Peeling skin syndrome 6

Summary

Peeling skin syndrome 6 (MONDO:0054852) is a disease caused by FLG2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: FLG2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peeling skin syndrome 6
Mondo ID	MONDO:0054852
OMIM	618084
DOID	DOID:0070525
UMLS	C4748093
MedGen	1648406
GARD	0025988
Is cancer (heuristic)	no

Also known as: peeling skin syndrome 6 · PSS6

Data availability: 9 ClinVar variants · 5 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 › peeling skin syndrome › peeling skin syndrome 6

Related subtypes (4): generalized peeling skin syndrome, peeling skin syndrome 4, acral peeling skin syndrome, 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

9 retrieved; paginated sample, class counts are floors:

2 conflicting classifications of pathogenicity, 2 uncertain significance, 1 benign/likely benign, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
559518	NM_001014342.3(FLG2):c.632C>G (p.Ser211Ter)	CCDST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
559519	NM_001014342.3(FLG2):c.1065T>A (p.Tyr355Ter)	FLG-AS1	Pathogenic	no assertion criteria provided
4849429	NM_001014342.3(FLG2):c.58A>T (p.Lys20Ter)	FLG2	Likely pathogenic	criteria provided, single submitter
2443044	NM_001014342.3(FLG2):c.3101_3104del (p.Gln1034fs)	CCDST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3377612	NM_001014342.3(FLG2):c.781C>T (p.Gln261Ter)	CCDST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779671	NM_001014342.3(FLG2):c.3939_3940dup (p.Thr1314fs)	CCDST	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779670	NM_001014342.3(FLG2):c.3989del (p.Gly1330fs)	FLG2	Uncertain significance	criteria provided, single submitter
2347191	NM_001014342.3(FLG2):c.2837T>C (p.Phe946Ser)	CCDST	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
982974	NM_001014342.3(FLG2):c.2595_2825del (p.Ser869_Thr945del)	FLG-AS1	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
FLG2	Strong	Autosomal recessive	peeling skin syndrome 6	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLG2	Orphanet:263548	Peeling skin syndrome type A

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLG2	HGNC:33276	ENSG00000143520	Q5D862	Filaggrin-2	gencc,clinvar
CCDST	HGNC:55988	ENSG00000236427		cervical cancer associated DHX9 suppressive transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLG2	Filaggrin-2	Essential for normal cell-cell adhesion in the cornified cell layers.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLG2	Other/Unknown	no		S100/CaBP7/8-like_CS, EF_hand_dom, Filaggrin
CCDST	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
penis	1
skin of hip	1
upper leg skin	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
quadriceps femoris	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLG2	122	tissue_specific	yes	upper leg skin, skin of hip, penis
CCDST	111	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, quadriceps femoris

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLG2	2,574
CCDST	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FLG2	Q5D862	33.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Neutrophil degranulation	1	23.1×	0.043	FLG2

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
epidermis morphogenesis	1	2808.7×	0.001	FLG2
establishment of skin barrier	1	455.5×	0.003	FLG2
cell adhesion	1	37.5×	0.027	FLG2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLG2	0	0
CCDST	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FLG2	6	Binding:6

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	2	FLG2, CCDST

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FLG2	6	—
CCDST	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.