CST5

Summary

CST5 (cystatin D, HGNC:2477) is a protein-coding gene on chromosome 20p11.21, encoding Cystatin-D (P28325). Cysteine proteinase inhibitor that possibly plays a protective role against proteinases present in the oral cavity.

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. 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 protein found in saliva and tears. The encoded protein may play a protective role against proteinases present in the oral cavity.

Source: NCBI Gene 1473 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 32 total
• MANE Select transcript: NM_001900

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2477
Approved symbol	CST5
Name	cystatin D
Location	20p11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170367
Ensembl biotype	protein_coding
OMIM	123858
Entrez	1473

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000304710, ENST00000967458

RefSeq mRNA: 1 — MANE Select: NM_001900 NM_001900

CCDS: CCDS13162

Canonical transcript exons

ENST00000304710 — 3 exons

Exon	Start	End
ENSE00001131251	23875934	23876271
ENSE00001131256	23879446	23879748
ENSE00001592538	23877505	23877618

Expression profiles

Bgee: expression breadth broad, 64 present calls, max score 86.19.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 39.5525 / max 36662.7110, expressed in 44 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186748	39.5218	43
186749	0.0307	4

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	86.19	gold quality
lower esophagus	UBERON:0013473	69.44	gold quality
lower esophagus muscularis layer	UBERON:0035833	69.36	gold quality
right adrenal gland cortex	UBERON:0035827	63.52	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	63.01	gold quality
olfactory bulb	UBERON:0002264	59.89	gold quality
type B pancreatic cell	CL:0000169	59.68	gold quality
adrenal tissue	UBERON:0018303	59.00	gold quality
right adrenal gland	UBERON:0001233	58.97	gold quality
lower esophagus mucosa	UBERON:0035834	58.23	gold quality
upper lobe of left lung	UBERON:0008952	56.98	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	56.18	gold quality
upper lobe of lung	UBERON:0008948	56.05	gold quality
adrenal cortex	UBERON:0001235	54.96	gold quality
left adrenal gland	UBERON:0001234	54.69	gold quality
adrenal gland	UBERON:0002369	54.23	gold quality
left adrenal gland cortex	UBERON:0035825	54.11	gold quality
right lung	UBERON:0002167	53.69	gold quality
paraflocculus	UBERON:0005351	53.02	gold quality
thymus	UBERON:0002370	53.01	gold quality
Brodmann (1909) area 46	UBERON:0006483	52.17	gold quality
nasal cavity mucosa	UBERON:0001826	51.66	gold quality
tonsil	UBERON:0002372	51.57	gold quality
esophagus	UBERON:0001043	51.26	gold quality
lung	UBERON:0002048	51.24	gold quality
ileal mucosa	UBERON:0000331	50.96	silver quality
quadriceps femoris	UBERON:0001377	50.89	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.47

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, VDR

miRNA regulators (miRDB)

14 targeting CST5, 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-4302	99.89	67.94	1187
HSA-MIR-6756-5P	99.82	67.97	2466
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-4489	99.50	65.56	785
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-1233-5P	98.19	66.71	1201

Literature-anchored findings (GeneRIF, showing 6)

• Compared with its homologues, cystatin D presents an unusual inhibition profile with a preferential inhibition cathepsin S > cathepsin H > cathepsin L and no inhibition of cathepsin B or pig legumain. (PMID:15728581)
• Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells. (PMID:19662683)
• activation of the RhoA-ROCK-p38MAPK-MSK signaling pathway is essential for the regulation of the phenotype and of the CST5/cystatin D candidate tumor suppressor and other target genes by 1,25(OH)2D3 in colon cancer cells (PMID:20223287)
• Results imply CST5 as an important mediator of tumor suppression by p53 in colorectal cancer. (PMID:26158294)
• These results support an unanticipated role of cystatin D in the cell nucleus, controlling the transcription of specific genes involved in crucial cellular functions, which may mediate its protective action in colon cancer. (PMID:26364852)
• CST5 has demonstrated the ability to differentiate between severely traumatic brain injury (TBI) patients and those with either mild or no brain injury within the first hour highlighting it as new TBI biomarker. (PMID:28694499)

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), CST2 (ENSG00000170369), CST1 (ENSG00000170373), CST9 (ENSG00000173335), CST6 (ENSG00000175315)

Protein

Protein identifiers

Cystatin-D — P28325 (reviewed: P28325)

Alternative names: Cystatin-5

All UniProt accessions (1): P28325

UniProt curated annotations — full annotation on UniProt →

Function. Cysteine proteinase inhibitor that possibly plays a protective role against proteinases present in the oral cavity. The order of preference for inhibition is cathepsin S > cathepsin H > cathepsin L > cathepsin B.

Subunit / interactions. Monomer.

Subcellular location. Secreted.

Tissue specificity. Expressed in submandibular and sublingual saliva but not in parotid saliva (at protein level). Expressed in parotid gland but not in seminal vesicle, prostate, epididymis, testis, ovary, placenta, thyroid, gastric corpus, small intestine, liver, or gall bladder tissue.

Similarity. Belongs to the cystatin family.

RefSeq proteins (1): NP_001891* (*=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 (15 total): strand 5, turn 2, disulfide bond 2, signal peptide 1, chain 1, short sequence motif 1, site 1, sequence variant 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1ROA	X-RAY DIFFRACTION	1.8
1RN7	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P28325-F1	88.46	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): 95–105, 119–139

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 51 (showing top): MORF_EPHA7, MORF_RAB3A, MORF_WNT1, DANG_BOUND_BY_MYC, MORF_DCC, GOMF_PEPTIDASE_REGULATOR_ACTIVITY, WINNEPENNINCKX_MELANOMA_METASTASIS_DN, chr20p11, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, GOMF_CYSTEINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY, SU_SALIVARY_GLAND, MARTENS_TRETINOIN_RESPONSE_UP, GOMF_ENDOPEPTIDASE_REGULATOR_ACTIVITY, ATF2_S_UP.V1_UP

GO Biological Process (0):

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

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), vesicle (GO:0031982), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
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
extracellular vesicle	1

Protein interactions and networks

STRING

637 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CST5	CSTB	P04080	619
CST5	CTSL	P07711	592
CST5	CSTA	P01040	567
CST5	DEFB131A	P59861	520
CST5	CST9	Q5W186	498
CST5	AZGP1	P25311	482
CST5	LTF	P02788	432
CST5	STATH	P02808	423
CST5	PAGE1	O75459	410
CST5	DCD	P58461	406
CST5	CPPED1	Q9BRF8	402
CST5	BPIFA2	Q96DR5	400
CST5	LGMN	Q99538	397
CST5	PAGE4	O60829	392
CST5	CHIT1	Q13231	387

IntAct

17 interactions, top by confidence:

A	B	Type	Score
FRMD1	A2ML1	psi-mi:“MI:0914”(association)	0.530
RHOBTB1	CST4	psi-mi:“MI:0914”(association)	0.530
PLEKHG6	CST4	psi-mi:“MI:0914”(association)	0.530
ZNF491	CST4	psi-mi:“MI:0914”(association)	0.530
RPP25L	RPP40	psi-mi:“MI:0914”(association)	0.530
SNRPF	GEMIN2	psi-mi:“MI:0914”(association)	0.350
RCAN1	CLEC3A	psi-mi:“MI:0914”(association)	0.350
KIR2DS2	LTN1	psi-mi:“MI:0914”(association)	0.350
HBQ1	IGLL5	psi-mi:“MI:0914”(association)	0.350
HINT2	CST4	psi-mi:“MI:0914”(association)	0.350
CST5	BCHE	psi-mi:“MI:0914”(association)	0.350
TIMM10	IGLL5	psi-mi:“MI:0914”(association)	0.350
CST5	HS3ST1	psi-mi:“MI:0914”(association)	0.350
IL20	HS3ST1	psi-mi:“MI:0914”(association)	0.350
CRH	CST4	psi-mi:“MI:0914”(association)	0.350
CST5	UCHL3	psi-mi:“MI:0914”(association)	0.350

BioGRID (36): CST5 (Affinity Capture-MS), CST5 (Affinity Capture-MS), CST5 (Affinity Capture-MS), CST5 (Affinity Capture-MS), CST5 (Affinity Capture-MS), CST5 (Affinity Capture-MS), CST5 (Affinity Capture-MS), CTSS (Reconstituted Complex), CST5 (Affinity Capture-MS), TENM3 (Affinity Capture-MS), SIRT2 (Affinity Capture-MS), UBR3 (Affinity Capture-MS), CST5 (Affinity Capture-MS), BCHE (Affinity Capture-MS), CST5 (Affinity Capture-MS)

ESM2 similar proteins: A0A0K0IP23, A0A1S3PBB7, A0A224AHH8, A0A3S6I186, A0A5C1J0Z8, A0A6B9KZ52, A1L015, A1L017, B1P1J3, B2Z450, B7PKZ1, B7PKZ2, D0NBV1, D0NBV4, E3P6N5, E3P6N6, E3P6N7, E3P6N9, E3P6P0, E3P6P1, E3P6P2, E3P6P4, J3RYX9, O60676, O88969, P01048, P08932, P08935, P0DXA0, P19313, P22085, P23779, P28325, P32766, P35481, P81714, P90698, Q15828, Q2XXN5, Q331K1

Diamond homologs: B1P1J3, E3P6N3, E3P6N4, E3P6N5, E3P6N6, E3P6N7, E3P6N8, E3P6N9, E3P6P0, E3P6P1, E3P6P2, E3P6P3, E3P6P4, J3RYX9, J3SE80, O19092, O19093, O97862, P01034, P01035, P01036, P01037, P01038, P08935, P09228, P0DXA0, P14841, P19313, P21460, P28325, P31726, P35481, P81061, P81714, P90698, Q10993, Q15828, Q2XXN5, Q41916, Q6QZV5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

261 predictions. Top by Δscore:

Variant	Effect	Δscore
20:23879491:AT:A	donor_gain	1.0000
20:23876268:CTTC:C	acceptor_gain	0.9900
20:23876272:C:A	acceptor_loss	0.9900
20:23876273:T:A	acceptor_loss	0.9900
20:23877500:CATA:C	donor_loss	0.9900
20:23877501:ATACC:A	donor_loss	0.9900
20:23877503:ACCTC:A	donor_loss	0.9900
20:23877504:C:CT	donor_loss	0.9900
20:23877504:CCT:C	donor_gain	0.9900
20:23877615:CGAT:C	acceptor_gain	0.9900
20:23877624:CGCG:C	acceptor_gain	0.9900
20:23877627:G:C	acceptor_gain	0.9900
20:23877627:G:GC	acceptor_gain	0.9900
20:23877636:C:CT	acceptor_gain	0.9900
20:23877637:A:T	acceptor_gain	0.9900
20:23879442:GCA:G	donor_loss	0.9900
20:23879443:CA:C	donor_loss	0.9900
20:23879445:C:G	donor_loss	0.9900
20:23879491:ATC:A	donor_gain	0.9900
20:23879492:T:C	donor_gain	0.9900
20:23879492:T:TA	donor_gain	0.9900
20:23876272:C:CC	acceptor_gain	0.9800
20:23876274:G:C	acceptor_gain	0.9800
20:23877503:A:AC	donor_gain	0.9800
20:23877504:C:CC	donor_gain	0.9800
20:23877616:GATC:G	acceptor_loss	0.9800
20:23877617:ATCTA:A	acceptor_loss	0.9800
20:23877618:TCT:T	acceptor_loss	0.9800
20:23877619:C:CC	acceptor_gain	0.9800
20:23877619:CT:C	acceptor_loss	0.9800

AlphaMissense

944 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:23876254:G:C	F121L	0.967
20:23876254:G:T	F121L	0.967
20:23876256:A:G	F121L	0.967
20:23879527:A:C	F50L	0.959
20:23879527:A:T	F50L	0.959
20:23879529:A:G	F50L	0.959
20:23876255:A:C	F121C	0.947
20:23876255:A:G	F121S	0.925
20:23876233:C:A	W128C	0.922
20:23876233:C:G	W128C	0.922
20:23876261:C:G	C119S	0.921
20:23876262:A:T	C119S	0.921
20:23877593:A:G	F86S	0.914
20:23877572:G:A	T93I	0.908
20:23879514:A:C	Y55D	0.895
20:23877537:A:G	C105R	0.893
20:23879525:G:T	A51D	0.893
20:23879446:C:A	Q77H	0.886
20:23879446:C:G	Q77H	0.886
20:23877536:C:G	C105S	0.882
20:23877537:A:T	C105S	0.882
20:23876201:C:G	C139S	0.870
20:23876202:A:T	C139S	0.870
20:23879513:T:G	Y55S	0.869
20:23876249:A:C	I123S	0.868
20:23877559:C:A	K97N	0.866
20:23877559:C:G	K97N	0.866
20:23877566:C:G	C95S	0.866
20:23877567:A:T	C95S	0.866
20:23877529:G:C	F107L	0.864

dbSNP variants (sampled 300 via entrez): RS1000308798 (20:23880324 G>A,C,T), RS1000669176 (20:23876987 C>G), RS1000863038 (20:23881335 G>A), RS1000912017 (20:23881085 G>A), RS1001207326 (20:23876745 C>A,G,T), RS1001803826 (20:23878689 C>G,T), RS1001812538 (20:23877736 C>A,T), RS1002075101 (20:23877968 T>C), RS1002664020 (20:23881710 C>T), RS1002669654 (20:23879049 A>G), RS1004196287 (20:23877692 A>G), RS1004311165 (20:23877547 G>A,C), RS1005322835 (20:23876522 G>T), RS1005332302 (20:23881173 C>A,G), RS1005628616 (20:23877361 G>A)

Disease associations

OMIM: gene MIM:123858 | 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
GCST000211_3	Response to TNF antagonist treatment	3.000000e-06
GCST004103_3	Body mass index (change over time) in cancer or chronic obstructive pulmonary disease	9.000000e-06
GCST006585_1143	Blood protein levels	7.000000e-186
GCST009144_9	Disease progression in age-related macular degeneration (adjusted for baseline)	6.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004653	response to TNF antagonist
EFO:0005937	longitudinal BMI measurement
EFO:0008336	disease progression measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs6138150	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Rheumatoid arthritis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6138150	CST5	3	2.25	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
Estradiol	affects expression, affects binding, increases reaction	2
bisphenol F	increases expression, affects cotreatment	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
N-acetyl-4-benzoquinoneimine	affects response to substance	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Fulvestrant	affects cotreatment, decreases methylation	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Carmustine	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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