TIMP3

Chr 22AD

TIMP metallopeptidase inhibitor 3

Also known as: HSMRK222, K222, K222TA2, SFD

NCBI Gene: 7078ENSG00000100234UniProt: P35625

This gene belongs to the TIMP gene family. The proteins encoded by this gene family are inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix (ECM). Expression of this gene is induced in response to mitogenic stimulation and this netrin domain-containing protein is localized to the ECM. Mutations in this gene have been associated with the autosomal dominant disorder Sorsby's fundus dystrophy. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Sorsby fundus dystrophyMIM #136900
AD
302
ClinVar variants
26
Pathogenic / LP
0.63
pLI score
1
Active trials
Clinical Summary— TIMP3
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.63) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
26 Pathogenic / Likely Pathogenic· 145 VUS of 302 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.53LOEUF
pLI 0.630
Z-score 2.64
OE 0.17 (0.07–0.53)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.83Z-score
OE missense 0.54 (0.44–0.66)
68 obs / 125.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.17 (0.07–0.53)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.54 (0.44–0.66)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 2 / 11.8Missense obs/exp: 68 / 125.7Syn Z: -0.13

ClinVar Variant Classifications

302 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic4
VUS145
Likely Benign73
Benign40
Conflicting10
22
Pathogenic
4
Likely Pathogenic
145
VUS
73
Likely Benign
40
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
7
15
0
22
Likely Pathogenic
0
3
1
0
4
VUS
0
71
73
1
145
Likely Benign
0
2
26
45
73
Benign
0
2
33
5
40
Conflicting
—10
Total08514851294

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

View in ClinVar →

Protein Context — Lollipop Plot

TIMP3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TIMP3-related Sorsby fundus dystrophy

definitive
ADLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Sorsby fundus dystrophy

MIM #136900

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Spectrum of Genetic Variants in the Most Common Genes Causing Inherited Retinal Disease in a Large Molecularly Characterized United Kingdom Cohort.
Lin S et al.·Ophthalmol Retina
2024Cohort
Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes.
Georgiou M et al.·Prog Retin Eye Res
2024Review
Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options.
Rahman N et al.·Br J Ophthalmol
2020Review
A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
Fritsche LG et al.·Nat Genet
2016
Chondroid Synoviocytic Neoplasm: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of a Distinctive Tumor of Synoviocytes.
Kao EY et al.·Mod Pathol
2024
Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer's disease.
Zeng X et al.·Mol Neurodegener
2024
LRP1 Repression by SNAIL Results in ECM Remodeling in Genetic Risk for Vascular Diseases.
Liu L et al.·Circ Res
2024Functional
Circular RNA circDCUN1D4 suppresses hepatocellular carcinoma development via targeting the miR-590-5p/ TIMP3 axis.
Li H et al.·Mol Cancer
2025
Macrophage nuclear factor erythroid 2-related factor 2 deficiency promotes innate immune activation by tissue inhibitor of metalloproteinase 3-mediated RhoA/ROCK pathway in the ischemic liver.
Rao J et al.·Hepatology
2022
Epigenetics and genomics in Turner syndrome.
Viuff M et al.·Am J Med Genet C Semin Med Genet
2019Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Hypoxia-inducible factor 1α exerts dual roles in bladder cancer progression through TIMP3-mediated regulation of angiogenesis and invasion.
Wang X et al.·Sci Rep
2026
miR-149-3p-mediated TIMP3 restoration suppresses tumor aggressiveness in sorafenib-resistant liver cancer cell.
Park S et al.·Biochim Biophys Acta Gene Regul Mech
2026
Zhimu-Huangbo ameliorates AQP4 depolarization in diabetic cognitive impairment rats by targeting the serum-derived exosomal TIMP3-mediated MMP9/β-DG pathway.
Li Y et al.·Drug Discov Ther
2026
TIMP3 attenuates vascular calcification by restoring autophagy in vascular smooth muscle cells through the STAT1/FOXO1 pathway.
Liu Y et al.·Biochem Biophys Res Commun
2026
Sorsby Fundus Dystrophy in an Asian Pedigree: Pathogenic Timp3 P.Y191c Variant Impairs Its Binding with Mmp2/9 and Cellular Localization.
Li M et al.·Clin Ophthalmol
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Knee Osteoarthritis

Dietary Supplementation With Blueberry in OA

ACTIVE NOT RECRUITING
NCT05784545Phase NAUniversity of ExeterStarted 2023-05-22
Blueberry powder supplementMaltodextrin supplementation

External Resources

Links to major genomics databases and tools