and triggers the secretion of inflammatory cytokines IL1B and IL18. Mutations cause a spectrum of autoinflammatory disorders including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and CINCA syndrome, as well as autosomal dominant hearing loss with or without inflammation. These conditions follow autosomal dominant inheritance and typically involve the skin, joints, central nervous system, and auditory system, with some presenting in the neonatal period.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Moderately missense-constrained (top ~2.5%)
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.
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
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
200 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 1 | 0 | 1 |
Likely Pathogenic | 0 | 2 | 1 | 0 | 3 |
VUS | 5 | 120 | 9 | 2 | 136 |
Likely Benign | 0 | 2 | 18 | 35 | 55 |
Benign | 1 | 0 | 1 | 0 | 2 |
Conflicting | — | 3 | |||
| Total | 6 | 124 | 30 | 37 | 200 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
NLRP3 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Effects of Gender-Affirming Hormone Therapy on Cardiovascular, Metabolic, and Mental Health Outcomes in Transgender Adults.
NOT YET RECRUITINGAdipose Tissue and Inflammation in Coronary Heart Disease
ACTIVE NOT RECRUITINGEffects of Specific Amino Acid Supplementation and Lifestyle Factors on Brain Ageing
RECRUITINGMechanistic Studies of Nicotinamide Riboside in Human Heart Failure
ACTIVE NOT RECRUITINGEffects of Different Fish Oil Types on Type 2 Diabetes Risk Factors in High-Risk Adults
NOT YET RECRUITINGTargeting Risk Factors for Diabetes in Subjects With Normal Blood Cholesterol Using Omega-3 Fatty Acids
RECRUITINGProbiotics in Mild Alzheimer's Disease
RECRUITINGEGR2 and NLRP3 Pathways in Obstructive Sleep Apnea-Related Cognitive and Mood Disorders
RECRUITINGNon-Ablative Laser to Treat Scarring Alopecia With Hair Follicle Gene Expression Analysis
RECRUITINGEvaluation of the Effect of Smoking on Pyroptosis in Periodontal Pathogenesis
ACTIVE NOT RECRUITINGStudies of the Natural History, Pathogenesis, and Outcome of Autoinflammatory Diseases Including Juvenile Dermatomyositis
RECRUITINGCircadian Rhythm Deregulation in Patients With CAPS
RECRUITINGExternal Resources
Links to major genomics databases and tools