CST3

Summary

CST3 (cystatin C, HGNC:2475) is a protein-coding gene on chromosome 20p11.21, encoding Cystatin-C (P01034). As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity.

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. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes the most abundant extracellular inhibitor of cysteine proteases, which is found in high concentrations in biological fluids and is expressed in virtually all organs of the body. A mutation in this gene has been associated with amyloid angiopathy. Expression of this protein in vascular wall smooth muscle cells is severely reduced in both atherosclerotic and aneurysmal aortic lesions, establishing its role in vascular disease. In addition, this protein has been shown to have an antimicrobial function, inhibiting the replication of herpes simplex virus. Alternative splicing results in multiple transcript variants encoding a single protein.

Source: NCBI Gene 1471 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ACys amyloidosis (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 70 total — 2 pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes
• MANE Select transcript: NM_000099

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2475
Approved symbol	CST3
Name	cystatin C
Location	20p11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000101439
Ensembl biotype	protein_coding
OMIM	604312
Entrez	1471

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000376925, ENST00000398409, ENST00000398411, ENST00000879178, ENST00000944274

RefSeq mRNA: 2 — MANE Select: NM_000099 NM_000099, NM_001288614

CCDS: CCDS13158

Canonical transcript exons

ENST00000376925 — 3 exons

Exon	Start	End
ENSE00000660936	23635254	23635367
ENSE00001472149	23633657	23633999
ENSE00001472169	23637620	23637955

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 99.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 531.5466 / max 14161.6762, expressed in 1808 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186716	478.4063	1802
186717	40.7620	1768
186715	12.3784	1639

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	99.90	gold quality
amygdala	UBERON:0001876	99.89	gold quality
nucleus accumbens	UBERON:0001882	99.86	gold quality
left testis	UBERON:0004533	99.86	gold quality
right testis	UBERON:0004534	99.86	gold quality
right coronary artery	UBERON:0001625	99.78	gold quality
pigmented layer of retina	UBERON:0001782	99.78	gold quality
apex of heart	UBERON:0002098	99.78	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.77	gold quality
descending thoracic aorta	UBERON:0002345	99.76	gold quality
ascending aorta	UBERON:0001496	99.75	gold quality
thoracic aorta	UBERON:0001515	99.75	gold quality
lower esophagus	UBERON:0013473	99.74	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.74	gold quality
left coronary artery	UBERON:0001626	99.73	gold quality
coronary artery	UBERON:0001621	99.72	gold quality
caudate nucleus	UBERON:0001873	99.72	gold quality
hypothalamus	UBERON:0001898	99.72	gold quality
right atrium auricular region	UBERON:0006631	99.72	gold quality
left uterine tube	UBERON:0001303	99.71	gold quality
monocyte	CL:0000576	99.70	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.70	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.69	gold quality
granulocyte	CL:0000094	99.68	gold quality
body of stomach	UBERON:0001161	99.68	gold quality
tibial nerve	UBERON:0001323	99.68	gold quality
adenohypophysis	UBERON:0002196	99.68	gold quality
prefrontal cortex	UBERON:0000451	99.67	gold quality
putamen	UBERON:0001874	99.66	gold quality
omental fat pad	UBERON:0010414	99.66	gold quality

Single-cell (SCXA)

Detected in 63 experiment(s), a significant marker in 54.

Experiment	Marker?	Max mean expression
E-CURD-120	yes	52787.80
E-HCAD-13	yes	49073.23
E-MTAB-8207	yes	43467.17
E-MTAB-10042	yes	43137.51
E-GEOD-135922	yes	22474.51
E-HCAD-24	yes	18572.32
E-MTAB-9906	yes	16963.51
E-CURD-88	yes	15047.61
E-MTAB-6701	yes	14963.60
E-MTAB-10553	yes	13886.53
E-HCAD-1	yes	12120.24
E-MTAB-7407	yes	11967.76
E-CURD-112	yes	11481.60
E-GEOD-84465	yes	11132.54
E-MTAB-8142	yes	10581.48

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT3

miRNA regulators (miRDB)

12 targeting CST3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6511B-5P	97.98	65.64	823
HSA-MIR-5089-3P	97.50	67.82	758
HSA-MIR-4508	90.37	59.62	240
HSA-MIR-6784-5P	84.56	60.91	126

Literature-anchored findings (GeneRIF, showing 40)

• localization, targetting and trafficking of cystatin C is investigated in cultured human retinal pigment epithelial (RPE) cells (PMID:11681790)
• Relationship between serum cystatin C and creatinine in kidney and liver transplant patients. (PMID:11750287)
• Associated with exudative age related macular degeneration. (PMID:11815350)
• Serum concentration of cystatin C is not affected by cellular proliferation in patients with proliferative haematological disorders. (PMID:12038606)
• Enhancement of proteinase inhibitory activity of recombinant human cystatin C (PMID:12479412)
• role in invasiveness of human glioblastoma cells (PMID:12483523)
• decrease of cystatin C in the CSF might contribute in the process of metastasis and spread of the cancer cells in the leptomeningeal tissues (PMID:12589965)
• May be a better marker of glomerular filtration rate in IDDM than creatinine. (PMID:12663624)
• A significant elevation in the content of cystatin C is measured in the cerebrospinal fluid of human patients experiencing persistent pain of strong intensity. (PMID:12670666)
• most sensitive marker at routinely used cutoff values and would be more clinically useful than B2M or serum creatinine in diabetic patients at risk for nephropathy (PMID:12738401)
• In fibroblasts from donors carrying A/A, A/B, and B/B CST3 pulse-chase experiments demonstrated that release of the B variant of cystatin c [CysC] has a different temporal pattern compared to that of the A. Fibroblasts B/B homozygous secreted less CysC (PMID:12758063)
• Cystatin C physically associates with A beta precursor protein (A beta PP), and may play a novel role in the pathogenesis of sporadic inclusion body myositis by influencing A beta PP processing and A beta deposition (PMID:12787072)
• levels of serum cystatin C may predict early prognostic stages of patients with type 2 diabetic nephropathy (PMID:12938144)
• a synergistic association of CST3 and APOE4 alleles was observed in predicting vascular dementia patients so CST3 might interact with APOE4 on conferring vascular pathologies. (PMID:14672279)
• cystatin C level is a useful and convenient parameter of renal function, and may also prove to be an early marker of the severity of end-organ damage in patients with essential hypertension (PMID:14714581)
• 7 polymorphisms, all in strong-linkage disequilibrium, were identified in the cystatin C gene. The mutant haplotype was associated with a higher average number of stenoses per coronary artery segment, implying an important role in coronary artery disease. (PMID:14726415)
• Serum creatinine is a more efficacious marker than serum cystatin C to assess renal function after renal transplantation. (PMID:15013312)
• presence of a susceptibility locus for Alzheimer’s disease in the vicinity of CST3 for very elderly subjects. (PMID:15034766)
• Identification of CystC as a novel TGF-beta receptor antagonist, as well as a novel CystC-mediated feedback loop that inhibits TGF-beta signaling. (PMID:15037657)
• Serum cystatin C appears to be influenced by factors other than renal function alone. (PMID:15086483)
• In a yeast two-hybrid system cystatin C has been identified as a neuroglobin-interacting protein. (PMID:15122877)
• Cystatin C association with betaAPP resulted in increased sbetaAPP but did not affect levels of secreted Abeta. Analysis of the association of cystatin C and Abeta demonstrated a specific, saturable an (PMID:15212828)
• ystatin C is an important regulator for normal and pathological proteolysis in the male reproductive system. (PMID:15223845)
• In calvarial bone explants recombinant human cystatin C decreases calcium release into the medium significantly. (PMID:15336605)
• A valid serum marker for glomerular filtration rate in renal transplantation. (PMID:15350470)
• an age-related macular degeneration-associated cystatin C variant is associated principally with mitochondria rather than the Golgi apparatus (PMID:15479453)
• An excellent blood marker for screening of renal dysfunction in children with liver disease and after liver transplantation. (PMID:15719405)
• The difference in localization of CyC and of CatS, -L, and -H in immature and mature DC shows that the regulatory potential of CyC toward CatS, -L, and -H inside DC is limited (PMID:15829557)
• Protein and mRNA levels of stefin B (p= 0.007), but not cystatin C, were significantly lower in atypical compared with benign meningiomas (PMID:15832773)
• The major haplotype -82G/-5G/+4A of the cystatin C gene determines plasma levels of cystatin C with homozygous persons having the highest plasma levels, but there was no association with secondary cardiovascular events in this study. (PMID:15860739)
• No effect of sex on serum cystatin C levels was observed, but average levels increased with age (PMID:16005452)
• The cystatin C expression is altered during the chronic phase of epilepsy and suggest that cystatin C plays a role in network reorganization in the epileptic dentate gyrus, especially in granule cell dispersion. (PMID:16049933)
• full-length cystatin C when crystallized in a new, tetragonal form, dimerizes by swapping the same secondary structure elements but with a very different overall structure generated by the flexibility of the hinge linking the moveable elements (PMID:16170782)
• the present findings represent the first demonstration of relationships between the AD genetic risk factor CST3 B and global neurophysiological phenotype (PMID:16213753)
• Cystatin C is an endogenous marker of glomerular filtration rate in kidney transplantation patients. (PMID:16386559)
• Cleavage of cystatin C to form a 12.5 kDa protein may identify a subgroup of patients with MS. (PMID:16437581)
• Conformational differences between the monomeric forms of wild-type cystatin C and its L68Q variant may be responsible for the higher tendency of the L68Q cystatin C to be amyloidogeneic. (PMID:16446102)
• Cystatin C is a novel cerebrospinal fluid protein whose content is altered by amyotrophic lateral sclerosis and may therefore serve as a biomarker for this disease. (PMID:16481598)
• hereditary cystatin C amyloid angiopathy is a rare, fatal amyloid disease in young people in Iceland caused by a mutation in cystatin C {REVIEW} (PMID:16612982)
• Accumulating data suggest involvement of cystatin C in the pathogenic processes leading to amyloid deposition in cerebral vasculature and most significantly to cerebral hemorrhage in patients with cerebral amyloid angiopathy {REVIEW} (PMID:16612983)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	cst3	ENSDARG00000007795
danio_rerio	zgc:163030	ENSDARG00000069192
mus_musculus	Cst3	ENSMUSG00000027447
mus_musculus	Cst5	ENSMUSG00000033156
rattus_norvegicus	Cst3	ENSRNOG00000005195
rattus_norvegicus	Cst5	ENSRNOG00000005545
rattus_norvegicus	P22k15	ENSRNOG00000030184
rattus_norvegicus	Cyss	ENSRNOG00000030857
rattus_norvegicus	Andpro	ENSRNOG00000031840
rattus_norvegicus	Cyssl1	ENSRNOG00000036952
rattus_norvegicus	AABR07054232.1	ENSRNOG00000043043
caenorhabditis_elegans		WBGENE00000534
caenorhabditis_elegans		WBGENE00000535
caenorhabditis_elegans		WBGENE00023486

Paralogs (11): CST7 (ENSG00000077984), CST9L (ENSG00000101435), CST4 (ENSG00000101441), CST8 (ENSG00000125815), CSTL1 (ENSG00000125823), CST11 (ENSG00000125831), CST5 (ENSG00000170367), CST2 (ENSG00000170369), CST1 (ENSG00000170373), CST9 (ENSG00000173335), CST6 (ENSG00000175315)

Protein

Protein identifiers

Cystatin-C — P01034 (reviewed: P01034)

Alternative names: Cystatin-3, Gamma-trace, Neuroendocrine basic polypeptide, Post-gamma-globulin

All UniProt accessions (2): P01034, A0A0K0K1J1

UniProt curated annotations — full annotation on UniProt →

Function. As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity.

Subunit / interactions. Homodimer.

Subcellular location. Secreted.

Tissue specificity. Expressed in submandibular and sublingual saliva but not in parotid saliva (at protein level). Expressed in various body fluids, such as the cerebrospinal fluid and plasma. Expressed in highest levels in the epididymis, vas deferens, brain, thymus, and ovary and the lowest in the submandibular gland.

Post-translational modifications. The Thr-25 variant is O-glycosylated with a core 1 or possibly core 8 glycan. The signal peptide of the O-glycosylated Thr-25 variant is cleaved between Ala-20 and Val-21.

Disease relevance. Cerebral amyloid angiopathy, CST3-related (CAA-CST3) [MIM:105150] An autosomal dominant disorder characterized by cystatin C amyloid accumulation in the walls of arteries, arterioles, and sometimes capillaries and veins of the brain, and in various organs including lymphoid tissue, spleen, salivary glands, and seminal vesicles. Amyloid deposition in the cerebral vessels results in intracranial hemorrhage and premature stroke. Cystatin C levels in the cerebrospinal fluid are abnormally low. The disease is caused by variants affecting the gene represented in this entry. Macular degeneration, age-related, 11 (ARMD11) [MIM:611953] A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Disease susceptibility is associated with variants affecting the gene represented in this entry. Leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy (ADLDWA) [MIM:621214] An autosomal dominant, adult-onset disorder characterized by recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits, slowly progressing motor symptoms and cognitive decline, and brain anomalies affecting the deep cerebral white matter, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles, and globus pallidus. Histopathologic analysis shows micro- to macrocystic degeneration of the white matter, and absence of cerebral amyloid angiopathy or amyloid deposition. Some patients show acute clinical deterioration and prolonged episodes with reduced consciousness and even early death. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Potential cerebrospinal fluid marker for the diagnosis of Creutzfeldt-Jakob disease.

Similarity. Belongs to the cystatin family.

RefSeq proteins (2): NP_000090, NP_001275543 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000010	Cystatin_dom	Domain
IPR018073	Prot_inh_cystat_CS	Conserved_site
IPR046350	Cystatin_sf	Homologous_superfamily

Pfam: PF00031

UniProt features (20 total): sequence variant 4, strand 4, helix 3, disulfide bond 2, signal peptide 1, chain 1, mutagenesis site 1, turn 1, short sequence motif 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
3GAX	X-RAY DIFFRACTION	1.7
3NX0	X-RAY DIFFRACTION	2.04
1R4C	X-RAY DIFFRACTION	2.18
3QRD	X-RAY DIFFRACTION	2.19
3S67	X-RAY DIFFRACTION	2.26
1G96	X-RAY DIFFRACTION	2.5
3PS8	X-RAY DIFFRACTION	2.55
6ROA	X-RAY DIFFRACTION	2.65
3SVA	X-RAY DIFFRACTION	3.02
1TIJ	X-RAY DIFFRACTION	3.03
6RPV	SOLUTION NMR, SOLUTION SCATTERING

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01034-F1	89.56	0.68

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 37 (reactive site)

Post-translational modifications (1): 43

Disulfide bonds (2): 99–109, 123–143

Mutagenesis-validated functional residues (1):

Position	Phenotype
25	shows a dual distribution to the golgi apparatus and to the mitochondria.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-6798695	Neutrophil degranulation
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-977225	Amyloid fiber formation

MSigDB gene sets: 327 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, REACTOME_INNATE_IMMUNE_SYSTEM, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOCC_SECRETORY_GRANULE, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, HSIAO_HOUSEKEEPING_GENES, GOBP_REGULATION_OF_EXTRACELLULAR_MATRIX_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOLDRATH_ANTIGEN_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_TISSUE_REMODELING, GOBP_REGULATION_OF_GLYCOPROTEIN_METABOLIC_PROCESS, JOHANSSON_BRAIN_CANCER_EARLY_VS_LATE_DN

GO Biological Process (9): defense response (GO:0006952), immune response (GO:0006955), negative regulation of collagen catabolic process (GO:0010711), negative regulation of extracellular matrix disassembly (GO:0010716), regulation of tissue remodeling (GO:0034103), negative regulation of proteolysis (GO:0045861), negative regulation of elastin catabolic process (GO:0060311), negative regulation of blood vessel remodeling (GO:0060313), supramolecular fiber organization (GO:0097435)

GO Molecular Function (7): amyloid-beta binding (GO:0001540), protease binding (GO:0002020), endopeptidase inhibitor activity (GO:0004866), cysteine-type endopeptidase inhibitor activity (GO:0004869), peptidase inhibitor activity (GO:0030414), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (11): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), vesicle (GO:0031982), extracellular exosome (GO:0070062), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of proteins	2
Innate Immune System	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular organelle lumen	3
cellular anatomical structure	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
response to stress	1
immune system process	1
response to stimulus	1
negative regulation of catabolic process	1
regulation of collagen catabolic process	1
negative regulation of collagen metabolic process	1
collagen catabolic process	1
regulation of extracellular matrix disassembly	1
extracellular matrix disassembly	1
negative regulation of extracellular matrix organization	1
tissue remodeling	1
regulation of multicellular organismal process	1
proteolysis	1
regulation of proteolysis	1
negative regulation of protein metabolic process	1
negative regulation of protein catabolic process	1
elastin catabolic process	1
regulation of elastin catabolic process	1
negative regulation of glycoprotein metabolic process	1
blood vessel remodeling	1
negative regulation of tissue remodeling	1
negative regulation of developmental process	1
regulation of blood vessel remodeling	1
cellular component organization	1
peptide binding	1
enzyme binding	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
protein binding	1

Protein interactions and networks

STRING

2108 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CST3	CTSB	P07858	950
CST3	CTSS	P25774	943
CST3	LCN2	P30150	924
CST3	B2M	P01884	916
CST3	HAVCR1	Q96D42	883
CST3	CRP	P02741	877
CST3	APP	P05067	868
CST3	ALB	P02768	820
CST3	ITM2B	Q9Y287	799
CST3	CSTB	P04080	796
CST3	TTR	P02766	784
CST3	FABP1	P07148	771
CST3	CPPED1	Q9BRF8	756
CST3	CLU	P10909	750
CST3	GDF15	P78360	746

IntAct

26 interactions, top by confidence:

A	B	Type	Score
CST3	CST3	psi-mi:“MI:0407”(direct interaction)	0.770
CST3	APP	psi-mi:“MI:0915”(physical association)	0.560
DDX31	IGLL5	psi-mi:“MI:0914”(association)	0.530
CST3	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
ALB	SH3BP5	psi-mi:“MI:0914”(association)	0.350
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
TEX101	GGT3P	psi-mi:“MI:0914”(association)	0.350
CST3	CTSV	psi-mi:“MI:0914”(association)	0.350
RSRP1	A2ML1	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
proS	CST3	psi-mi:“MI:0915”(physical association)	0.000
gmhB	CST3	psi-mi:“MI:0915”(physical association)	0.000
ATXN1	CST3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): CST3 (Affinity Capture-MS), CST3 (Reconstituted Complex), CST3 (Co-localization), CST3 (Affinity Capture-MS), CST3 (Biochemical Activity), CST3 (Reconstituted Complex), CTSH (Affinity Capture-MS), CTSB (Affinity Capture-MS), CTSV (Affinity Capture-MS), SAPCD2 (Affinity Capture-MS), CTSC (Affinity Capture-MS), ZER1 (Affinity Capture-MS), LNPEP (Affinity Capture-MS), CTSO (Affinity Capture-MS), ME1 (Affinity Capture-MS)

ESM2 similar proteins: E3P6N3, E3P6N4, E3P6N5, E3P6N6, E3P6N7, E3P6N8, E3P6N9, E3P6P0, E3P6P1, E3P6P2, E3P6P3, E3P6P4, J3RYX9, J3SE80, O19092, O19093, O75173, O77805, O77835, O97862, P01034, P01035, P01036, P01037, P01038, P01231, P04651, P09228, P14841, P17405, P21460, P81061, Q04519, Q0VD19, Q29RH0, Q2IAL6, Q2IAL7, Q2NKZ5, Q32KQ9, Q5RFQ8

Diamond homologs: A0A0K0IP23, B1P1J3, G5ECM9, G5EDZ9, O19092, P01034, P01037, P22085, Q6QZV5, Q91195, Q9JM84, B2Z450, E3P6N3, E3P6N7, E3P6N8, E3P6N9, E3P6P0, E3P6P3, J3RYX9, J3SE80, O19093, O89098, O97862, P01035, P01038, P08935, P14841, P19313, P21460, P35481, P81061, Q15828, Q2XXN5, Q6T6T4, Q80ZN5, Q98967, Q9H114, E3P6N4, E3P6N5, E3P6N6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

70 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	36
Likely benign	12
Benign	9

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3901246	CST3, IVS2DS, G-T, +1	Pathogenic
5634	NM_000099.4(CST3):c.281T>A (p.Leu94Gln)	Pathogenic

SpliceAI

540 predictions. Top by Δscore:

Variant	Effect	Δscore
20:23635252:AC:A	donor_gain	1.0000
20:23635253:CC:C	donor_gain	1.0000
20:23633923:T:TA	donor_gain	0.9900
20:23635249:CATA:C	donor_loss	0.9900
20:23635250:ATACC:A	donor_loss	0.9900
20:23635251:TACC:T	donor_loss	0.9900
20:23635252:A:AC	donor_gain	0.9900
20:23635252:A:AG	donor_loss	0.9900
20:23635253:C:CC	donor_gain	0.9900
20:23635364:CGAT:C	acceptor_gain	0.9900
20:23635365:GATC:G	acceptor_loss	0.9900
20:23635368:C:CC	acceptor_gain	0.9900
20:23635368:C:T	acceptor_loss	0.9900
20:23635374:A:C	acceptor_gain	0.9900
20:23635376:G:C	acceptor_gain	0.9900
20:23635376:G:GC	acceptor_gain	0.9900
20:23637616:GCACC:G	donor_loss	0.9900
20:23637617:CACC:C	donor_loss	0.9900
20:23637618:A:T	donor_loss	0.9900
20:23633912:ACC:A	donor_gain	0.9800
20:23633913:CCC:C	donor_gain	0.9800
20:23635248:ACAT:A	donor_loss	0.9800
20:23635250:ATAC:A	donor_gain	0.9800
20:23635252:ACC:A	donor_gain	0.9800
20:23635253:CCC:C	donor_gain	0.9800
20:23637619:CCTG:C	donor_gain	0.9800
20:23635373:CATG:C	acceptor_gain	0.9700
20:23635374:A:AC	acceptor_gain	0.9700
20:23635366:AT:A	acceptor_gain	0.9600
20:23635371:CACA:C	acceptor_gain	0.9600

AlphaMissense

941 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:23633961:C:A	W132C	0.999
20:23633961:C:G	W132C	0.999
20:23633989:C:G	C123S	0.996
20:23633990:A:T	C123S	0.996
20:23635321:G:A	T97I	0.996
20:23637696:G:T	A56D	0.996
20:23633983:A:C	F125C	0.995
20:23633989:C:T	C123Y	0.995
20:23633929:C:G	C143S	0.994
20:23633930:A:T	C143S	0.994
20:23633982:G:C	F125L	0.994
20:23633982:G:T	F125L	0.994
20:23633984:A:G	F125L	0.994
20:23635315:C:G	C99S	0.994
20:23635316:A:T	C99S	0.994
20:23637698:A:C	F55L	0.994
20:23637698:A:T	F55L	0.994
20:23637700:A:G	F55L	0.994
20:23635285:C:G	C109S	0.993
20:23635286:A:T	C109S	0.993
20:23637620:C:A	Q81H	0.993
20:23637620:C:G	Q81H	0.993
20:23633988:G:C	C123W	0.992
20:23635286:A:G	C109R	0.992
20:23635315:C:T	C99Y	0.992
20:23633929:C:T	C143Y	0.991
20:23633963:A:G	W132R	0.991
20:23633963:A:T	W132R	0.991
20:23633990:A:G	C123R	0.991
20:23635316:A:G	C99R	0.991

dbSNP variants (sampled 300 via entrez): RS1000115335 (20:23627758 T>C), RS1000226172 (20:23632825 T>C), RS1000338173 (20:23637980 G>A,C,T), RS1000407215 (20:23628004 T>C), RS1000553459 (20:23637526 G>A,T), RS1000605718 (20:23637365 C>G,T), RS1000962520 (20:23627472 AT>A,ATT), RS1001010599 (20:23629269 G>A), RS1001071098 (20:23632751 G>T), RS1001332782 (20:23639883 G>A), RS1001505493 (20:23629037 C>T), RS1002123191 (20:23631462 G>A), RS1002174291 (20:23635176 T>C), RS1002420137 (20:23630437 G>C), RS1002474053 (20:23631720 C>A)

Disease associations

OMIM: gene MIM:604312 | disease phenotypes: MIM:621214, MIM:105150, MIM:611953

GenCC curated gene-disease

Disease	Classification	Inheritance
ACys amyloidosis	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy	Limited	AD

Mondo (3): leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy (MONDO:0979226), ACys amyloidosis (MONDO:0007098), age related macular degeneration 11 (MONDO:0012767)

Orphanet (2): ACys amyloidosis (Orphanet:100008), Hereditary cerebral amyloid angiopathy (Orphanet:85458)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000238	Hydrocephalus
HP:0000608	Macular degeneration
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000726	Dementia
HP:0000739	Anxiety
HP:0000989	Pruritus
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001297	Stroke
HP:0001300	Parkinsonism
HP:0001337	Tremor
HP:0001342	Cerebral hemorrhage
HP:0002059	Cerebral atrophy
HP:0002076	Migraine
HP:0002170	Intracranial hemorrhage
HP:0002186	Apraxia
HP:0002197	Generalized-onset seizure
HP:0002315	Headache
HP:0002362	Shuffling gait
HP:0002381	Aphasia
HP:0002453	Abnormal globus pallidus morphology
HP:0002669	Osteosarcoma

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000091_1	Cystatin C levels	9.000000e-09
GCST000649_20	Chronic kidney disease	2.000000e-138
GCST002406_1	Plasma cystastin c levels in acute coronary syndrome	1.000000e-26
GCST002406_2	Plasma cystastin c levels in acute coronary syndrome	4.000000e-07
GCST004293_2	Glomerular filtration rate (cystatin C)	4.000000e-153

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004617	cystatin C measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567450	Macular Degeneration, Age-Related, 11 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4742267 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

67 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects cotreatment, decreases reaction, increases expression	3
Tretinoin	increases expression	3
bisphenol A	affects expression, increases methylation	2
sodium arsenite	increases expression, decreases expression	2
chloropicrin	decreases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Valproic Acid	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
triphenyl phosphate	affects expression	1
cobaltous chloride	decreases secretion	1
perfluorooctanoic acid	decreases expression	1
tamibarotene	increases expression	1
4-phenylbutyric acid	affects localization, decreases reaction, increases expression	1
esculentoside A	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	increases reaction, affects binding	1
corosolic acid	increases expression	1
K 7174	decreases expression	1
scriptaid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
nutlin 3	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	increases expression, affects cotreatment	1
MT19c compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Decitabine	affects cotreatment, affects expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	decreases expression	1
Vorinostat	affects expression, affects cotreatment	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4713757	Binding	Protac activity at CRBN/CST3 in human BxPC-3 cells assessed as CST3 degradation incubated for 16 hrs by proteomic analysis	Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91. — J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7WT	Abcam Raji CST3 KO	Cancer cell line	Male
CVCL_B9XC	Abcam THP-1 CST3 KO	Cancer cell line	Male
CVCL_C6Z9	Abcam PC-3 CST3 KO	Cancer cell line	Male
CVCL_D1S1	Abcam U-87MG CST3 KO	Cancer cell line	Male
CVCL_SJ97	HAP1 CST3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

31 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03542656	PHASE3	COMPLETED	Application of Amyloid PET in Cerebral Amyloid Angiopathy
NCT03969732	PHASE3	UNKNOWN	Multimodal Biomarkers for Diagnosis and Prognosis in CAA
NCT04604587	PHASE3	UNKNOWN	MRI-visible Enlarged Perivascular Spaces and the Alteration of Lymphatic Drainage System in CAA
NCT07250035	PHASE3	NOT_YET_RECRUITING	Jiedu Huayu Oral Prescription in the Treatment of Intracranial Hemorrhage Associated With Cerebral Amyloid Angiopathy
NCT01821118	PHASE2	COMPLETED	Study Evaluating the Safety,Tolerability and Efficacy of PF-04360365 in Adults With Probable Cerebral Amyloid Angiopathy
NCT05709314	PHASE2	RECRUITING	A Study of AMDX-2011P in Participants With CAA
NCT06393712	PHASE2	RECRUITING	A Phase 2 Trial of ALN-APP in Patients With Cerebral Amyloid Angiopathy
NCT06421532	PHASE2	ENROLLING_BY_INVITATION	Stimulating Amyloid Clearance in Cerebral Amyloid Angiopathy
NCT07026994	PHASE2	RECRUITING	Colchicine for the Prevention of Recurrence in Cerebral Amyloid Angiopathy RElated IntraCerebral Hemorrhage
NCT05680389	PHASE1/PHASE2	UNKNOWN	Antibiotics Against Amyloid Angiopathy
NCT01382849	Not specified	WITHDRAWN	F-18-AV-45 Uptake, Spot Sign Presence and Cerebral Amyloid Angiopathy (CAA) in Primary Intracranial Hemorrhage (ICH)
NCT01856699	Not specified	UNKNOWN	Superficial Siderosis in Patients With Suspected Cerebral Amyloid Angiopathy
NCT02361411	Not specified	UNKNOWN	Methods of Etiological Diagnosis of Cerebral Amyloid Angiopathy
NCT03464344	Not specified	COMPLETED	Cortical Superficial Siderosis and Risk of Recurrent Intracerebral Hemorrhage in Cerebral Amyloid Angiopathy.
NCT03824197	Not specified	COMPLETED	Auburn University Research on Olive Oil for Alzheimer’s Disease (AU-ROOAD)
NCT04204642	Not specified	RECRUITING	SEarchiNg biomarkErs Cerebral Amyloid Angiopathy (SENECA)
NCT04654026	Not specified	UNKNOWN	the Safety and Efficacy of Antiplatelet Therapy in Patients of CAA
NCT04757597	Not specified	UNKNOWN	Remote Ischemic Conditioning for Cerebral Amyloid Angiopathy-related Intracerebral Hemorrhage
NCT04825808	Not specified	COMPLETED	Detailed Clinical and MRI Characteristics in Primary Non-traumatic Convexity Subarachnoid Haemorrhage Elderly Patients.
NCT05082194	Not specified	COMPLETED	Balance Eyesight and Muscle Tension in the Cervical Spine in Cerebral Amyloid Angiopathy
NCT05207475	Not specified	UNKNOWN	Safety and Efficacy of Remote Ischemic Conditioning on Cerebral Amyloid Angiopathy. (RIC-CAA)
NCT05394636	Not specified	COMPLETED	Cerebellar Superficial Siderosis in Cerebral Amyloid Angiopathy
NCT05486897	Not specified	COMPLETED	Periventricular White Matter Hyperintensities in Cerebral Amyloid Angiopathy and Hypertensive Arteriopathy
NCT05499169	Not specified	TERMINATED	Coach Pilot Study: Assessing Cognitive Function and Related Small Vessel Disease Markers After Intracerebral Hemorrhage
NCT05565144	Not specified	COMPLETED	Brain Hemorrhage and Functional Outcome in Stroke Patients With CAA Features on Pre-thrombolysis MRI Treated With Intravenous Thrombolysis (Thrombolysis in CAA) ( Thromb in CAA )
NCT05734378	Not specified	RECRUITING	Prognosis of Cerebral Small Vessel Disease
NCT06128824	Not specified	ACTIVE_NOT_RECRUITING	High Frequency Imaging in Cerebral Amyloid Angiopathy
NCT06714097	Not specified	RECRUITING	Application of Digital Twins’ Technology in Patients Who Had a Stroke, With Moyamoya Disease and With Cerebral Amyloid Angiopathy (CAA) During the Secondary Prevention Phase: A Proof of Concept Using a Randomized Control Trial (Clinical Study 6, STRATIF-AI Project)
NCT06888882	Not specified	COMPLETED	Dilated Perivascular Spaces in the Dentate Nucleus on MRI in Patients With Hypertensive Angiopathy or Cerebral Amyloid Angiopathy
NCT06933212	Not specified	RECRUITING	Effect of the Mediterranean Diet in Patients Affected by CADASIL and Cerebral Amyloid Angiopathy.
NCT06960538	Not specified	COMPLETED	Enpowering Progression Risk of Cerebral Amyloid Angiopathy