Peeling skin syndrome 4

Summary

Peeling skin syndrome 4 (MONDO:0011937) is a disease caused by CSTA (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CSTA (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peeling skin syndrome 4
Mondo ID	MONDO:0011937
MeSH	C564309
OMIM	607936
DOID	DOID:0070523
UMLS	C4225407
MedGen	895692
GARD	0018426
Is cancer (heuristic)	no

Also known as: CSTA peeling skin syndrome · peeling skin syndrome 4 · peeling skin syndrome caused by mutation in CSTA · peeling skin syndrome type 4 · PSS4

Data availability: 5 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › epidermal disease › ichthyosis › inherited ichthyosis › autosomal recessive congenital ichthyosis › exfoliative ichthyosis › peeling skin syndrome 4

Related subtypes (2): superficial epidermolytic ichthyosis, peeling skin syndrome 5

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208472	NM_005213.4(CSTA):c.64A>T (p.Lys22Ter)	CSTA	Pathogenic	criteria provided, multiple submitters, no conflicts
29892	NM_005213.4(CSTA):c.67-2A>T	CSTA	Pathogenic	no assertion criteria provided
29893	NM_005213.4(CSTA):c.256C>T (p.Gln86Ter)	CSTA	Pathogenic	no assertion criteria provided
208473	NM_005213.4(CSTA):c.172C>T (p.Arg58Ter)	CSTA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3779552	NM_005213.4(CSTA):c.105C>A (p.Tyr35Ter)	CSTA	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CSTA	Strong	Autosomal recessive	peeling skin syndrome 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CSTA	Orphanet:263534	Acral peeling skin syndrome
CSTA	Orphanet:289586	Exfoliative ichthyosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CSTA	HGNC:2481	ENSG00000121552	P01040	Cystatin-A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CSTA	Cystatin-A	This is an intracellular thiol proteinase inhibitor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CSTA	Other/Unknown	no		Cystatin_dom, Prot_inh_stefin, Prot_inh_cystat_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	1
oral cavity	1
pharyngeal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CSTA	248	ubiquitous	marker	pharyngeal mucosa, oral cavity, gingiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CSTA	2,102

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CSTA	P01040	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the cornified envelope	1	87.8×	0.011	CSTA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peptide cross-linking	1	1404.3×	0.003	CSTA
negative regulation of proteolysis	1	674.1×	0.003	CSTA
keratinocyte differentiation	1	247.8×	0.005	CSTA
cell-cell adhesion	1	101.5×	0.010	CSTA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CSTA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CSTA

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CSTA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.