Palmoplantar keratoderma, nonepidermolytic, focal or diffuse

Summary

Palmoplantar keratoderma, nonepidermolytic, focal or diffuse (MONDO:0014327) is a disease caused by KRT6C (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KRT6C (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	palmoplantar keratoderma, nonepidermolytic, focal or diffuse
Mondo ID	MONDO:0014327
OMIM	615735
Orphanet	402003
DOID	DOID:0111710
UMLS	C3810394
MedGen	816724
GARD	0017669
Is cancer (heuristic)	no

Also known as: autosomal dominant focal non-epidermolytic palmoplantar keratoderma with plantar blistering · palmoplantar keratoderma, nonepidermolytic, focal or diffuse · PPKNEFD

Data availability: 17 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 › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › palmoplantar keratoderma, nonepidermolytic, focal or diffuse

Related subtypes (7): palmoplantar keratoderma i, striate, focal, or diffuse, diffuse palmoplantar keratoderma, focal palmoplantar keratoderma, punctate palmoplantar keratoderma, alopecia congenita keratosis palmoplantaris, Olmsted syndrome, palmoplantar keratoderma, epidermolytic

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

17 retrieved; paginated sample, class counts are floors:

14 benign, 1 pathogenic/likely pathogenic, 1 uncertain significance, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
126527	NM_173086.5(KRT6C):c.1414G>A (p.Glu472Lys)	KRT6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4056571	NM_173086.5(KRT6C):c.356C>T (p.Ala119Val)	KRT6C	Uncertain significance	criteria provided, single submitter
1300090	NM_173086.5(KRT6C):c.1503C>T (p.Ser501=)	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300091	NM_173086.5(KRT6C):c.1460-10C>A	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300092	NM_173086.5(KRT6C):c.1441G>A (p.Val481Ile)	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300093	NM_173086.5(KRT6C):c.1314G>A (p.Lys438=)	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300094	NM_173086.5(KRT6C):c.816+13A>G	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300095	NM_173086.5(KRT6C):c.755+13T>C	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300096	NM_173086.5(KRT6C):c.687C>G (p.Val229=)	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300097	NM_173086.5(KRT6C):c.545G>A (p.Arg182Gln)	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300098	NM_173086.5(KRT6C):c.428G>A (p.Ser143Asn)	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300099	NM_173086.5(KRT6C):c.417C>T (p.Thr139=)	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300100	NM_173086.5(KRT6C):c.198C>A (p.Gly66=)	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300101	NM_173086.5(KRT6C):c.183G>A (p.Leu61=)	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300102	NM_173086.5(KRT6C):c.181C>T (p.Leu61=)	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
1300103	NM_173086.5(KRT6C):c.180T>C (p.Ser60=)	KRT6C	Benign	criteria provided, multiple submitters, no conflicts
768547	NM_173086.5(KRT6C):c.1257A>C (p.Ala419=)	KRT6C	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
KRT6A	Strong	Autosomal dominant	palmoplantar keratoderma, nonepidermolytic, focal or diffuse	9
KRT6C	Strong	Autosomal dominant	palmoplantar keratoderma, nonepidermolytic, focal or diffuse	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT6C	Orphanet:402003	Autosomal dominant focal non-epidermolytic palmoplantar keratoderma with plantar blistering
KRT6A	Orphanet:2309	Pachyonychia congenita

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT6C	HGNC:20406	ENSG00000170465	P48668	Keratin, type II cytoskeletal 6C	gencc,clinvar
KRT6A	HGNC:6443	ENSG00000205420	P02538	Keratin, type II cytoskeletal 6A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT6A	Keratin, type II cytoskeletal 6A	Epidermis-specific type I keratin involved in wound healing.

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)
KRT6C	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
KRT6A	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar vermis	1
esophagus mucosa	1
lower esophagus mucosa	1
gingiva	1
gingival epithelium	1
squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT6C	100	tissue_specific	marker	esophagus mucosa, cerebellar vermis, lower esophagus mucosa
KRT6A	187	broad	marker	gingiva, gingival epithelium, squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT6A	2,160
KRT6C	217

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRT6A	P02538	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT6C	P48668	69.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 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 2 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	2	87.8×	4e-04	KRT6C, KRT6A
Keratinization	2	55.7×	5e-04	KRT6C, KRT6A
Developmental Biology	2	14.5×	0.005	KRT6C, KRT6A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intermediate filament organization	2	240.7×	1e-04	KRT6C, KRT6A
keratinization	2	234.1×	1e-04	KRT6C, KRT6A
negative regulation of entry of bacterium into host cell	1	2808.7×	0.001	KRT6A
intermediate filament cytoskeleton organization	1	468.1×	0.006	KRT6C
morphogenesis of an epithelium	1	172.0×	0.013	KRT6A
killing of cells of another organism	1	135.9×	0.013	KRT6A
wound healing	1	113.9×	0.014	KRT6A
antimicrobial humoral immune response mediated by antimicrobial peptide	1	81.0×	0.017	KRT6A
defense response to Gram-positive bacterium	1	63.8×	0.019	KRT6A
positive regulation of cell population proliferation	1	16.8×	0.064	KRT6A
cell differentiation	1	14.6×	0.068	KRT6A

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
KRT6C	0	0
KRT6A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	KRT6C, KRT6A

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)
KRT6C	0	—
KRT6A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.