CSTB

Summary

CSTB (cystatin B, HGNC:2482) is a protein-coding gene on chromosome 21q22.3, encoding Cystatin-B (P04080). This is an intracellular thiol proteinase 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 kininogens. This gene encodes a stefin that functions as an intracellular thiol protease inhibitor. The protein is able to form a dimer stabilized by noncovalent forces, inhibiting papain and cathepsins l, h and b. The protein is thought to play a role in protecting against the proteases leaking from lysosomes. Evidence indicates that mutations in this gene are responsible for the primary defects in patients with progressive myoclonic epilepsy (EPM1). One type of mutation responsible for EPM1 is the expansion in the promoter region of this gene of a CCCCGCCCCGCG repeat from 2-3 copies to 30-78 copies.

Source: NCBI Gene 1476 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Unverricht-Lundborg syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 182 total — 11 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000100

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2482
Approved symbol	CSTB
Name	cystatin B
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	CST6, PME
Ensembl gene	ENSG00000160213
Ensembl biotype	protein_coding
OMIM	601145
Entrez	1476

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000291568, ENST00000639959, ENST00000640406, ENST00000675996, ENST00000896953, ENST00000937601

RefSeq mRNA: 1 — MANE Select: NM_000100 NM_000100

CCDS: CCDS13701

Canonical transcript exons

ENST00000291568 — 3 exons

Exon	Start	End
ENSE00000000331	43773950	43774330
ENSE00001050609	43774658	43774759
ENSE00001137740	43776204	43776308

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 100.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 712.9757 / max 15313.9391, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190719	704.8367	1828
190720	6.1114	1517
190721	2.0276	959

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	100.00	gold quality
tongue squamous epithelium	UBERON:0006919	99.98	gold quality
pharyngeal mucosa	UBERON:0000355	99.97	gold quality
oral cavity	UBERON:0000167	99.96	gold quality
esophagus mucosa	UBERON:0002469	99.96	gold quality
esophagus squamous epithelium	UBERON:0006920	99.96	gold quality
gingiva	UBERON:0001828	99.95	gold quality
body of tongue	UBERON:0011876	99.95	gold quality
gingival epithelium	UBERON:0001949	99.94	gold quality
squamous epithelium	UBERON:0006914	99.93	gold quality
epithelium of esophagus	UBERON:0001976	99.90	gold quality
amniotic fluid	UBERON:0000173	99.84	gold quality
tongue	UBERON:0001723	99.84	gold quality
cervix epithelium	UBERON:0004801	99.84	gold quality
cervix squamous epithelium	UBERON:0006922	99.80	gold quality
buccal mucosa cell	CL:0002336	99.79	gold quality
mammalian vulva	UBERON:0000997	99.77	gold quality
superior surface of tongue	UBERON:0007371	99.68	gold quality
bronchial epithelial cell	CL:0002328	99.65	gold quality
penis	UBERON:0000989	99.60	gold quality
epithelium of bronchus	UBERON:0002031	99.59	gold quality
epithelium of nasopharynx	UBERON:0001951	99.57	gold quality
bronchus	UBERON:0002185	99.56	gold quality
vagina	UBERON:0000996	99.52	gold quality
mouth mucosa	UBERON:0003729	99.52	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.51	gold quality
palpebral conjunctiva	UBERON:0001812	99.49	gold quality
eye	UBERON:0000970	99.47	gold quality
minor salivary gland	UBERON:0001830	99.45	gold quality
upper leg skin	UBERON:0004262	99.43	gold quality

Single-cell (SCXA)

Detected in 29 experiment(s), a significant marker in 25.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	68394.66
E-MTAB-10596	yes	12201.88
E-MTAB-6653	yes	8000.59
E-MTAB-10042	yes	6732.87
E-MTAB-8322	yes	5127.39
E-HCAD-15	yes	4565.00
E-HCAD-29	yes	4444.02
E-MTAB-6701	yes	3907.07
E-HCAD-13	yes	3632.71
E-CURD-122	yes	3416.46
E-MTAB-8207	yes	3390.68
E-CURD-126	yes	3011.20
E-MTAB-9435	yes	2477.24
E-CURD-79	yes	2116.70
E-CURD-112	yes	1507.32

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AIRE, MYC, SIM2

miRNA regulators (miRDB)

36 targeting CSTB, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-6871-5P	98.90	66.67	671
HSA-MIR-876-3P	98.76	68.23	945
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-518C-5P	98.53	69.20	1640
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-541-5P	98.24	67.77	1181
HSA-MIR-30C-1-3P	97.80	66.36	1499

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Oligonucleotides containing EPM1 repeat adopt secondary structures that may facilitate strand slippage thereby causing the expansion. (PMID:11697734)
• Intramolecular i-motif structure at acidic pH for progressive myoclonus epilepsy (EPM1) repeat d(CCCCGCCCCGCG)n. (PMID:11697735)
• analysed eight markers flanking CSTB(GT10-D21S1890-D21S1885-D21S2040-D21S1259- CSTB-D21S1912-PFKL-D21S171) and one intragenic variant in the CSTB 3’ UTR (A2575G) (PMID:12215838)
• first demonstration of cysteine protease activity being regulated by CSTB activity in a biological context; effects of decreased CSTB activity in EPM1 pathogenesis may be mediated by cathepsins through increased activity of cathepsins S and L (PMID:12452481)
• By using ThT fluorescence, X-ray diffraction, and atomic force microscopy (AFM), it has been shown that human stefins A and B (subfamily A of cystatins) form amyloid fibrils (PMID:15048832)
• Protein and mRNA levels of stefin B (p= 0.007), but not cystatin C, were significantly lower in atypical compared with benign meningiomas (PMID:15832773)
• Prefibrillar oligomers/aggregates of stefin B also increase the surface pressure at an air-water interface, i.e. they have amphipathic character and are surface seeking. (PMID:15955063)
• These data show that cystatin B inhibits bone resorption by down-regulating intracellular cathepsin K activity despite increased osteoclast survival. (PMID:16321512)
• Chimeras of stefinA and B have been prepared and guanidine denaturation curves and folding rates have been examined. (PMID:16342276)
• Study shows that copper binding by stefin B inhibits the amyloid fibril formation and, to a lesser degree, the initial aggregation. (PMID:16939620)
• only stefins A and B, i.e. type I cystatins, are up-regulated in lung tumours and thus able to counteract harmful tumour-associated proteolytic activity (PMID:16969475)
• Several alternatively spliced CSTB isoforms were identified in patients with progressive myoclonus epilepsy of Unverricht-Lundborg type . (PMID:17003839)
• Results describe the influence of pH and trifluoroethanol on amyloid fibril growth and morphology from human stefin B. (PMID:17701471)
• cystatin B in vivo has a polymeric structure sensitive to the redox environment and that overexpression of the protein generates aggregates. (PMID:17920138)
• CSTB is specifically overexpressed in most HCCs and is also elevated in the serum of a large proportion of HCC patients (PMID:18281540)
• Data show that wild-type stefin B and its Y31 isoform are able to form pores in planar lipid bilayers, whereas the G4R isoform destroys the bilayer by a non pore-forming process. (PMID:18397316)
• The mechanism of amyloid-fibril formation by stefin B: temperature and protein concentration dependence of the rates;the observed kinetics follow the nucleation and growth behavior observed for many other amyloidogenic proteins. (PMID:18636508)
• potential role for CSTB in HIV replication in placental macrophages (PMID:18951626)
• cystatin B interacts with STAT-1 and the levels of STAT-1 tyrosine phosphorylation (but not serine phosphorylation) between uninfected and HIV-infected PM and MDM are differentially regulated. (PMID:19342095)
• oligomers of stefin B and amyloid-beta interact in vitro and in cells (PMID:19955183)
• Stefin B interacts with histones and cathepsin L in the nucleus (PMID:20075068)
• Intracellular stefin b aggregation shows a negative correlation with cell survival (PMID:20078424)
• patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations seem to have a severer form of Unverricht-Lundborg disease (EPM1) than patients homozygous for the expansion mutation (PMID:21757863)
• At pH 7.0 the mutant H75W folded in three kinetic phases to a native-like intermediate, analogous to folding of stefin B at pH 4.8. (PMID:22033403)
• S-glutathionylation and S-cysteinylation were described as extensive PTM of a salivary protein and the first time that these PTMs were detected in naturally occurring cystatin B. (PMID:22057043)
• Elevated StefA mRNA level is associated with invasive glioblastoma. (PMID:22287159)
• Skull thickening and an increased prevalence of abnormal findings in skeletal radiographs of patients with EPM1 suggest that this condition is connected to defective cystatin B function. (PMID:23010349)
• This study suggested that CSTB mutations other than the common dodecamer expansion predict particular phenotypes, including marked seizure severity and polymorphous seizure types. (PMID:23205931)
• The co-localization of stefin B wild type and EPM1 mutants with cathepsins showed that cathepsins accumulate around the aggregates formed by the EPM1 mutants. (PMID:23362198)
• High levels of bioactive recombinant stefins A and B can be produced by fermentation in P. pastoris. (PMID:23656633)
• detected a homozygous expansion of dodecamer repeats in the CSTB gene in four patients with clinical diagnosis of ULD. (PMID:23883076)
• A reciprocal influence of CSTB and SOD1 at the gene expression level and for a direct interaction of the two proteins, is reported. (PMID:24234043)
• The increased CSTB expression in ovarian tissue represents tumor progression and is dysregulated by the TGF-beta signaling pathway. (PMID:24452274)
• The present study was performed on two more missense mutants of human stefin B, G50E and Q71P, and they similarly showed numerous aggregates upon overexpression. (PMID:24909779)
• The study shows detection of stefin B dimers in HEK293 cells and the importance of their residual activity. (PMID:25047918)
• glutamate dehydrogenase is a euchromatin-associated enzyme, and its H3 clipping activity is regulated by chromatin structure, histone modifications and an in vivo inhibitor. (PMID:25263734)
• Data shows that CYTB and ANXA4 overexpression may be involved in carcinogenesis and histopathological differentiation of ovarian clear cell carcinoma and suggest they may serve as a potential diagnostic biomarkers. (PMID:25633807)
• A role for disease-causing mutations in cystatin B gene in patients with juvenile myoclonic epilepsy was not supported. (PMID:25752200)
• Even though the majority of EPM1 patients have a uniform genetic mutation, the actual size of the longer CSTB expansion mutation allele is likely to have a modulating effect on the age at disease onset, myoclonus severity, and cortical neurophysiology. (PMID:25770194)
• High expression of stefin B may be an important factor contributing to the development and metastasis of Hepatocellular Carcinoma. (PMID:26753874)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cst14a.1	ENSDARG00000028164
danio_rerio	cst14a.2	ENSDARG00000045352
mus_musculus	Cstb	ENSMUSG00000005054
rattus_norvegicus	Cstb	ENSRNOG00000001201

Paralogs (1): CSTA (ENSG00000121552)

Protein

Protein identifiers

Cystatin-B — P04080 (reviewed: P04080)

Alternative names: CPI-B, Liver thiol proteinase inhibitor, Stefin-B

All UniProt accessions (4): P04080, A0A1W2PQG6, A0A1W2PS52, Q76LA1

UniProt curated annotations — full annotation on UniProt →

Function. This is an intracellular thiol proteinase inhibitor. Tightly binding reversible inhibitor of cathepsins L, H and B.

Subunit / interactions. Able to form dimers stabilized by noncovalent forces.

Subcellular location. Cytoplasm. Nucleus.

Disease relevance. Epilepsy, progressive myoclonic 1 (EPM1) [MIM:254800] A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM1 is an autosomal recessive form characterized by severe, stimulus-sensitive myoclonus and tonic-clonic seizures. The onset, occurring between 6 and 13 years of age, is characterized by convulsions. Myoclonus begins 1 to 5 years later. The twitchings occur predominantly in the proximal muscles of the extremities and are bilaterally symmetrical, although asynchronous. At first small, they become late in the clinical course so violent that the victim is thrown to the floor. Mental deterioration and eventually dementia develop. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the cystatin family.

RefSeq proteins (1): NP_000091* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000010	Cystatin_dom	Domain
IPR001713	Prot_inh_stefin	Family
IPR018073	Prot_inh_cystat_CS	Conserved_site
IPR046350	Cystatin_sf	Homologous_superfamily

Pfam: PF00031

UniProt features (11 total): strand 4, chain 1, short sequence motif 1, site 1, modified residue 1, sequence variant 1, sequence conflict 1, helix 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2OCT	X-RAY DIFFRACTION	1.4
4N6V	X-RAY DIFFRACTION	1.8
1STF	X-RAY DIFFRACTION	2.37

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04080-F1	95.81	0.96

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): 4 (reactive site)

Post-translational modifications (1): 1

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 408 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_BEHAVIOR, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_ADULT_BEHAVIOR, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_G_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, HSIAO_HOUSEKEEPING_GENES, GOBP_ADULT_LOCOMOTORY_BEHAVIOR, chr11q13

GO Biological Process (3): adult locomotory behavior (GO:0008344), negative regulation of proteolysis (GO:0045861), amyloid fibril formation (GO:1990000)

GO Molecular Function (5): protease binding (GO:0002020), RNA binding (GO:0003723), endopeptidase inhibitor activity (GO:0004866), cysteine-type endopeptidase inhibitor activity (GO:0004869), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (11): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular matrix (GO:0031012), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular organelle lumen	2
locomotory behavior	1
adult behavior	1
proteolysis	1
regulation of proteolysis	1
negative regulation of protein metabolic process	1
protein metabolic process	1
supramolecular fiber organization	1
enzyme binding	1
nucleic acid binding	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
external encapsulating structure	1
secretory granule	1
cytoplasmic vesicle lumen	1
extracellular vesicle	1
tertiary granule	1
ficolin-1-rich granule	1

Protein interactions and networks

STRING

1804 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSTB	CTSS	P25774	895
CSTB	CTSL	P07711	886
CSTB	RRP1B	Q14684	875
CSTB	CTSB	P07858	845
CSTB	NHLRC1	Q6VVB1	822
CSTB	PRICKLE1	Q96MT3	808
CSTB	RRP1	P56182	802
CSTB	CST3	P01034	796
CSTB	TRAPPC10	P48553	792
CSTB	APOD	P05090	781
CSTB	C1QB	P02746	766
CSTB	MT2A	P02795	737
CSTB	CST4	P01036	712
CSTB	CST2	P09228	683
CSTB	KCNQ3	O43525	675

IntAct

58 interactions, top by confidence:

A	B	Type	Score
CFTR	XPO1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
LGMN	CSTB	psi-mi:“MI:0570”(protein cleavage)	0.440
	CSTB	psi-mi:“MI:0407”(direct interaction)	0.440
PTPN11	CSTB	psi-mi:“MI:0915”(physical association)	0.400
SPRY2	CSTB	psi-mi:“MI:0915”(physical association)	0.370
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
LIN54	HDAC3	psi-mi:“MI:0914”(association)	0.350
DND1	RPSA2	psi-mi:“MI:0914”(association)	0.350
DCUN1D1	RGSL1	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
ARHGAP35	CSTB	psi-mi:“MI:0914”(association)	0.350
ARHGAP31	TIMM23	psi-mi:“MI:0914”(association)	0.350
TRIM24	DDTL	psi-mi:“MI:0914”(association)	0.350
PDIK1L	CSTB	psi-mi:“MI:0914”(association)	0.350
IRAK4	PRMT5	psi-mi:“MI:0914”(association)	0.350
AURKC	CSTB	psi-mi:“MI:0914”(association)	0.350
MAP1LC3A		psi-mi:“MI:0914”(association)	0.350
GABARAPL1		psi-mi:“MI:0914”(association)	0.350
GABARAP		psi-mi:“MI:0914”(association)	0.350
AKT1	CSTB	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (125): CSTB (Affinity Capture-MS), CSTB (Co-fractionation), GSTT1 (Co-fractionation), PDCD6 (Co-fractionation), CSTB (Affinity Capture-MS), CSTB (Affinity Capture-MS), CSTB (Affinity Capture-MS), CSTB (Affinity Capture-MS), HIST1H3A (Affinity Capture-Western), CSTB (Affinity Capture-MS), CSTB (Affinity Capture-MS), CSTB (Affinity Capture-MS), CSTB (Affinity Capture-MS), CSTB (Affinity Capture-MS), CSTB (Affinity Capture-MS)

ESM2 similar proteins: A0A224AHH8, A0A6B9KZ52, A0A6I8TMQ9, B1P1J3, B2Z449, B2Z450, B7PKZ2, J7FQE8, P01039, P01040, P01041, P04080, P0DXA0, P25417, P30086, P31044, P35173, P35174, P35175, P35478, P35479, P35481, P48737, P56567, P60575, P60576, P70296, P80416, Q06445, Q10994, Q28986, Q28987, Q28988, Q29290, Q3YIX4, Q5R1U3, Q5R4R0, Q62426, Q65YR7, Q65YR8

Diamond homologs: B2Z449, J7FQE8, P01040, P01041, P04080, P25417, P35173, P35174, P35175, P35478, P35479, P56567, P60575, P60576, P80416, Q10994, Q28986, Q28987, Q28988, Q29290, Q5R1U3, Q62426, Q65YR7, Q76LA0, Q862Z5, Q8I030, Q8WNR9, P01039, P80736, Q65YR8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	8
Uncertain significance	73
Likely benign	59
Benign	7

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1074795	NC_000021.8:g.(?45194083)(45196150_?)del	Pathogenic
1455136	NM_000100.4(CSTB):c.121del (p.Val41fs)	Pathogenic
1807163	NM_000100.4(CSTB):c.145del (p.Ala49fs)	Pathogenic
4725737	NM_000100.4(CSTB):c.67-1G>A	Pathogenic
55956	NG_011545.1(CSTB):g.4900_4935CCCCGCCCCGCG[30_125]	Pathogenic
659184	NM_000100.4(CSTB):c.200_203dup (p.Val69fs)	Pathogenic
8395	NM_000100.4(CSTB):c.67-1G>C	Pathogenic
8396	NM_000100.4(CSTB):c.202C>T (p.Arg68Ter)	Pathogenic
8397	NM_000100.4(CSTB):c.10G>C (p.Gly4Arg)	Pathogenic
8398	NM_000100.3(CSTB):c.-210CCCCGCCCCGCG[2_3]	Pathogenic
8400	NM_000100.4(CSTB):c.212A>C (p.Gln71Pro)	Pathogenic
1791620	NM_000100.4(CSTB):c.246_247del (p.Leu82fs)	Likely pathogenic
3376548	NM_000100.4(CSTB):c.76C>T (p.Gln26Ter)	Likely pathogenic
431700	NM_000100.4(CSTB):c.10G>T (p.Gly4Trp)	Likely pathogenic
55957	NM_000100.4(CSTB):c.125C>A (p.Ser42Ter)	Likely pathogenic
55958	NM_000100.4(CSTB):c.168G>A (p.Lys56=)	Likely pathogenic
55959	NM_000100.4(CSTB):c.169-2A>G	Likely pathogenic
55961	NM_000100.4(CSTB):c.66G>A (p.Gln22=)	Likely pathogenic
809294	NM_000100.4(CSTB):c.43G>T (p.Glu15Ter)	Likely pathogenic

SpliceAI

328 predictions. Top by Δscore:

Variant	Effect	Δscore
21:43774654:CTAC:C	donor_loss	1.0000
21:43774655:TACCT:T	donor_loss	1.0000
21:43774656:ACCTT:A	donor_loss	1.0000
21:43774657:C:A	donor_loss	1.0000
21:43774755:CTCAC:C	acceptor_gain	1.0000
21:43774756:TCAC:T	acceptor_gain	1.0000
21:43774757:CAC:C	acceptor_gain	1.0000
21:43774757:CACC:C	acceptor_gain	1.0000
21:43774758:ACCTA:A	acceptor_loss	1.0000
21:43774759:CCTAG:C	acceptor_loss	1.0000
21:43774760:CTA:C	acceptor_loss	1.0000
21:43776201:CAC:C	donor_loss	1.0000
21:43776203:CCT:C	donor_loss	1.0000
21:43774329:ACC:A	acceptor_loss	0.9900
21:43774330:CCTG:C	acceptor_loss	0.9900
21:43774332:T:A	acceptor_loss	0.9900
21:43774758:AC:A	acceptor_gain	0.9900
21:43774759:CC:C	acceptor_gain	0.9900
21:43774760:C:CC	acceptor_gain	0.9900
21:43774765:C:CT	acceptor_gain	0.9900
21:43774766:A:T	acceptor_gain	0.9900
21:43776200:CCACC:C	donor_gain	0.9800
21:43774328:CAC:C	acceptor_gain	0.9700
21:43774331:C:CC	acceptor_gain	0.9700
21:43774684:C:CT	donor_gain	0.9700
21:43774685:C:CT	donor_gain	0.9700
21:43774756:TCACC:T	acceptor_gain	0.9700
21:43774683:A:AC	donor_gain	0.9600
21:43774758:ACCT:A	acceptor_gain	0.9600
21:43774655:TA:T	donor_gain	0.9500

AlphaMissense

649 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:43774205:G:C	F98L	0.959
21:43774205:G:T	F98L	0.959
21:43774207:A:G	F98L	0.959
21:43774299:A:G	L67P	0.954
21:43774677:C:T	G50E	0.944
21:43774678:C:A	G50W	0.939
21:43774293:A:T	V69E	0.935
21:43774289:G:C	F70L	0.934
21:43774289:G:T	F70L	0.934
21:43774291:A:G	F70L	0.934
21:43774662:A:T	I55N	0.930
21:43774677:C:A	G50V	0.929
21:43774296:C:G	R68P	0.925
21:43774681:C:G	A49P	0.921
21:43774697:G:C	F43L	0.914
21:43774697:G:T	F43L	0.914
21:43774699:A:G	F43L	0.914
21:43774664:G:C	F54L	0.899
21:43774664:G:T	F54L	0.899
21:43774666:A:G	F54L	0.899
21:43774688:C:A	Q46H	0.898
21:43774688:C:G	Q46H	0.898
21:43776259:C:T	G4E	0.896
21:43774329:A:T	V57E	0.894
21:43774683:A:T	V48D	0.894
21:43776260:C:A	G4W	0.894
21:43774678:C:G	G50R	0.891
21:43774678:C:T	G50R	0.891
21:43774658:C:A	K56N	0.888
21:43774658:C:G	K56N	0.888

dbSNP variants (sampled 300 via entrez): RS1001673886 (21:43774499 A>T), RS1001978235 (21:43773580 C>A,T), RS1001985965 (21:43776959 C>A), RS1003876641 (21:43773609 C>T), RS1004066944 (21:43776102 G>A), RS1004069458 (21:43773805 G>A), RS1006228849 (21:43774835 G>A), RS1006364391 (21:43775084 G>A,T), RS1006564419 (21:43775778 A>G), RS1007806609 (21:43776451 CG>C), RS1007979492 (21:43776647 G>A,C), RS1008479131 (21:43774412 A>G), RS1008560434 (21:43777723 T>A), RS1009313714 (21:43776716 G>A), RS1009937868 (21:43773488 TAGA>T)

Disease associations

OMIM: gene MIM:601145 | disease phenotypes: MIM:254800, MIM:117100

GenCC curated gene-disease

Disease	Classification	Inheritance
Unverricht-Lundborg syndrome	Definitive	Autosomal recessive
autosomal recessive hypohidrotic ectodermal dysplasia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Unverricht-Lundborg syndrome	Definitive	AR
genetic developmental and epileptic encephalopathy	Moderate	AR

Mondo (7): progressive myoclonus epilepsy (MONDO:0020074), Unverricht-Lundborg syndrome (MONDO:0009698), microcephaly (MONDO:0001149), choreatic disease (MONDO:0001595), dystonic disorder (MONDO:0003441), self-limited epilepsy with centrotemporal spikes (MONDO:0007295), autosomal recessive hypohidrotic ectodermal dysplasia (MONDO:0016619)

Orphanet (4): Progressive myoclonic epilepsy type 1 (Orphanet:308), Progressive myoclonic epilepsy (Orphanet:98261), Benign hereditary chorea (Orphanet:1429), Self-limited epilepsy with centrotemporal spikes (Orphanet:1945)

HPO phenotypes

28 total (30 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000685	Hypoplasia of teeth
HP:0000726	Dementia
HP:0000958	Dry skin
HP:0000966	Hypohidrosis
HP:0000992	Cutaneous photosensitivity
HP:0001231	Abnormal fingernail morphology
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001336	Myoclonus
HP:0001595	Abnormal hair morphology
HP:0001596	Alopecia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002070	Limb ataxia
HP:0002080	Intention tremor
HP:0002121	Generalized non-motor (absence) seizure
HP:0002213	Fine hair
HP:0002392	EEG with polyspike wave complexes
HP:0003621	Juvenile onset
HP:0006323	Premature loss of primary teeth
HP:0006482	Abnormal dental morphology
HP:0007000	Morning myoclonic jerks
HP:0008388	Abnormal toenail morphology
HP:0010850	EEG with spike-wave complexes
HP:0011182	Interictal epileptiform activity
HP:0000252	Microcephaly
HP:0002072	Chorea

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009731_66	Blood protein levels in cardiovascular risk	8.000000e-57

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004617	cystatin C measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D002819	Chorea	C10.228.662.262.249; C10.597.350.250; C23.888.592.350.250
D020821	Dystonic Disorders	C10.228.662.300
D053360	Ectodermal Dysplasia, Hypohidrotic, Autosomal Recessive	C16.131.077.350.348; C16.131.831.350.348; C16.320.850.250.348; C17.800.804.350.348; C17.800.827.250.348
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D020191	Myoclonic Epilepsies, Progressive	C10.228.140.490.375.130.650; C10.228.140.490.493.063.650
D020194	Unverricht-Lundborg Syndrome	C10.228.140.490.375.130.650.900; C10.228.140.490.493.063.650.900; C10.574.500.875; C16.320.400.940

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066979 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.16	Kd	6955	nM	CHEMBL3752910
5.16	ED50	6955	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148166: Binding affinity to human CSTB incubated for 45 mins by Kinobead based pull down assay	kd	6.9549	uM

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression	2
Arsenic Trioxide	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	increases expression, increases methylation	2
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
trichostatin A	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
tetrahydropalmatine	increases expression	1
3,4-dichloroaniline	increases expression	1
sodium arsenite	increases expression	1
tetrathiomolybdate	decreases expression	1
ochratoxin A	increases expression	1
cupric chloride	affects binding	1
perfluorodecanoic acid	decreases expression	1
ciglitazone	increases expression, affects binding	1
diallyl trisulfide	decreases expression	1
chloropicrin	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
K 7174	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol S	increases expression	1
jinfukang	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
perfluoroundecanoic acid	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Arsenates	affects cotreatment, increases expression	1
Atrazine	affects cotreatment, increases expression	1
Vehicle Emissions	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651208	Binding	Binding affinity to human CSTB incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

4 cell lines: 3 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A7KZ	UNIMGi003-A	Induced pluripotent stem cell	Male
CVCL_A7LA	UNIMGi004-A	Induced pluripotent stem cell	Female
CVCL_B2VB	Abcam HEK293T CSTB KO	Transformed cell line	Female
CVCL_D0N4	UEFi004-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00142259	PHASE4	UNKNOWN	Efficacy and Safety of DBS of the GPi in Patients With Primary Generalized and Segmental Dystonia
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02263417	PHASE4	COMPLETED	A Randomized Controlled Trail Comparing Subthalamic and Pallidal Deep Brain Stimulation for Dystonia
NCT03490487	PHASE4	UNKNOWN	Electroclinical Effect of Steroid in Patients With Benign Childhood Epilepsy With Centrotemporal Spikes
NCT04610879	PHASE4	TERMINATED	Changing Agendas on Sleep, Treatment and Learning in Epilepsy
NCT00357669	PHASE3	COMPLETED	Brivaracetam as add-on Treatment of Unverricht-Lundborg Disease in Adolescents and Adults
NCT00368251	PHASE3	COMPLETED	Brivaracetam as add-on Treatment of Unverricht-Lundborg Disease (ULD) in Adolescents and Adults
NCT03351569	PHASE3	UNKNOWN	Intravenous Immunoglobulin for Unverricht-Lundborg Disease.
NCT00169403	PHASE3	UNKNOWN	Pallidal Stimulation in Patients With Idiopathic Generalised Dystonia
NCT03232320	PHASE3	COMPLETED	Meditoxin® Treatment in Patients With Cervical Dystonia
NCT00639119	PHASE2	UNKNOWN	Effect of Ropinirole Hydrochloride in Progressive Myoclonic Epilepsy of Unverricht-Lundborg Type
NCT00001784	PHASE2	COMPLETED	Mexiletine for the Treatment of Focal Dystonia
NCT00105430	PHASE2	COMPLETED	Deep Brain Stimulation for Cervical Dystonia
NCT00106782	PHASE2	COMPLETED	Transcranial Electrical Polarization to Treat Focal Hand Dystonia
NCT00122044	PHASE2	COMPLETED	Childhood Hypertonia of Central Origin: A Trial of Anticholinergic Treatment Effects
NCT00169338	PHASE2	COMPLETED	Pallidal Stimulation in Patients With Post-anoxic and Idiopathic Dystonia
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT02107261	PHASE2	COMPLETED	Incobotulinum Toxin A (Xeomin®) As A Treatment For Focal Task-Specific Dystonia Of The Musician’s Hand
NCT02470325	PHASE2	UNKNOWN	The Effects of Cannabis on Dystonia and Spasticity on Pediatric Patients
NCT05027997	PHASE2	COMPLETED	Exploratory Study of Dipraglurant (ADX48621) for the Treatment of Patients With Blepharospasm
NCT06412653	PHASE2	COMPLETED	Prospective Pilot Trial to Address Feasibility and Safety of Oral Zinc in GNAO1 Associated Disorders
NCT07304089	PHASE2	RECRUITING	A Study to Evaluate the Efficacy, Safety, and Tolerability of VIM0423 in Individuals With Isolated Dystonia
NCT01433757	PHASE1	COMPLETED	Ampicillin for DYT-1 Dystonia Motor Symptoms
NCT01698450	PHASE1	COMPLETED	Magnetic Resonance (MR) Guided Functional Ultrasound-Neurosurgery for Movement Disorders
NCT02982304	PHASE1	UNKNOWN	Multi-Target Pallidal and Thalamic Deep Brain Stimulation for Hemi-Dystonia
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT06554288	PHASE1	RECRUITING	Pharmacogenomic Contributions to Trihexyphenidyl Biotransformation and Response in Children With Dystonic Cerebral Palsy
NCT06593951	Not specified	RECRUITING	Registry and Natural History Study for Progressive Myoclonus Epilepsy Type 1 (EPM1)
NCT06923241	Not specified	COMPLETED	Nutri-score Labelling in a UK Restaurant Setting: a Randomised Control Trial
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome