CSTB

Chr 21AR

cystatin B

Also known as: CPI-B, CST6, EPM1, EPM1A, PME, STFB, ULD

NCBI Gene: 1476 ENSG00000160213 UniProt: P04080 OMIM: 601145

CSTB encodes cystatin B, an intracellular thiol protease inhibitor that reversibly inhibits cathepsins L, H, and B, protecting cells against proteases that leak from lysosomes. Mutations cause Unverricht-Lundborg disease (progressive myoclonic epilepsy type 1A), a childhood-onset progressive myoclonic epilepsy inherited in an autosomal recessive pattern. The gene shows low constraint against loss-of-function variants (pLI 0.007, LOEUF 1.85), consistent with its recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Jul 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.851 OMIM phenotype

Clinical Summary— CSTB

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Gene-Disease Validity (ClinGen)

Unverricht-Lundborg syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

23 unique Pathogenic / Likely Pathogenic· 71 VUS of 184 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CSTB

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.85LOEUF

pLI 0.007

Z-score 0.01

OE 0.99 (0.43–1.85)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.02Z-score

OE missense 0.99 (0.79–1.25)

52 obs / 52.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.99 (0.43–1.85)

0≤0.351.4

Missense OE?0.99 (0.79–1.25)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 3 / 3.0Missense obs/exp: 52 / 52.3Syn Z: 0.58

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCSTB-related Unverricht-Lundborg diseaseLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7326th %ile

GOF

0.4480th %ile

LOF

0.2775th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

184 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic13

VUS71

Likely Benign65

Benign8

Conflicting11

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	1	3	0	10
Likely Pathogenic	9	2	0	2	13
VUS	1	53	16	1	71
Likely Benign	0	0	36	29	65
Benign	0	0	8	0	8
Conflicting	—				11
Total	16	56	63	32	178

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

89 pathogenic / likely-pathogenic (of 112) ClinVar copy-number / structural variants overlap CSTB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →