CST9L

Summary

CST9L (cystatin 9 like, HGNC:16233) is a protein-coding gene on chromosome 20p11.21, encoding Cystatin-9-like (Q9H4G1).

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 mouse cystatin 9. Based on its testis-specific expression, it is likely to have a role in tissue reorganization during early testis development.

Source: NCBI Gene 128821 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 23 total
• MANE Select transcript: NM_080610

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16233
Approved symbol	CST9L
Name	cystatin 9 like
Location	20p11.21
Locus type	gene with protein product
Status	Approved
Aliases	bA218C14.1, CTES7B
Ensembl gene	ENSG00000101435
Ensembl biotype	protein_coding
OMIM	616536
Entrez	128821

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000376979

RefSeq mRNA: 1 — MANE Select: NM_080610 NM_080610

CCDS: CCDS13157

Canonical transcript exons

ENST00000376979 — 3 exons

Exon	Start	End
ENSE00000660933	23565974	23566087
ENSE00001472323	23564732	23565037
ENSE00001472328	23568211	23568484

Expression profiles

Bgee: expression breadth broad, 44 present calls, max score 97.24.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0966 / max 99.6898, expressed in 5 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186706	0.0572	3
186705	0.0306	4
186707	0.0055	3
186708	0.0033	2

Top tissues by expression

217 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	97.24	gold quality
left testis	UBERON:0004533	96.98	gold quality
right testis	UBERON:0004534	96.96	gold quality
testis	UBERON:0000473	94.83	gold quality
adult organism	UBERON:0007023	87.78	gold quality
corpus epididymis	UBERON:0004359	75.73	gold quality
tibialis anterior	UBERON:0001385	56.25	silver quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
epithelial cell of pancreas	CL:0000083	53.36	gold quality
caput epididymis	UBERON:0004358	51.85	gold quality
deltoid	UBERON:0001476	51.51	gold quality
ileal mucosa	UBERON:0000331	50.96	silver quality
myocardium	UBERON:0002349	50.25	gold quality
pancreatic ductal cell	CL:0002079	49.34	silver quality
nasal cavity epithelium	UBERON:0005384	47.03	gold quality
quadriceps femoris	UBERON:0001377	46.77	gold quality
vastus lateralis	UBERON:0001379	45.40	gold quality
layer of synovial tissue	UBERON:0007616	43.55	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
skin of hip	UBERON:0001554	42.36	silver quality
muscle tissue	UBERON:0002385	41.51	gold quality
skeletal muscle tissue	UBERON:0001134	41.47	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
middle temporal gyrus	UBERON:0002771	41.20	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	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

miRNA regulators (miRDB)

21 targeting CST9L, 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-548AW	99.99	72.57	3559
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-6811-3P	98.62	66.54	944
HSA-MIR-4252	98.45	66.37	987
HSA-MIR-147A	98.33	66.40	795
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-219B-5P	97.91	65.80	531
HSA-MIR-3200-5P	97.34	65.97	826
HSA-MIR-8056	97.15	64.49	769
HSA-MIR-5192	96.89	63.35	879

Literature-anchored findings (GeneRIF, showing 2)

• Results describe the sequence, genomic structure, chromosomal location, and expression pattern of the human testatin gene. (PMID:11756564)
• 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

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:busm1-57f23.1	ENSDARG00000074425
mus_musculus	Cst9	ENSMUSG00000027445
mus_musculus	Cstdc2	ENSMUSG00000027446
rattus_norvegicus	Cst9l	ENSRNOG00000005162
rattus_norvegicus	Cstdc2	ENSRNOG00000005178
caenorhabditis_elegans		WBGENE00000534
caenorhabditis_elegans		WBGENE00000535
caenorhabditis_elegans		WBGENE00023486

Paralogs (11): CST7 (ENSG00000077984), CST3 (ENSG00000101439), CST4 (ENSG00000101441), CST8 (ENSG00000125815), CSTL1 (ENSG00000125823), CST11 (ENSG00000125831), CST5 (ENSG00000170367), CST2 (ENSG00000170369), CST1 (ENSG00000170373), CST9 (ENSG00000173335), CST6 (ENSG00000175315)

Protein

Protein identifiers

Cystatin-9-like — Q9H4G1 (reviewed: Q9H4G1)

Alternative names: Testatin

All UniProt accessions (2): Q9H4G1, A0A140VJH1

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted.

Tissue specificity. Specifically expressed in testis.

Miscellaneous. Lacks critical consensus sites important for cysteine protease inhibition.

Similarity. Belongs to the cystatin family.

RefSeq proteins (1): NP_542177* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000010	Cystatin_dom	Domain
IPR043250	CST9-like	Family
IPR046350	Cystatin_sf	Homologous_superfamily

Pfam: PF00031

UniProt features (7 total): glycosylation site 2, disulfide bond 2, signal peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H4G1-F1	86.54	0.55

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): 98–108, 122–142

Glycosylation sites (2): 117, 139

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 40 (showing top): GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, WEBER_METHYLATED_LCP_IN_FIBROBLAST_DN, GOBP_HUMORAL_IMMUNE_RESPONSE, WEBER_METHYLATED_LCP_IN_SPERM_UP, GOMF_PEPTIDASE_REGULATOR_ACTIVITY, chr20p11, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, GOMF_CYSTEINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_QTL_TRANS, GOMF_ENDOPEPTIDASE_REGULATOR_ACTIVITY, MIR371A_5P, MIR3911, MIR8075

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

GO Molecular Function (3): cysteine-type endopeptidase inhibitor activity (GO:0004869), protein binding (GO:0005515), 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
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

475 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CST9L	GZF1	Q9H116	531
CST9L	VSIG1	Q86XK7	488
CST9L	FAM163A	Q96GL9	474
CST9L	NXT1	Q9UKK6	461
CST9L	SPSB2	Q99619	453
CST9L	CST11	Q9H112	437
CST9L	NT5DC2	Q9H857	423
CST9L	KIAA1210	Q9ULL0	417
CST9L	ACSS1	Q9NUB1	410
CST9L	DYNC2I1	Q8WVS4	410
CST9L	MAGEB18	Q96M61	405
CST9L	AFG2B	Q9BVQ7	392
CST9L	FATE1	Q969F0	389
CST9L	CST8	O60676	371
CST9L	CST6	Q15828	370

IntAct

28 interactions, top by confidence:

A	B	Type	Score
	CST9L	psi-mi:“MI:0915”(physical association)	0.560
CST9L	KRTAP10-9	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	CST9L	psi-mi:“MI:0915”(physical association)	0.560
CST9L	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
CST9L		psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLC	CST9L	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-1	CST9L	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	CST9L	psi-mi:“MI:0915”(physical association)	0.560
MEI4	CST9L	psi-mi:“MI:0915”(physical association)	0.560
CST9L	CCR5	psi-mi:“MI:0915”(physical association)	0.370
SLC22A2	CST9L	psi-mi:“MI:0915”(physical association)	0.370
CST9L	TAB2	psi-mi:“MI:0915”(physical association)	0.370
CST9L	QSOX1	psi-mi:“MI:0914”(association)	0.350
NDP	MYCBP2	psi-mi:“MI:0914”(association)	0.350
CST9L	NOTCH2NLC	psi-mi:“MI:0915”(physical association)	0.000
CST9L	KRTAP5-1	psi-mi:“MI:0915”(physical association)	0.000
CST9L	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000
CST9L	MEI4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (78): KRTAP10-9 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), CYSRT1 (Two-hybrid), KRTAP5-1 (Two-hybrid), NOTCH2NL (Two-hybrid), MEI4 (Two-hybrid), NBPF19 (Two-hybrid), CST9L (Affinity Capture-MS), PCSK5 (Affinity Capture-MS), CNTNAP3B (Affinity Capture-MS), TPPP2 (Affinity Capture-MS), ARSK (Affinity Capture-MS), MAN2A2 (Affinity Capture-MS), SEMA4D (Affinity Capture-MS)

ESM2 similar proteins: E3P6N3, E3P6N4, E3P6N5, E3P6N6, E3P6N7, E3P6N8, E3P6N9, E3P6P0, E3P6P1, E3P6P2, E3P6P3, E3P6P4, J3RYX9, J3SE80, O19092, O19093, O75173, O77805, O77835, O97862, P01034, P01035, P01036, P01037, P01038, P01231, P04651, P09228, P14841, P17405, P21460, P81061, Q04519, Q0VD19, Q29RH0, Q2IAL6, Q2IAL7, Q2NKZ5, Q32KQ9, Q5RFQ8

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

327 predictions. Top by Δscore:

Variant	Effect	Δscore
20:23565038:C:CC	acceptor_gain	0.9900
20:23565972:A:AC	donor_gain	0.9900
20:23565973:C:CC	donor_gain	0.9900
20:23568206:CCAA:C	donor_loss	0.9900
20:23568208:AACC:A	donor_loss	0.9900
20:23568209:ACCTG:A	donor_loss	0.9900
20:23568210:CCT:C	donor_loss	0.9900
20:23565035:AGTCT:A	acceptor_loss	0.9800
20:23565037:TC:T	acceptor_loss	0.9800
20:23565038:CTGAG:C	acceptor_loss	0.9800
20:23565963:T:TA	donor_gain	0.9800
20:23568198:CGTGG:C	donor_gain	0.9800
20:23568219:T:TA	donor_gain	0.9800
20:23565034:AAGT:A	acceptor_gain	0.9700
20:23565036:GT:G	acceptor_gain	0.9700
20:23568200:TGGTC:T	donor_gain	0.9700
20:23568210:CCTG:C	donor_gain	0.9700
20:23568211:C:G	donor_loss	0.9700
20:23565033:AAAGT:A	acceptor_gain	0.9500
20:23565035:AGT:A	acceptor_gain	0.9500
20:23565973:CA:C	donor_gain	0.9400
20:23568207:CAACC:C	donor_gain	0.9200
20:23566085:CACCT:C	acceptor_loss	0.9100
20:23566086:AC:A	acceptor_loss	0.9100
20:23566087:CC:C	acceptor_loss	0.9100
20:23566088:CTATT:C	acceptor_loss	0.9100
20:23566089:T:C	acceptor_loss	0.9100
20:23567838:A:AC	donor_gain	0.9100
20:23565938:G:C	donor_gain	0.9000
20:23567875:T:C	donor_gain	0.9000

AlphaMissense

977 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:23564987:G:C	F135L	0.983
20:23564987:G:T	F135L	0.983
20:23564989:A:G	F135L	0.983
20:23568292:A:C	F53L	0.983
20:23568292:A:T	F53L	0.983
20:23568294:A:G	F53L	0.983
20:23568277:G:C	F58L	0.979
20:23568277:G:T	F58L	0.979
20:23568279:A:G	F58L	0.979
20:23565020:G:C	F124L	0.968
20:23565020:G:T	F124L	0.968
20:23565022:A:G	F124L	0.968
20:23564999:C:A	W131C	0.956
20:23564999:C:G	W131C	0.956
20:23568290:G:T	A54D	0.949
20:23566035:C:G	C98S	0.938
20:23566036:A:T	C98S	0.938
20:23565026:G:C	C122W	0.937
20:23566067:G:C	F87L	0.934
20:23566067:G:T	F87L	0.934
20:23566069:A:G	F87L	0.934
20:23565021:A:C	F124C	0.929
20:23568274:G:C	N59K	0.928
20:23568274:G:T	N59K	0.928
20:23564988:A:C	F135C	0.922
20:23566056:A:G	L91P	0.922
20:23565028:A:G	C122R	0.921
20:23566028:T:A	K100N	0.917
20:23566028:T:G	K100N	0.917
20:23568293:A:C	F53C	0.917

dbSNP variants (sampled 300 via entrez): RS1000511328 (20:23567319 C>T), RS1001276163 (20:23567827 A>G,T), RS1001516711 (20:23568524 C>A,G,T), RS1002403191 (20:23564763 A>G), RS1002529296 (20:23569826 G>A), RS1002779811 (20:23565029 G>A), RS1003227203 (20:23564290 G>A), RS1003377550 (20:23566202 C>T), RS1003667693 (20:23564502 C>A), RS1003718819 (20:23569539 G>A), RS1003795493 (20:23569735 G>C), RS1003816430 (20:23565854 G>A,T), RS1004157161 (20:23565731 G>A), RS1004406309 (20:23567098 C>T), RS1005691261 (20:23569756 G>A)

Disease associations

OMIM: gene MIM:616536 | 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
GCST000091_1	Cystatin C levels	9.000000e-09

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

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
testosterone enanthate	affects cotreatment, increases expression	1
cetrorelix	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	increases methylation	1
Methotrexate	increases expression	1
Desogestrel	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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