CST2

Summary

CST2 (cystatin SA, HGNC:2474) is a protein-coding gene on chromosome 20p11.21, encoding Cystatin-SA (P09228). Thiol protease inhibitor.

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 a secreted thiol protease inhibitor found at high levels in saliva, tears and seminal plasma.

Source: NCBI Gene 1470 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 54 total
• MANE Select transcript: NM_001322

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2474
Approved symbol	CST2
Name	cystatin SA
Location	20p11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170369
Ensembl biotype	protein_coding
OMIM	123856
Entrez	1470

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000304725

RefSeq mRNA: 1 — MANE Select: NM_001322 NM_001322

CCDS: CCDS13161

Canonical transcript exons

ENST00000304725 — 3 exons

Exon	Start	End
ENSE00001424244	23823769	23824103
ENSE00001601194	23826433	23826729
ENSE00001625618	23825210	23825323

Expression profiles

Bgee: expression breadth ubiquitous, 116 present calls, max score 95.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 44.6392 / max 69694.6692, expressed in 167 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186746	44.5629	166
186745	0.0481	2
186744	0.0281	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	95.98	gold quality
decidua	UBERON:0002450	89.52	gold quality
olfactory bulb	UBERON:0002264	82.15	gold quality
vena cava	UBERON:0004087	82.13	gold quality
adrenal tissue	UBERON:0018303	81.78	gold quality
pancreatic ductal cell	CL:0002079	81.77	silver quality
type B pancreatic cell	CL:0000169	81.20	gold quality
tongue	UBERON:0001723	79.86	silver quality
seminal vesicle	UBERON:0000998	79.78	gold quality
ventral tegmental area	UBERON:0002691	79.67	gold quality
pericardium	UBERON:0002407	79.32	silver quality
subthalamic nucleus	UBERON:0001906	78.80	gold quality
cardia of stomach	UBERON:0001162	78.74	gold quality
inferior vagus X ganglion	UBERON:0005363	78.60	gold quality
dorsal plus ventral thalamus	UBERON:0001897	78.53	silver quality
diaphragm	UBERON:0001103	78.31	gold quality
cerebellar vermis	UBERON:0004720	78.03	gold quality
lateral globus pallidus	UBERON:0002476	77.99	gold quality
body of tongue	UBERON:0011876	77.90	gold quality
nipple	UBERON:0002030	77.65	gold quality
pharyngeal mucosa	UBERON:0000355	77.58	silver quality
substantia nigra pars reticulata	UBERON:0001966	77.51	gold quality
lateral nuclear group of thalamus	UBERON:0002736	77.41	gold quality
substantia nigra pars compacta	UBERON:0001965	77.18	gold quality
pylorus	UBERON:0001166	77.05	gold quality
pons	UBERON:0000988	76.50	gold quality
synovial joint	UBERON:0002217	76.28	gold quality
renal medulla	UBERON:0000362	76.14	gold quality
penis	UBERON:0000989	73.77	gold quality
thymus	UBERON:0002370	73.46	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting CST2, 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-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4447	99.85	67.81	2900
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-92A-2-5P	99.75	67.01	2164
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-3665	97.73	65.08	975
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-6753-5P	94.70	64.08	470

Literature-anchored findings (GeneRIF, showing 8)

• cystatins SA1 and SA2 adhere to human fibroblasts and that the event results in tyrosine phosphorylation and upregulation of the release of IL-6 mediated enhancement of NF-kappa B activity. (PMID:12413693)
• Murine monoclonal antibodies were made which can distinguish between CST1 and CST2. (PMID:15829315)
• Identification of cystatin SA as a novel inhibitor of acid ceramidase. (PMID:21846728)
• This data suggests an autoimmune mechanism behind chronic mucocutaneous candidiasis in autoimmune polyendocrine syndrome type I and provides rationale for evaluating cystatin SA1 in antifungal therapy. (PMID:23122533)
• interactions of human family 1 & 2 cystatins with cathepsin L1 (PMID:27764212)
• tumor biomarker cystatin 2 as part of a four gene transcript score has prognostic value for metastatic-lethal progression in men treated for localized prostate cancer (PMID:31376183)
• Cystatin 2 leads to a worse prognosis in patients with gastric cancer. (PMID:33302616)
• Cystatin SA attenuates gastric cancer cells growth and increases sensitivity to oxaliplatin via PI3K/AKT signaling pathway. (PMID:38717526)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:busm1-57f23.1	ENSDARG00000074425
caenorhabditis_elegans		WBGENE00000534
caenorhabditis_elegans		WBGENE00000535
caenorhabditis_elegans		WBGENE00023486

Paralogs (11): CST7 (ENSG00000077984), CST9L (ENSG00000101435), CST3 (ENSG00000101439), CST4 (ENSG00000101441), CST8 (ENSG00000125815), CSTL1 (ENSG00000125823), CST11 (ENSG00000125831), CST5 (ENSG00000170367), CST1 (ENSG00000170373), CST9 (ENSG00000173335), CST6 (ENSG00000175315)

Protein

Protein identifiers

Cystatin-SA — P09228 (reviewed: P09228)

Alternative names: Cystatin-2, Cystatin-S5

All UniProt accessions (1): P09228

UniProt curated annotations — full annotation on UniProt →

Function. Thiol protease inhibitor.

Subcellular location. Secreted.

Tissue specificity. Expressed in submandibular and sublingual saliva but not in parotid saliva (at protein level). Expressed in submandibular gland and parotid gland.

Similarity. Belongs to the cystatin family.

RefSeq proteins (1): NP_001313* (*=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 (6 total): disulfide bond 2, signal peptide 1, chain 1, short sequence motif 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09228-F1	89.89	0.74

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): 32 (reactive site)

Disulfide bonds (2): 94–104, 118–138

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 36 (showing top): GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, VETTER_TARGETS_OF_PRKCA_AND_ETS1_DN, GOBP_DETECTION_OF_CHEMICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION_OF_TASTE, GOBP_SENSORY_PERCEPTION_OF_TASTE, GOBP_DETECTION_OF_STIMULUS, GOBP_SENSORY_PERCEPTION, GOMF_PEPTIDASE_REGULATOR_ACTIVITY, chr20p11, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, GOMF_CYSTEINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY, CHICAS_RB1_TARGETS_SENESCENT, GOBP_DETECTION_OF_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, GOBP_SENSORY_PERCEPTION_OF_BITTER_TASTE, GOMF_ENDOPEPTIDASE_REGULATOR_ACTIVITY

GO Biological Process (1): detection of chemical stimulus involved in sensory perception of bitter taste (GO:0001580)

GO Molecular Function (3): cysteine-type endopeptidase inhibitor activity (GO:0004869), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), vesicle (GO:0031982), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
detection of chemical stimulus involved in sensory perception of taste	1
sensory perception of bitter taste	1
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
intracellular anatomical structure	1
membrane-bounded organelle	1

Protein interactions and networks

STRING

625 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CST2	CPPED1	Q9BRF8	916
CST2	CSTB	P04080	683
CST2	CSTA	P01040	658
CST2	BST2	Q10589	588
CST2	AZGP1	P25311	542
CST2	CTSS	P25774	506
CST2	C1orf198	Q9H425	493
CST2	LGMN	Q99538	473
CST2	CST9	Q5W186	448
CST2	CTSB	P07858	431
CST2	LCN1	P31025	424
CST2	CKS1B	P33551	420
CST2	STATH	P02808	399
CST2	LGALSL	Q3ZCW2	398
CST2	DCD	P58461	395

IntAct

77 interactions, top by confidence:

A	B	Type	Score
COMMD1	VPS26C	psi-mi:“MI:0914”(association)	0.730
	CST2	psi-mi:“MI:0915”(physical association)	0.560
PSMA3	CST2	psi-mi:“MI:0915”(physical association)	0.560
ADAMTSL4	CST2	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	CST2	psi-mi:“MI:0915”(physical association)	0.560
CST2	PSMA3	psi-mi:“MI:0915”(physical association)	0.560
CST2	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
CST2		psi-mi:“MI:0915”(physical association)	0.560
CST2	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	CST2	psi-mi:“MI:0915”(physical association)	0.560
CST2	KRTAP1-1	psi-mi:“MI:0915”(physical association)	0.560
CST2	APPBP2	psi-mi:“MI:0915”(physical association)	0.560
P4HB	CST2	psi-mi:“MI:0915”(physical association)	0.560
CST2	NOTCH2NLC	psi-mi:“MI:0915”(physical association)	0.560
FRMD1	A2ML1	psi-mi:“MI:0914”(association)	0.530
DDX31	IGLL5	psi-mi:“MI:0914”(association)	0.530
RHOBTB1	CST4	psi-mi:“MI:0914”(association)	0.530
TSFM	CST4	psi-mi:“MI:0914”(association)	0.530
UCP2	CST4	psi-mi:“MI:0914”(association)	0.530
GTF2B	CST4	psi-mi:“MI:0914”(association)	0.530
ZNF491	CST4	psi-mi:“MI:0914”(association)	0.530
KIR2DS2	RHOBTB3	psi-mi:“MI:0914”(association)	0.530

BioGRID (72): PSMA3 (Two-hybrid), ADAMTSL4 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), CST2 (Affinity Capture-MS), CST2 (Affinity Capture-MS), CST2 (Affinity Capture-MS), CST2 (Affinity Capture-MS), CST2 (Affinity Capture-MS), CST2 (Affinity Capture-MS), CST2 (Affinity Capture-MS), CST2 (Affinity Capture-MS), CST2 (Affinity Capture-MS), CST2 (Affinity Capture-MS), CST2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0K0IP23, A0A1S3PBB7, B2Z450, E3P6N3, E3P6N4, E3P6N5, E3P6N6, E3P6N7, E3P6N8, E3P6N9, E3P6P0, E3P6P1, E3P6P2, E3P6P3, E3P6P4, J3RYX9, J3SE80, O60676, O88969, O97862, P01036, P01037, P01038, P01048, P08932, P08935, P09228, P19313, P28325, P32766, P33046, P35481, P49928, P49929, P49930, P54229, P54230, P81714, Q15828, Q2XXN5

Diamond homologs: B1P1J3, E3P6N3, E3P6N4, E3P6N5, E3P6N6, E3P6N7, E3P6N8, E3P6N9, E3P6P0, E3P6P1, E3P6P2, E3P6P3, E3P6P4, J3RYX9, J3SE80, O19092, O19093, O97862, P01034, P01035, P01037, P01038, P08935, P09228, P0DXA0, P14841, P19313, P21460, P31726, P35481, P81061, P81714, P90698, Q10993, Q15828, Q2XXN5, Q41916, Q6QZV5, Q6T6T4, Q7M429

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	7
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

238 predictions. Top by Δscore:

Variant	Effect	Δscore
20:23825205:CGTA:C	donor_loss	1.0000
20:23825207:TA:T	donor_loss	1.0000
20:23825208:ACCTT:A	donor_loss	1.0000
20:23825320:CGAT:C	acceptor_gain	1.0000
20:23826428:CCCA:C	donor_loss	1.0000
20:23826430:CA:C	donor_loss	1.0000
20:23826431:ACCT:A	donor_loss	1.0000
20:23826432:C:CT	donor_loss	1.0000
20:23826479:T:C	donor_gain	1.0000
20:23824104:C:CC	acceptor_gain	0.9900
20:23824106:G:C	acceptor_gain	0.9900
20:23825204:ACGT:A	donor_loss	0.9900
20:23825209:CCTT:C	donor_gain	0.9900
20:23825324:C:CA	acceptor_loss	0.9900
20:23825324:C:CC	acceptor_gain	0.9900
20:23825325:T:C	acceptor_loss	0.9900
20:23825332:A:C	acceptor_gain	0.9900
20:23826438:C:CA	donor_gain	0.9900
20:23826478:A:AC	donor_gain	0.9900
20:23826478:AT:A	donor_gain	0.9900
20:23826478:ATCTT:A	donor_gain	0.9900
20:23824103:TC:T	acceptor_loss	0.9800
20:23824104:C:A	acceptor_loss	0.9800
20:23825327:C:CT	acceptor_gain	0.9800
20:23826432:CCTG:C	donor_gain	0.9800
20:23824099:TGTTT:T	acceptor_gain	0.9700
20:23824101:TTT:T	acceptor_gain	0.9700
20:23824102:TT:T	acceptor_gain	0.9700
20:23824106:G:GC	acceptor_gain	0.9700
20:23825331:C:CT	acceptor_gain	0.9700

AlphaMissense

917 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:23824065:C:A	W127C	0.959
20:23824065:C:G	W127C	0.959
20:23824086:G:C	F120L	0.933
20:23824086:G:T	F120L	0.933
20:23824088:A:G	F120L	0.933
20:23826511:A:C	F50L	0.920
20:23826511:A:T	F50L	0.920
20:23826513:A:G	F50L	0.920
20:23824093:C:G	C118S	0.908
20:23824094:A:T	C118S	0.908
20:23825235:A:C	F106C	0.906
20:23825277:G:A	T92I	0.905
20:23825234:G:C	F106L	0.887
20:23825234:G:T	F106L	0.887
20:23825236:A:G	F106L	0.887
20:23824033:C:G	C138S	0.875
20:23824034:A:T	C138S	0.875
20:23825271:C:G	C94S	0.874
20:23825272:A:T	C94S	0.874
20:23825241:C:G	C104S	0.862
20:23825242:A:T	C104S	0.862
20:23826433:C:A	Q76H	0.859
20:23826433:C:G	Q76H	0.859
20:23825272:A:G	C94R	0.845
20:23826512:A:C	F50C	0.843
20:23825264:C:A	K96N	0.834
20:23825264:C:G	K96N	0.834
20:23825271:C:T	C94Y	0.831
20:23825242:A:G	C104R	0.830
20:23826434:T:G	Q76P	0.829

dbSNP variants (sampled 300 via entrez): RS1000290244 (20:23825265 T>G), RS1001293150 (20:23824432 C>T), RS1001427500 (20:23828022 C>T), RS1001899751 (20:23828245 A>C), RS1002445016 (20:23827144 T>C), RS1002497484 (20:23827351 A>T), RS1002752182 (20:23823878 G>A), RS1003803569 (20:23823275 C>T), RS1003855992 (20:23827395 C>T), RS1003969157 (20:23827204 C>T), RS1004349174 (20:23824094 A>T), RS1004954519 (20:23826278 G>A), RS1005503166 (20:23823307 A>G), RS1005855034 (20:23825750 G>T), RS1006865552 (20:23825924 ACCT>A,ACCTCCT)

Disease associations

OMIM: gene MIM:123856 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_1808	Blood protein levels	1.000000e-78

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
chlorophyllin	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
Zoledronic Acid	increases expression	1
Antimony Potassium Tartrate	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Lucanthone	increases expression	1
Silicon Dioxide	decreases expression	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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