CTSS

protein-coding

cathepsin S, the group of Cathepsins

Gene summary

The preproprotein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that participates in the degradation of antigenic proteins to peptides for presentation on MHC class II molecules. The mature protein cleaves the invariant chain of MHC class II molecules in endolysosomal compartments and enables the formation of antigen-MHC class II complexes and the proper display of extracellular antigenic peptides by MHC-II. The mature protein also functions as an elastase over a broad pH range. When secreted from cells, this protein can remodel components of the extracellular matrix such as elastin, collagen, and fibronectin. This gene is implicated in the pathology of many inflammatory and autoimmune diseases and, given its elastase activity, plays a significant role in some pulmonary diseases. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2020]

MANE transcript

NM_004079.5

Inheritance

—

ClinVar variants

U:18B:3

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr1:150,730,079-150,765,957

External References & Databases

Ensembl (ENSG00000163131)

Transcript & Mutation Effects

hg38 • Region Span ~35.9 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 CTSS variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 19

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004079.5. 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			1 clinvar		1 clinvar	2
missense			17 clinvar	2 clinvar		19
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	18	2	1	21

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004079.5	RefSeq	NP_004070.3	7	MANE Select
ENST00000368985.8	Ensembl	ENSP00000357981.3	7	MANE Select
NM_001199739.2	RefSeq	NP_001186668.1	6	Standard
ENST00000448301.7	Ensembl	ENSP00000408414.2	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antigen processing and presentation - Homo sapiens (human)
Phagosome - Homo sapiens (human)
Lysosome - Homo sapiens (human)
Tuberculosis - Homo sapiens (human)
Apoptosis - Homo sapiens (human)

Biological Process

toll-like receptor signaling pathway
adaptive immune response
proteolysis
immune response
response to acidic pH

Molecular Function

fibronectin binding
cysteine-type endopeptidase activity
serine-type endopeptidase activity
collagen binding
laminin binding

Cellular Component

extracellular region
extracellular space
lysosome
endolysosome lumen
lysosomal lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368985
Coding exons: 7
Length: 35762
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125748
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.24	96	181	0.531	0.00000906	2174
Missense (PolyPhen)		30	81.025	0.37025		953
Synonymous	0.986	54	64.0	0.843	0.00000319	615
Loss of Function	2.98	4	17.4	0.229	8.32e-7	219

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Thiol protease. Key protease responsible for the removal of the invariant chain from MHC class II molecules. The bond- specificity of this proteinase is in part similar to the specificities of cathepsin L.;

Recessive Scores

pRec: 0.312

Intolerance Scores

LoFtool: 0.251
RVIS EVS: 0.22
RVIS percentile EVS: 67.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.688

Gene Damage Prediction

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