CTSK

Chr 1AR

cathepsin K

Also known as: CTS02, CTSO, CTSO1, CTSO2, PKND, PYCD

NCBI Gene: 1513ENSG00000143387UniProt: P43235

The protein encoded by this gene is a lysosomal cysteine proteinase involved in bone remodeling and resorption. This protein, which is a member of the peptidase C1 protein family, is predominantly expressed in osteoclasts. However, the encoded protein is also expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness. Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature. [provided by RefSeq, Apr 2013]

Primary Disease Associations & Inheritance

PycnodysostosisMIM #265800
AR
460
ClinVar variants
141
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— CTSK
🧬
Gene-Disease Validity (ClinGen)
pycnodysostosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
141 Pathogenic / Likely Pathogenic· 116 VUS of 460 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
Tolerant — LoF & missense variants common in population
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.
0.94LOEUF
pLI 0.000
Z-score 1.75
OE 0.55 (0.34–0.94)
Tolerant

Typical tolerance to LoF variation

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.
1.00Z-score
OE missense 0.79 (0.68–0.91)
134 obs / 170.7 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.0.55 (0.34–0.94)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.68–0.91)
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.0.89
0≤1.21.6
LoF obs/exp: 10 / 18.0Missense obs/exp: 134 / 170.7Syn Z: 0.66

ClinVar Variant Classifications

460 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic56
Likely Pathogenic85
VUS116
Likely Benign177
Benign17
Conflicting9
56
Pathogenic
85
Likely Pathogenic
116
VUS
177
Likely Benign
17
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
28
7
21
0
56
Likely Pathogenic
43
19
23
0
85
VUS
0
85
24
7
116
Likely Benign
0
3
69
105
177
Benign
0
0
16
1
17
Conflicting
—9
Total71114153113460

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

View in ClinVar →

Protein Context — Lollipop Plot

CTSK · protein map & ClinVar variants

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

Gene2Phenotype Curations

CTSK-related pycnodysostosis

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
CATHEPSIN K; CTSK
MIM #601105 · *

Pycnodysostosis

MIM #265800

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — CTSK
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Integrating single-cell and bulk RNA sequencing data unveils antigen presentation and process-related CAFS and establishes a predictive signature in prostate cancer.
Wang W et al.·J Transl Med
2024
A multi-stem cell basis for craniosynostosis and calvarial mineralization.
Bok S et al.·Nature
2023
Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data.
Tachmazidou I et al.·Nat Genet
2019
Gut microbiota-stimulated cathepsin K secretion mediates TLR4-dependent M2 macrophage polarization and promotes tumor metastasis in colorectal cancer.
Li R et al.·Cell Death Differ
2019
A novel lineage of osteoprogenitor cells with dual epithelial and mesenchymal properties govern maxillofacial bone homeostasis and regeneration after MSFL.
Weng Y et al.·Cell Res
2022
IL-17RA/CTSK axis mediates H. pylori-induced castration-resistant prostate cancer growth.
Lin G et al.·Oncogene
2024
Cathepsin K (CTSK) in Inflammatory and Immune-Mediated Diseases.
Lin S et al.·Immunol Invest
2026Review
Targeting EZH2 attenuates the ferroptosis-mediated osteoblast-osteoclast imbalance in rheumatoid arthritis.
Piao X et al.·Int Immunopharmacol
2024
Identification of CTSK as a TLR-related critical biomarker in liver cirrhosis via integrative bioinformatics and pathological characterization.
Wang J et al.·Sci Rep
2025
Clinical and genetic characterization of three Russian patients with pycnodysostosis due to pathogenic variants in the CTSK gene.
Markova TV et al.·Mol Genet Genomic Med
2022Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Adolescent Idiopathic Scoliosis

Identification of Circulating microRNAs in Adolescent Idiopathic Scoliosis

RECRUITING
NCT04746586Istituto Ortopedico RizzoliStarted 2020-07-22
Circulating MiRNA indentification

External Resources

Links to major genomics databases and tools