CST4

protein-coding

cystatin S, the group of Cystatins, type 2

Gene summary

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 type 2 salivary cysteine peptidase inhibitor. The protein is an S-type cystatin, based on its high level of expression in saliva, tears and seminal plasma. The specific role in these fluids is unclear but antibacterial and antiviral activity is present, consistent with a protective function. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001899.3

Inheritance

—

ClinVar variants

U:27B:11

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 1.46

Max pathogenic AF

—

Genomic locus

chr20:23,685,640-23,689,038

External References & Databases

Ensembl (ENSG00000101441)

Transcript & Mutation Effects

hg38 • Region Span ~3.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CST4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 30

not providedTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001899.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				3 clinvar	2 clinvar	5
missense			27 clinvar	3 clinvar	3 clinvar	33
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	27	6	5	38

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001899.3	RefSeq	NP_001890.1	3	MANE Select
ENST00000217423.4	Ensembl	ENSP00000217423.3	3	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Salivary secretion - Homo sapiens (human)

Biological Process

detection of chemical stimulus involved in sensory perception of bitter taste
retina homeostasis
negative regulation of endopeptidase activity
negative regulation of proteolysis

Molecular Function

cysteine-type endopeptidase inhibitor activity

Cellular Component

extracellular space
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000217423
Coding exons: 3
Length: 3401
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125746
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-2.07	138	84.5	1.63	0.00000512	913
Missense (PolyPhen)		37	22.93	1.6136		261
Synonymous	-2.63	53	33.6	1.58	0.00000203	269
Loss of Function	-1.01	8	5.46	1.46	3.16e-7	55

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00076	0.00076	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.000033	0.000033	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This protein strongly inhibits papain and ficin, partially inhibits stem bromelain and bovine cathepsin C, but does not inhibit porcine cathepsin B or clostripain. Papain is inhibited non-competitively.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.858
RVIS EVS: 0.26
RVIS percentile EVS: 70.44

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.223

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium