CST7

Summary

CST7 (cystatin F, HGNC:2479) is a protein-coding gene on chromosome 20p11.21, encoding Cystatin-F (O76096). Inhibits papain and cathepsin L but with affinities lower than other cystatins.

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. This gene encodes a glycosylated cysteine protease inhibitor with a putative role in immune regulation through inhibition of a unique target in the hematopoietic system. Expression of the protein has been observed in various human cancer cell lines established from malignant tumors.

Source: NCBI Gene 8530 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 22 total
• MANE Select transcript: NM_003650

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2479
Approved symbol	CST7
Name	cystatin F
Location	20p11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000077984
Ensembl biotype	protein_coding
OMIM	603253
Entrez	8530

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000480798, ENST00000874360

RefSeq mRNA: 1 — MANE Select: NM_003650 NM_003650

CCDS: CCDS13165

Canonical transcript exons

ENST00000480798 — 4 exons

Exon	Start	End
ENSE00000660959	24957287	24957459
ENSE00000660960	24958928	24959044
ENSE00001471913	24949269	24949575
ENSE00001887147	24959635	24959928

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 99.55.

FANTOM5 (CAGE): breadth broad, TPM avg 44.6158 / max 10994.0432, expressed in 489 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183909	31.5488	467
183910	13.0482	358
183911	0.0187	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.55	gold quality
blood	UBERON:0000178	97.97	gold quality
bone marrow	UBERON:0002371	97.91	gold quality
bone marrow cell	CL:0002092	97.46	gold quality
trabecular bone tissue	UBERON:0002483	97.35	gold quality
spleen	UBERON:0002106	96.53	gold quality
right lung	UBERON:0002167	93.69	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.86	gold quality
upper lobe of left lung	UBERON:0008952	90.66	gold quality
upper lobe of lung	UBERON:0008948	88.92	gold quality
lymph node	UBERON:0000029	88.53	gold quality
gall bladder	UBERON:0002110	86.80	gold quality
vermiform appendix	UBERON:0001154	85.24	gold quality
omental fat pad	UBERON:0010414	84.88	gold quality
periodontal ligament	UBERON:0008266	84.83	gold quality
peritoneum	UBERON:0002358	84.80	gold quality
leukocyte	CL:0000738	84.40	gold quality
adipose tissue of abdominal region	UBERON:0007808	84.02	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.89	gold quality
mononuclear cell	CL:0000842	83.00	gold quality
monocyte	CL:0000576	82.57	gold quality
left uterine tube	UBERON:0001303	81.97	gold quality
right lobe of liver	UBERON:0001114	81.63	gold quality
lung	UBERON:0002048	80.47	gold quality
caecum	UBERON:0001153	80.15	gold quality
mucosa of transverse colon	UBERON:0004991	79.83	gold quality
superficial temporal artery	UBERON:0001614	79.45	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.27	gold quality
small intestine	UBERON:0002108	77.10	gold quality
right coronary artery	UBERON:0001625	76.45	gold quality

Single-cell (SCXA)

Detected in 39 experiment(s), a significant marker in 34.

Experiment	Marker?	Max mean expression
E-CURD-120	yes	2687.06
E-CURD-55	yes	2661.10
E-MTAB-8911	yes	2335.43
E-HCAD-15	yes	2297.99
E-CURD-122	yes	2279.15
E-GEOD-149689	yes	2187.66
E-MTAB-9467	yes	2093.90
E-MTAB-6653	yes	2088.54
E-MTAB-10553	yes	2073.86
E-CURD-77	yes	1977.24
E-GEOD-139324	yes	1791.04
E-MTAB-8207	yes	1773.96
E-HCAD-4	yes	1763.81
E-HCAD-1	yes	1627.28
E-CURD-95	yes	1626.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TREM2

miRNA regulators (miRDB)

5 targeting CST7, 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-590-3P	99.96	74.34	6478
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-4793-5P	96.88	65.90	872

Literature-anchored findings (GeneRIF, showing 13)

• cystatin F is an intracellular cysteine peptidase inhibitor with readily regulated expression (PMID:12423348)
• CST7 is secreted, but artificial modification of its C-terminus can induce its endocytic targeting. (PMID:15212960)
• Cystatin F was not colocalized with cystatin C shich suggests distinct functions for these two cysteine protease inhibitors in U937 cells. (PMID:15752368)
• analysis of reduction-dependent activation of human cystatin F (PMID:16601115)
• A latent protease inhibitor which is itself regulated by proteolysis in the endocytic pathway. (PMID:18256700)
• Data demonstrate the addition of N-linked sugars to an Asn-X-Cys motif in cystatin F and suggest that the mannose 6-phosphate sorting machinery is used to divert cystatin F from the secretory pathway and to mediate its uptake from extracellular pools. (PMID:19192250)
• Transgenic cystatin F is expressed in model mice only during demyelination; in chronic demyelination, remyelinating ability is lost. (PMID:21344476)
• Regulation of cathepsins S and L by cystatin F during maturation of dendritic cells. (PMID:22365146)
• during monocyte to macrophage differentiation, the endosomal/lysosomal proteolytic activity can be regulated by cystatin F whose expression is under the control of transcriptional factor C/EBP alpha. (PMID:30033148)
• Cystatin F was identified as the key subunit of family 2 cystatins in survival analysis. Pancreatic ductal adenocarcinoma (PDAC) patients who harbored a higher expression level of CST7 had a lower risk in overall survival. The prognostic nomogram indicated that the CST7 expression model effectively predicted the outcomes of patients with earlystage PDAC. (PMID:31059105)
• Exploring the factors underlying remyelination arrest by studying the post-transcriptional regulatory mechanisms of cystatin F gene. (PMID:32947653)
• Transcriptomic Profiling Identifies Neutrophil-Specific Upregulation of Cystatin F as a Marker of Acute Inflammation in Humans. (PMID:33868254)
• Cystatin F acts as a mediator of immune suppression in glioblastoma. (PMID:34189679)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000101340
mus_musculus	Cst7	ENSMUSG00000068129
rattus_norvegicus	Cst7	ENSRNOG00000006767
caenorhabditis_elegans		WBGENE00000534
caenorhabditis_elegans		WBGENE00000535
caenorhabditis_elegans		WBGENE00023486

Paralogs (11): CST9L (ENSG00000101435), CST3 (ENSG00000101439), CST4 (ENSG00000101441), CST8 (ENSG00000125815), CSTL1 (ENSG00000125823), CST11 (ENSG00000125831), CST5 (ENSG00000170367), CST2 (ENSG00000170369), CST1 (ENSG00000170373), CST9 (ENSG00000173335), CST6 (ENSG00000175315)

Protein

Protein identifiers

Cystatin-F — O76096 (reviewed: O76096)

Alternative names: Cystatin-7, Cystatin-like metastasis-associated protein, Leukocystatin

All UniProt accessions (1): O76096

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits papain and cathepsin L but with affinities lower than other cystatins. May play a role in immune regulation through inhibition of a unique target in the hematopoietic system.

Subunit / interactions. Homodimer; disulfide-linked.

Subcellular location. Secreted. Cytoplasm.

Tissue specificity. Primarily expressed in peripheral blood cells and spleen.

Similarity. Belongs to the cystatin family.

RefSeq proteins (1): NP_003641* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000010	Cystatin_dom	Domain
IPR042886	Cystatin-F	Family
IPR046350	Cystatin_sf	Homologous_superfamily

Pfam: PF00031

UniProt features (17 total): disulfide bond 4, helix 3, strand 3, glycosylation site 2, signal peptide 1, chain 1, turn 1, short sequence motif 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2CH9	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O76096-F1	89.78	0.77

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)

Disulfide bonds (4): 26, 63, 99–110, 124–144

Glycosylation sites (2): 62, 115

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 362 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, MODULE_52, GOBP_INFLAMMATORY_RESPONSE, MODULE_151, MODULE_45, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_MACROPHAGE_ACTIVATION, GOBP_REGULATION_OF_MYELINATION, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, MODULE_16, MODULE_118, MODULE_75

GO Biological Process (5): regulation of antigen processing and presentation (GO:0002577), immune response (GO:0006955), positive regulation of myelination (GO:0031643), negative regulation of microglial cell activation (GO:1903979), lysosomal protein catabolic process (GO:1905146)

GO Molecular Function (6): protease binding (GO:0002020), endopeptidase inhibitor activity (GO:0004866), cysteine-type endopeptidase inhibitor activity (GO:0004869), peptidase inhibitor activity (GO:0030414), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (10): obsolete extracellular space (GO:0005615), lysosome (GO:0005764), endosome (GO:0005768), late endosome (GO:0005770), multivesicular body (GO:0005771), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), cytoplasmic vesicle (GO:0031410), extracellular region (GO:0005576), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	3
cytoplasm	3
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
regulation of immune system process	1
antigen processing and presentation	1
immune system process	1
response to stimulus	1
regulation of myelination	1
positive regulation of nervous system process	1
myelination	1
positive regulation of cellular process	1
microglial cell activation	1
negative regulation of macrophage activation	1
negative regulation of neuroinflammatory response	1
regulation of microglial cell activation	1
lysosome	1
protein catabolic process in the vacuole	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
identical protein binding	1
protein dimerization activity	1
binding	1
lytic vacuole	1
cytoplasmic vesicle	1
endosome	1
late endosome	1
intracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1318 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CST7	CTSL	P07711	913
CST7	TMEM119	Q4V9L6	718
CST7	P2RY12	Q9H244	701
CST7	LGMN	Q99538	673
CST7	CLEC7A	Q9BXN2	664
CST7	TREM2	Q9NZC2	654
CST7	TYROBP	O43914	651
CST7	APOE	P02649	604
CST7	CTSC	P53634	595
CST7	PTPRC	P08575	524
CST7	NKG7	Q16617	523
CST7	CSTB	P04080	502
CST7	FGL2	Q14314	491
CST7	CTSS	P25774	487
CST7	CX3CR1	P49238	475

IntAct

12 interactions, top by confidence:

A	B	Type	Score
TPT1	CST7	psi-mi:“MI:0914”(association)	0.530
CST7	CTSL	psi-mi:“MI:0914”(association)	0.530
CST7	H2BC14	psi-mi:“MI:0915”(physical association)	0.400
STK32A	CST7	psi-mi:“MI:0915”(physical association)	0.400
CST7	CTSC	psi-mi:“MI:0915”(physical association)	0.400
CTSC	CST7	psi-mi:“MI:0915”(physical association)	0.400
CST7		psi-mi:“MI:0914”(association)	0.350
ZCCHC17	SHTN1	psi-mi:“MI:0914”(association)	0.350
CST7	APOD	psi-mi:“MI:0914”(association)	0.350
CST7	tktA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): POTEE (Affinity Capture-MS), TUBA3C (Affinity Capture-MS), ITIH3 (Affinity Capture-MS), GALC (Affinity Capture-MS), CTSL (Affinity Capture-MS), CST7 (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), CST7 (Affinity Capture-MS), HIST1H2BM (Proximity Label-MS), ITIH3 (Affinity Capture-MS), CST7 (Affinity Capture-MS), TUBA3C (Affinity Capture-MS), CST7 (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), CTSL (Affinity Capture-MS)

ESM2 similar proteins: A9QWQ1, O14625, O22969, O46675, O46676, O46677, O46678, O62657, O76096, O89098, O97919, P09341, P10147, P10855, P13236, P13501, P14097, P16619, P19875, P19876, P30782, P30882, P40224, P46632, P47854, P48061, P50229, P50230, P50231, P97272, Q17QA1, Q53S33, Q5EBF6, Q5I1Z0, Q68A92, Q68AZ0, Q711P4, Q8HYQ1, Q8HYQ2, Q8HYQ3

Diamond homologs: B1P1J3, B2Z450, E3P6N3, E3P6N4, E3P6N5, E3P6N6, E3P6N7, E3P6N8, E3P6N9, E3P6P0, E3P6P1, E3P6P2, E3P6P3, E3P6P4, J3RYX9, J3SE80, O19092, O19093, O76096, O97862, P01034, P01035, P01037, P01038, P08935, P09228, P0DXA0, P14841, P19313, P21460, P31726, P35481, P81061, P81714, P90698, Q10993, Q15828, Q2XXN5, Q6T6T4, Q7M429

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

700 predictions. Top by Δscore:

Variant	Effect	Δscore
20:24957283:TCA:T	acceptor_loss	1.0000
20:24957284:CA:C	acceptor_loss	1.0000
20:24957285:A:AG	acceptor_gain	1.0000
20:24957285:AGATA:A	acceptor_loss	1.0000
20:24957286:G:A	acceptor_loss	1.0000
20:24957286:G:GA	acceptor_gain	1.0000
20:24957286:GAT:G	acceptor_gain	1.0000
20:24957286:GATA:G	acceptor_gain	1.0000
20:24957286:GATAC:G	acceptor_gain	1.0000
20:24957456:TCAG:T	donor_loss	1.0000
20:24957457:CAGGT:C	donor_loss	1.0000
20:24957461:T:G	donor_loss	1.0000
20:24958924:CCA:C	acceptor_loss	1.0000
20:24958925:CAG:C	acceptor_loss	1.0000
20:24958926:A:AG	acceptor_gain	1.0000
20:24958926:AGAT:A	acceptor_loss	1.0000
20:24958927:G:GA	acceptor_gain	1.0000
20:24958927:GA:G	acceptor_gain	1.0000
20:24958927:GAT:G	acceptor_gain	1.0000
20:24958927:GATA:G	acceptor_gain	1.0000
20:24959041:GCAG:G	donor_gain	1.0000
20:24959042:CAG:C	donor_loss	1.0000
20:24959043:AGGTA:A	donor_loss	1.0000
20:24959044:GG:G	donor_loss	1.0000
20:24959046:T:A	donor_loss	1.0000
20:24957275:T:TA	acceptor_gain	0.9900
20:24957286:GA:G	acceptor_gain	0.9900
20:24957386:TTGAA:T	donor_gain	0.9900
20:24959282:G:GT	donor_gain	0.9900
20:24949573:CAGGT:C	donor_loss	0.9800

AlphaMissense

948 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:24957424:T:C	F70L	0.974
20:24957426:C:A	F70L	0.974
20:24957426:C:G	F70L	0.974
20:24957399:C:A	N61K	0.973
20:24957399:C:G	N61K	0.973
20:24957418:T:C	F68L	0.972
20:24957420:C:A	F68L	0.972
20:24957420:C:G	F68L	0.972
20:24957382:A:C	S56R	0.968
20:24957384:T:A	S56R	0.968
20:24957384:T:G	S56R	0.968
20:24959673:G:C	W133C	0.967
20:24959673:G:T	W133C	0.967
20:24959644:T:A	C124S	0.953
20:24959645:G:C	C124S	0.953
20:24958937:G:C	G85R	0.945
20:24959704:T:A	C144S	0.945
20:24959705:G:C	C144S	0.945
20:24958972:A:C	R96S	0.944
20:24958972:A:T	R96S	0.944
20:24958974:C:T	T97I	0.943
20:24957394:T:C	F60L	0.942
20:24957396:C:A	F60L	0.942
20:24957396:C:G	F60L	0.942
20:24959646:C:G	C124W	0.940
20:24959645:G:A	C124Y	0.938
20:24959012:T:A	C110S	0.937
20:24959013:G:C	C110S	0.937
20:24957398:A:T	N61I	0.936
20:24959644:T:C	C124R	0.935

dbSNP variants (sampled 300 via entrez): RS1000079209 (20:24947625 A>T), RS1000094451 (20:24954621 A>G), RS1000425101 (20:24952156 T>C), RS1000695595 (20:24955941 G>A,T), RS1000799465 (20:24957704 C>T), RS1001077965 (20:24948741 A>T), RS1001186907 (20:24957096 T>A,C,G), RS1001385050 (20:24947852 C>T), RS1001391292 (20:24952777 G>A), RS1001525728 (20:24949702 G>A,T), RS1001796428 (20:24958849 C>T), RS1001827566 (20:24959138 G>A,C), RS1001992390 (20:24953818 C>A,T), RS1002083702 (20:24949563 G>A,C), RS1002104406 (20:24956854 G>A)

Disease associations

OMIM: gene MIM:603253 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006585_375	Blood protein levels	5.000000e-302
GCST006585_509	Blood protein levels	8.000000e-28
GCST007328_59	Alcohol consumption (drinks per week)	5.000000e-08
GCST011741_63	LDL cholesterol levels in HIV infection	5.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Decitabine	increases expression	2
Methotrexate	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
alpha phellandrene	decreases expression	1
beta-lapachone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CD 437	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Bortezomib	increases expression	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Benzoates	increases expression	1
Cyclophosphamide	decreases expression	1
Fluorouracil	affects response to substance, decreases expression	1
Nickel	increases expression	1
Tretinoin	decreases expression	1
Mifepristone	decreases expression	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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