CST6

Chr 11AR

cystatin E/M

Also known as: ECTD15

NCBI Gene: 1474ENSG00000175315UniProt: P04080

The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. This gene encodes a cystatin from the type 2 family, which is down-regulated in metastatic breast tumor cells as compared to primary tumor cells. Loss of expression is likely associated with the progression of a primary tumor to a metastatic phenotype. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Ectodermal dysplasia 15, hypohidrotic/hair typeMIM #618535
AR
UniProtEpilepsy, progressive myoclonic 1
39
ClinVar variants
11
Pathogenic / LP
0.37
pLI score
0
Active trials
Clinical Summary— CST6
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.21) despite low pLI — interpret in context.
📋
ClinVar Variants
11 Pathogenic / Likely Pathogenic· 25 VUS of 39 total submissions

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.
0.99LOEUF
pLI 0.372
Z-score 1.59
OE 0.21 (0.07–0.99)
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.
1.25Z-score
OE missense 0.63 (0.51–0.79)
58 obs / 91.7 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.0.21 (0.07–0.99)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.63 (0.51–0.79)
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: 1 / 4.7Missense obs/exp: 58 / 91.7Syn Z: -0.09

ClinVar Variant Classifications

39 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic2
VUS25
Likely Benign2
Benign1
9
Pathogenic
2
Likely Pathogenic
25
VUS
2
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
9
0
9
Likely Pathogenic
0
0
2
0
2
VUS
0
21
4
0
25
Likely Benign
0
1
0
1
2
Benign
0
1
0
0
1
Total02315139

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

View in ClinVar →

Protein Context — Lollipop Plot

CST6 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
CYSTATIN 6; CST6
MIM #601891 · *

?Ectodermal dysplasia 15, hypohidrotic/hair type

MIM #618535

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis.
Li X et al.·Theranostics
2021
Measurement of Organ-Specific and Acute-Phase Blood Protein Levels in Early Lyme Disease.
Zhou Y et al.·J Proteome Res
2020
Cathepsin B as a potential cystatin M/E target in the mouse hair follicle.
Oortveld MAW et al.·FASEB J
2017Functional
Proteomic Analysis of Aqueous Humor Identified Clinically Relevant Molecular Targets for Neovascular Complications in Diabetic Retinopathy.
Oh JW et al.·Mol Cell Proteomics
2025
Ectodermal dysplasias and isolated ectodermal anomalies: expanding the clinical and molecular spectrum in a cohort of 36 patients.
Doğan Arı AB et al.·Eur J Pediatr
2025Cohort
CO(2) sensing in fungi: at the heart of metabolic signaling.
Martin R et al.·Curr Genet
2017Review
COADREADx: A comprehensive algorithmic dissection of colorectal cancer unravels salient biomarkers and actionable insights into its discrete progression.
Palaniappan A et al.·PeerJ
2024
The human cystatin M/E gene (CST6): exclusion candidate gene for harlequin ichthyosis.
Zeeuwen PL et al.·J Invest Dermatol
2003
Correlation of Cystatin E/M with Clinicopathological Features and Prognosis in Triple-Negative Breast Cancer.
Li Q et al.·Ann Clin Lab Sci
2018
A novel necroptosis-related gene index for predicting prognosis and a cold tumor immune microenvironment in stomach adenocarcinoma.
Khan M et al.·Front Immunol
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Cystatin 6 (CST6) and Legumain (LGMN) are potential mediators in the pathogenesis of preeclampsia.
Botha SM et al.·Sci Rep
2025🔓 Open Access
Epigenetic regulation and tumor suppressive function of lncRNA EP300-AS1 in nasopharyngeal carcinoma through activation of TFAP2C binding to CST6: implications for diagnosis, prognosis, and therapy.
Xing C et al.·Am J Cancer Res
2025
Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility.
Ollinger TL et al.·Antimicrob Agents Chemother
2025🔓 Open Access
Alleviating role of ketamine in breast cancer cell-induced osteoclastogenesis and tumor bone metastasis-induced bone cancer pain through an SRC/EGR1/CST6 axis.
Zhang X et al.·BMC Cancer
2024🔓 Open Access
Predictive Values of Homeobox Gene A-Antisense Transcript 3 (HOXA-AS3), Cystatin 6 (CST6), and Chromobox Homolog 4 (CBX4) Expressions in Cancer Tissues for Recurrence of Early Colon Cancer After Surgery.
Zhu X et al.·Int J Gen Med
2024🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools