CST8

Summary

CST8 (cystatin 8, HGNC:2480) is a protein-coding gene on chromosome 20p11.21, encoding Cystatin-8 (O60676). Performs a specialized role during sperm development and maturation.

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 similar to type 2 cystatins. The encoded protein exhibits highly tissue-specific expression in the reproductive tract, suggesting implicit roles in reproduction. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10047 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 33 total
• MANE Select transcript: NM_005492

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2480
Approved symbol	CST8
Name	cystatin 8
Location	20p11.21
Locus type	gene with protein product
Status	Approved
Aliases	CRES, CTES5
Ensembl gene	ENSG00000125815
Ensembl biotype	protein_coding
OMIM	608683
Entrez	10047

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000246012, ENST00000449810

RefSeq mRNA: 2 — MANE Select: NM_005492 NM_001281730, NM_005492

CCDS: CCDS13156

Canonical transcript exons

ENST00000246012 — 4 exons

Exon	Start	End
ENSE00000859436	23492958	23493071
ENSE00000859437	23491525	23491898
ENSE00001025776	23491117	23491342
ENSE00001131377	23495831	23496010

Expression profiles

Bgee: expression breadth broad, 21 present calls, max score 86.34.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0383 / max 42.4020, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183864	0.0383	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.34	gold quality
right testis	UBERON:0004534	83.61	gold quality
left testis	UBERON:0004533	83.40	gold quality
buccal mucosa cell	CL:0002336	82.88	silver quality
testis	UBERON:0000473	80.54	gold quality
sperm	CL:0000019	79.03	silver quality
male germ cell	CL:0000015	78.55	silver quality
hair follicle	UBERON:0002073	73.44	gold quality
tongue squamous epithelium	UBERON:0006919	68.71	gold quality
diaphragm	UBERON:0001103	68.61	gold quality
tibialis anterior	UBERON:0001385	66.59	silver quality
olfactory bulb	UBERON:0002264	65.42	gold quality
type B pancreatic cell	CL:0000169	65.34	gold quality
cervix squamous epithelium	UBERON:0006922	64.96	gold quality
gingival epithelium	UBERON:0001949	64.47	gold quality
squamous epithelium	UBERON:0006914	64.12	gold quality
amniotic fluid	UBERON:0000173	63.66	gold quality
epithelial cell of pancreas	CL:0000083	62.63	gold quality
CA1 field of hippocampus	UBERON:0003881	62.56	gold quality
deltoid	UBERON:0001476	62.20	gold quality
esophagus squamous epithelium	UBERON:0006920	61.83	gold quality
choroid plexus epithelium	UBERON:0003911	61.69	gold quality
gingiva	UBERON:0001828	61.28	gold quality
thymus	UBERON:0002370	61.06	gold quality
epithelium of esophagus	UBERON:0001976	60.73	gold quality
adult organism	UBERON:0007023	60.45	gold quality
mucosa of paranasal sinus	UBERON:0005030	60.33	gold quality
quadriceps femoris	UBERON:0001377	60.23	gold quality
cerebellar vermis	UBERON:0004720	60.16	gold quality
orbitofrontal cortex	UBERON:0004167	59.88	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB

miRNA regulators (miRDB)

8 targeting CST8, 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-1250-3P	99.96	70.04	4038
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-1261	98.62	68.10	896
HSA-MIR-3977	98.00	68.17	1500
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-490-5P	96.75	65.81	661

Literature-anchored findings (GeneRIF, showing 2)

• studies show that cystatin-related epididymal spermatogenic protein is present in the sperm equatorial segment and becomes accessible to the extracellular environment during fertilization (PMID:12193387)
• We show with phylogenetic relations that the CTES genes are clustered into three original groups, a testatin, a Cres, and a CstL1 group (PMID:20565543)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:busm1-57f23.1	ENSDARG00000074425
mus_musculus	Cst8	ENSMUSG00000027442
rattus_norvegicus	Cst8	ENSRNOG00000004989
caenorhabditis_elegans		WBGENE00000534
caenorhabditis_elegans		WBGENE00000535
caenorhabditis_elegans		WBGENE00023486

Paralogs (11): CST7 (ENSG00000077984), CST9L (ENSG00000101435), CST3 (ENSG00000101439), CST4 (ENSG00000101441), CSTL1 (ENSG00000125823), CST11 (ENSG00000125831), CST5 (ENSG00000170367), CST2 (ENSG00000170369), CST1 (ENSG00000170373), CST9 (ENSG00000173335), CST6 (ENSG00000175315)

Protein

Protein identifiers

Cystatin-8 — O60676 (reviewed: O60676)

Alternative names: Cystatin-related epididymal spermatogenic protein

All UniProt accessions (3): O60676, A0A384MDQ4, A2A2N0

UniProt curated annotations — full annotation on UniProt →

Function. Performs a specialized role during sperm development and maturation.

Subcellular location. Secreted.

Tissue specificity. Proximal caput region of the epididymis. Lower expression in the testis. Within the testis it is localized to the elongating spermatids, whereas within the epididymis it is exclusively synthesized by the proximal caput epithelium.

Similarity. Belongs to the cystatin family.

RefSeq proteins (2): NP_001268659, NP_005483* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000010	Cystatin_dom	Domain
IPR046350	Cystatin_sf	Homologous_superfamily
IPR052691	Sperm_Mat_Cystatin	Family

Pfam: PF00031

UniProt features (9 total): glycosylation site 2, disulfide bond 2, sequence variant 2, signal peptide 1, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60676-F1	87.12	0.70

Functional residue map

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

Disulfide bonds (2): 95–105, 119–139

Glycosylation sites (2): 27, 39

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 48 (showing top): GOCC_CELL_SURFACE, WEBER_METHYLATED_LCP_IN_SPERM_UP, GOMF_PEPTIDASE_REGULATOR_ACTIVITY, chr20p11, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, YOSHIMURA_MAPK8_TARGETS_UP, GOMF_CYSTEINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY, GOMF_ENDOPEPTIDASE_REGULATOR_ACTIVITY, FOXN3_TARGET_GENES, SIPA1_TARGET_GENES, MIR1250_3P, MIR3977, MIR490_5P, NABA_ECM_REGULATORS

GO Biological Process (0):

GO Molecular Function (2): cysteine-type endopeptidase inhibitor activity (GO:0004869), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (3): extracellular region (GO:0005576), cytoplasm (GO:0005737), cell surface (GO:0009986)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

737 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CST8	CST9	Q5W186	753
CST8	CTPS1	P17812	558
CST8	GATA1	P15976	549
CST8	CEBPA	P49715	492
CST8	LCN8	Q6JVE9	483
CST8	GZF1	Q9H116	456
CST8	GHSR	Q92847	411
CST8	NXT1	Q9UKK6	408
CST8	TMEM167B	Q9NRX6	384
CST8	ACSS1	Q9NUB1	372
CST8	CST9L	Q9H4G1	371
CST8	RILPL1	Q5EBL4	368
CST8	TMEM225	Q6GV28	367
CST8	GALNT9	Q9HCQ5	366
CST8	ECSCR	Q19T08	364

IntAct

10 interactions, top by confidence:

A	B	Type	Score
FAM9C	NDC80	psi-mi:“MI:0914”(association)	0.670
IQCF2	TRAFD1	psi-mi:“MI:0914”(association)	0.350
SPO16	CST8	psi-mi:“MI:0914”(association)	0.350
MGST2	CST8	psi-mi:“MI:0914”(association)	0.350
RGS5	CST8	psi-mi:“MI:0914”(association)	0.350
CDKN3	CST8	psi-mi:“MI:0914”(association)	0.350
CST8	ITIH2	psi-mi:“MI:0914”(association)	0.350
CST8	HS3ST1	psi-mi:“MI:0914”(association)	0.350
CST8	VGF	psi-mi:“MI:0914”(association)	0.350

BioGRID (44): ARMC8 (Affinity Capture-MS), CST8 (Affinity Capture-MS), LAMA3 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), TUBA1B (Affinity Capture-MS), CST8 (Affinity Capture-MS), B4GALT6 (Affinity Capture-MS), MKLN1 (Affinity Capture-MS), CST8 (Affinity Capture-MS), SPCS3 (Affinity Capture-MS), HEATR6 (Affinity Capture-MS), DDX19B (Affinity Capture-MS), KHK (Affinity Capture-MS), MAEA (Affinity Capture-MS), PXDN (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: B2Z450, E3P6N3, E3P6N4, E3P6N5, E3P6N6, E3P6N7, E3P6N8, E3P6N9, E3P6P0, E3P6P1, E3P6P2, E3P6P3, E3P6P4, J3RYX9, J3SE80, O19092, O19093, O60676, O76096, O88969, O89098, O97862, P01034, P01035, P01036, P01037, P01038, P08935, P09228, P14841, P19313, P21460, P22085, P28325, P32766, P35481, P81061, P81714, P90698, Q15828

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

405 predictions. Top by Δscore:

Variant	Effect	Δscore
20:23493070:GG:G	donor_gain	0.9900
20:23493071:GG:G	donor_gain	0.9900
20:23491897:AGGTA:A	donor_loss	0.9800
20:23491900:T:C	donor_loss	0.9800
20:23495829:A:AG	acceptor_gain	0.9800
20:23495830:G:GG	acceptor_gain	0.9800
20:23495830:GA:G	acceptor_gain	0.9800
20:23495830:GAA:G	acceptor_gain	0.9800
20:23493071:GGTA:G	donor_loss	0.9700
20:23495827:TCA:T	acceptor_loss	0.9700
20:23495829:A:C	acceptor_loss	0.9700
20:23495830:G:GA	acceptor_loss	0.9700
20:23491856:G:GG	donor_gain	0.9600
20:23492952:CAACA:C	acceptor_loss	0.9500
20:23492953:AACAG:A	acceptor_loss	0.9500
20:23492954:ACAG:A	acceptor_loss	0.9500
20:23492955:CAGG:C	acceptor_loss	0.9500
20:23492956:AGGT:A	acceptor_loss	0.9500
20:23495757:G:GT	donor_gain	0.9500
20:23495830:GAAA:G	acceptor_gain	0.9400
20:23495830:GAAAT:G	acceptor_gain	0.9300
20:23493076:G:C	donor_loss	0.9100
20:23491855:A:AG	donor_gain	0.9000
20:23491871:G:GA	donor_gain	0.9000
20:23491204:G:GT	donor_gain	0.8800
20:23491340:GGG:G	donor_gain	0.8700
20:23491341:GGG:G	donor_gain	0.8700
20:23493075:G:GC	donor_loss	0.8700
20:23491203:GGGA:G	donor_gain	0.8600
20:23491870:TGGTC:T	donor_gain	0.8600

AlphaMissense

933 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:23495879:T:C	F132L	0.978
20:23495881:C:A	F132L	0.978
20:23495881:C:G	F132L	0.978
20:23491863:T:C	F66L	0.977
20:23491865:C:A	F66L	0.977
20:23491865:C:G	F66L	0.977
20:23491811:T:G	C48W	0.975
20:23491818:T:C	F51L	0.974
20:23491820:T:A	F51L	0.974
20:23491820:T:G	F51L	0.974
20:23495869:G:C	W128C	0.972
20:23495869:G:T	W128C	0.972
20:23491822:C:A	A52D	0.968
20:23495847:T:G	F121C	0.963
20:23493003:A:C	S93R	0.961
20:23493005:C:A	S93R	0.961
20:23493005:C:G	S93R	0.961
20:23495846:T:C	F121L	0.960
20:23495847:T:C	F121S	0.960
20:23495848:T:A	F121L	0.960
20:23495848:T:G	F121L	0.960
20:23492977:A:C	Y84S	0.955
20:23491809:T:C	C48R	0.951
20:23495840:T:A	C119S	0.951
20:23495841:G:C	C119S	0.951
20:23492976:T:G	Y84D	0.947
20:23492997:G:C	A91P	0.947
20:23495867:T:A	W128R	0.947
20:23495867:T:C	W128R	0.947
20:23492976:T:C	Y84H	0.943

dbSNP variants (sampled 300 via entrez): RS1000021993 (20:23500007 A>G,T), RS1000143913 (20:23498122 T>G), RS1000196691 (20:23498446 C>T), RS1000276092 (20:23505161 T>G), RS1000904377 (20:23494971 C>A,T), RS1001012619 (20:23489531 A>G), RS1001090710 (20:23501887 C>A,T), RS1001438598 (20:23501736 T>C), RS1001794715 (20:23507096 C>A,T), RS1001988261 (20:23504003 A>G), RS1002018846 (20:23497497 CT>C), RS1002069780 (20:23497751 T>C), RS1002354260 (20:23490654 G>A), RS1002708337 (20:23506722 C>T), RS1002762122 (20:23489939 C>T)

Disease associations

OMIM: gene MIM:608683 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation	1
Fluorouracil	affects expression	1

Clinical trials (associated diseases)

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