TIMP4
Chr 3TIMP metallopeptidase inhibitor 4
Also known as: TIMP-4
The protein inhibits matrix metalloproteinases by binding to their catalytic zinc cofactor, regulating extracellular matrix degradation and playing roles in platelet aggregation and endometrial remodeling. Mutations cause autosomal recessive Joubert syndrome and related cerebellar disorders, typically presenting in infancy with characteristic brain malformations affecting the cerebellum and brainstem. The gene shows tolerance to loss-of-function variants (low constraint), which is consistent with the recessive inheritance pattern observed in affected individuals.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
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.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
88 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 | 27 | 0 | 27 |
Likely Pathogenic | 0 | 0 | 1 | 0 | 1 |
VUS | 0 | 53 | 0 | 0 | 53 |
Likely Benign | 0 | 1 | 0 | 1 | 2 |
Benign | 0 | 0 | 0 | 1 | 1 |
| Total | 0 | 54 | 28 | 2 | 84 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TIMP4 · 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
External Resources
Links to major genomics databases and tools