CTSK

Chr 1AR

cathepsin K

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

NCBI Gene: 1513 ENSG00000143387 UniProt: P43235 OMIM: 601105

Cathepsin K is a lysosomal cysteine protease that degrades extracellular matrix and mediates osteoclastic bone resorption. Mutations cause pycnodysostosis, an autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, and increased bone fragility. The gene shows very low constraint against loss-of-function variants (pLI 0.00003), which is consistent with the recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.941 OMIM phenotype

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

138 unique Pathogenic / Likely Pathogenic· 113 VUS of 463 total submissions

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — CTSK

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.75

OE 0.55 (0.34–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.00Z-score

OE missense 0.79 (0.68–0.91)

134 obs / 170.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.55 (0.34–0.94)

0≤0.351.4

Missense OE?0.79 (0.68–0.91)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 10 / 18.0Missense obs/exp: 134 / 170.7Syn Z: 0.66

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCTSK-related pycnodysostosisLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.81top 10%

GOF

0.7127th %ile

LOF

0.2386th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

463 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41

Likely Pathogenic97

VUS113

Likely Benign177

Benign17

Conflicting9

Pathogenic

Likely Pathogenic

113

VUS

177

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	33	5	3	0	41
Likely Pathogenic	74	21	2	0	97
VUS	0	91	15	7	113
Likely Benign	0	3	69	105	177
Benign	0	0	16	1	17
Conflicting	—				9
Total	107	120	105	113	454

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap CTSK — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →