CST9

Summary

CST9 (cystatin 9, HGNC:13261) is a protein-coding gene on chromosome 20p11.21, encoding Cystatin-9 (Q5W186). May be involved in testis development.

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 protein that may play a role in hematopoietic differentiation or inflammation.

Source: NCBI Gene 128822 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 34 total
• MANE Select transcript: NM_001008693

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13261
Approved symbol	CST9
Name	cystatin 9
Location	20p11.21
Locus type	gene with protein product
Status	Approved
Aliases	CLM, CTES7A
Ensembl gene	ENSG00000173335
Ensembl biotype	protein_coding
OMIM	616543
Entrez	128822

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000376971

RefSeq mRNA: 1 — MANE Select: NM_001008693 NM_001008693

CCDS: CCDS33450

Canonical transcript exons

ENST00000376971 — 2 exons

Exon	Start	End
ENSE00001472299	23602410	23603734
ENSE00001472300	23605610	23605917

Expression profiles

Bgee: expression breadth broad, 21 present calls, max score 67.72.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	67.72	gold quality
tendon of biceps brachii	UBERON:0008188	65.00	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	58.52	gold quality
biceps brachii	UBERON:0001507	55.19	gold quality
endothelial cell	CL:0000115	54.24	gold quality
lateral globus pallidus	UBERON:0002476	53.44	gold quality
middle temporal gyrus	UBERON:0002771	48.59	gold quality
substantia nigra pars reticulata	UBERON:0001966	47.27	gold quality
caput epididymis	UBERON:0004358	46.75	silver quality
lateral nuclear group of thalamus	UBERON:0002736	46.04	gold quality
amniotic fluid	UBERON:0000173	45.75	gold quality
corpus epididymis	UBERON:0004359	44.87	gold quality
vastus lateralis	UBERON:0001379	44.26	gold quality
quadriceps femoris	UBERON:0001377	44.16	gold quality
globus pallidus	UBERON:0001875	43.95	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
nipple	UBERON:0002030	42.86	gold quality
medial globus pallidus	UBERON:0002477	42.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	42.64	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
lower esophagus	UBERON:0013473	42.57	gold quality
heart right ventricle	UBERON:0002080	42.31	gold quality
epithelium of nasopharynx	UBERON:0001951	42.28	gold quality
subthalamic nucleus	UBERON:0001906	42.20	gold quality
jejunum	UBERON:0002115	42.18	gold quality
Brodmann (1909) area 23	UBERON:0013554	41.94	gold quality
gingiva	UBERON:0001828	41.93	gold quality
dorsal plus ventral thalamus	UBERON:0001897	41.60	gold quality
skeletal muscle tissue	UBERON:0001134	41.55	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.82

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• Data report the cloning of a novel human cystatin-like molecule (CLM) from human bone marrow stromal cell (BMSC) cDNA library. (PMID:12535658)
• The current report is the first to show the immunomodulatory and antimicrobial functions of rCST9 against Francisella tularensis. (PMID:23922243)

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

Protein

Protein identifiers

Cystatin-9 — Q5W186 (reviewed: Q5W186)

Alternative names: Cystatin-like molecule

All UniProt accessions (1): Q5W186

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in testis development. May play a role in hematopoietic differentiation or inflammation. Has immunomodulatory and antimicrobial functions against Francisella tularensis, a Gram-negative bacteria.

Subcellular location. Secreted.

Tissue specificity. Expressed in heart, placenta, lung, liver, skeletal muscle and pancreas. Not expressed in brain. Expressed in epididymis, kidney, testis, spinal cord, and thymus with a strong expression in epididymis and kidney and a weak expression in the spinal cord and thymus.

Induction. Up-regulated by bacterial lipopolysaccharides (LPS), in some cancer cells such as promyelocytic leukemia cells (HL-60) or myelomonocytic leukemia cells (U-937).

Similarity. Belongs to the cystatin family.

RefSeq proteins (1): NP_001008693* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR043250	CST9-like	Family
IPR046350	Cystatin_sf	Homologous_superfamily

Pfam: PF00666

UniProt features (3 total): signal peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5W186-F1	68.21	0.10

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 35 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_HUMORAL_IMMUNE_RESPONSE, GOMF_PEPTIDASE_REGULATOR_ACTIVITY, chr20p11, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, GOMF_CYSTEINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY, MARTENS_TRETINOIN_RESPONSE_UP, GOMF_ENDOPEPTIDASE_REGULATOR_ACTIVITY, RB_DN.V1_DN, DYRK1A_TARGET_GENES, ZNF592_TARGET_GENES, MIR1468_3P

GO Biological Process (1): antimicrobial humoral response (GO:0019730)

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

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
humoral immune response	1
defense response to symbiont	1
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

601 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CST9	CST8	O60676	753
CST9	CSTL1	Q9H114	582
CST9	CST11	Q9H112	541
CST9	CST3	P01034	531
CST9	CST4	P01036	514
CST9	CST6	Q15828	502
CST9	CST5	P28325	498
CST9	BPIFA3	Q9BQP9	473
CST9	DEFB127	Q9H1M4	453
CST9	RNF212	Q495C1	452
CST9	REC8	O95072	449
CST9	CST2	P09228	448
CST9	AFG2B	Q9BVQ7	442
CST9	HFM1	A2PYH4	434
CST9	AARD	Q4LEZ3	431

IntAct

3 interactions, top by confidence:

A	B	Type	Score
CST9	ITGA4	psi-mi:“MI:0914”(association)	0.530

BioGRID (11): UBR4 (Affinity Capture-MS), ITGA4 (Affinity Capture-MS), KCMF1 (Affinity Capture-MS), ANKRD46 (Affinity Capture-MS), ITGA4 (Affinity Capture-MS), PCP2 (Affinity Capture-MS), KCMF1 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), KCMF1 (Affinity Capture-MS), PCP2 (Affinity Capture-MS), ITGA4 (Affinity Capture-MS)

ESM2 similar proteins: O19131, O70280, O95998, P19438, P29590, P49788, P50555, Q06VW1, Q0ZFW8, Q13477, Q27967, Q29108, Q29RH0, Q29RS5, Q2IAL6, Q2IAL7, Q2NKZ5, Q5DRQ8, Q5R551, Q5W186, Q62522, Q62740, Q68US5, Q6AZ51, Q6BAA4, Q6QLQ5, Q6UWN0, Q6WN34, Q6ZVW7, Q70TH4, Q711S8, Q76LW6, Q8BH06, Q8HDG8, Q8IZI9, Q8K1I3, Q8N1F8, Q8N907, Q8NAC3, Q8NFR9

Diamond homologs: Q29RH0, Q2NKZ5, Q32KQ9, Q5W186, Q5W188, Q80ZN5, Q8VIH8, Q8VII2, Q8VII3, Q9DAN8, Q9H4G1, Q9Z0H6, O19092, O19093, O97862, P01034, P01036, P01037, P09228, E3P6N7, P01035, P01038, P14841, P19313, P81061, J3SE80, O88969, P21460, P28325, P32766, Q9JM84

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

340 predictions. Top by Δscore:

Variant	Effect	Δscore
20:23603730:CGCCA:C	acceptor_gain	0.9900
20:23603735:C:CC	acceptor_gain	0.9900
20:23603732:CCA:C	acceptor_gain	0.9800
20:23603733:CA:C	acceptor_gain	0.9800
20:23603733:CAC:C	acceptor_gain	0.9800
20:23602717:G:T	acceptor_gain	0.9700
20:23605674:T:TA	donor_gain	0.9700
20:23602716:C:CT	acceptor_gain	0.9600
20:23605607:AACC:A	donor_loss	0.9600
20:23605608:ACC:A	donor_loss	0.9600
20:23605609:C:G	donor_loss	0.9600
20:23605788:G:C	donor_gain	0.9600
20:23603619:A:AC	donor_gain	0.9500
20:23603620:C:CC	donor_gain	0.9500
20:23605605:CCAA:C	donor_loss	0.9500
20:23605630:C:A	donor_gain	0.9500
20:23605755:C:CT	donor_gain	0.9500
20:23605610:C:G	donor_loss	0.9400
20:23602716:C:T	acceptor_gain	0.9200
20:23605609:CCTTT:C	donor_gain	0.9200
20:23605751:A:AC	donor_gain	0.9100
20:23603731:GCCAC:G	acceptor_loss	0.9000
20:23603733:CACTG:C	acceptor_loss	0.9000
20:23603734:ACT:A	acceptor_loss	0.9000
20:23603735:C:G	acceptor_loss	0.9000
20:23603736:T:C	acceptor_loss	0.9000
20:23603737:G:C	acceptor_loss	0.9000
20:23603731:GCCA:G	acceptor_gain	0.8900
20:23603732:CCAC:C	acceptor_gain	0.8900
20:23603744:A:T	acceptor_loss	0.8900

AlphaMissense

1069 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:23605691:G:C	F58L	0.985
20:23605691:G:T	F58L	0.985
20:23605693:A:G	F58L	0.985
20:23603714:G:C	F92L	0.981
20:23603714:G:T	F92L	0.981
20:23603716:A:G	F92L	0.981
20:23605706:A:C	F53L	0.981
20:23605706:A:T	F53L	0.981
20:23605708:A:G	F53L	0.981
20:23603703:A:G	L96P	0.975
20:23603682:C:G	C103S	0.968
20:23603683:A:T	C103S	0.968
20:23603652:C:G	C113S	0.962
20:23603653:A:T	C113S	0.962
20:23603683:A:G	C103R	0.961
20:23603653:A:G	C113R	0.957
20:23603697:A:G	L98P	0.954
20:23603688:G:A	T101I	0.953
20:23605688:G:C	N59K	0.953
20:23605688:G:T	N59K	0.953
20:23603682:C:T	C103Y	0.950
20:23605692:A:G	F58S	0.950
20:23603646:A:C	F115C	0.946
20:23603703:A:T	L96Q	0.943
20:23603715:A:G	F92S	0.943
20:23605704:G:T	A54D	0.943
20:23603651:G:C	C113W	0.942
20:23603681:A:C	C103W	0.938
20:23603645:A:C	F115L	0.934
20:23603645:A:T	F115L	0.934

dbSNP variants (sampled 300 via entrez): RS1000330923 (20:23602905 G>T), RS1000383209 (20:23602670 T>C), RS1001175202 (20:23606802 G>A), RS1001448287 (20:23602789 A>G,T), RS1002330767 (20:23605535 C>G), RS1002840571 (20:23605909 G>A,T), RS1002894531 (20:23606088 AG>A), RS1003177364 (20:23604638 C>G,T), RS1003230076 (20:23604897 A>T), RS1003338989 (20:23606528 A>G), RS1004236149 (20:23602314 G>C,T), RS1004381203 (20:23607859 T>C), RS1004589494 (20:23602592 C>A,T), RS1004898925 (20:23606366 AG>A), RS1005182297 (20:23603671 C>A,T)

Disease associations

OMIM: gene MIM:616543 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000091_1	Cystatin C levels	9.000000e-09
GCST000649_20	Chronic kidney disease	2.000000e-138
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

2 total (human), top 2 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1

Clinical trials (associated diseases)

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