Hereditary palmoplantar keratoderma

Summary

Hereditary palmoplantar keratoderma (MONDO:0019272) is a disease (an umbrella term covering 8 Mondo subtypes) caused by KLF4 (GenCC Strong), with 6 cohort genes.

At a glance

• Causal gene: KLF4 (GenCC Strong)
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary palmoplantar keratoderma
Mondo ID	MONDO:0019272
Orphanet	79357
ICD-11	1941547119
SNOMED CT	239066003
UMLS	C0406757
MedGen	590657
GARD	0018988
Is cancer (heuristic)	no

Also known as: hereditary keratosis palmoplantaris · hereditary palmoplantar hyperkeratosis · hereditary palmoplantar keratosis · hereditary PPK

Data availability: 7 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma

Related subtypes (1): aquagenic palmoplantar keratoderma

Subtypes (8): palmoplantar keratoderma i, striate, focal, or diffuse, palmoplantar keratoderma, nonepidermolytic, 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

7 retrieved; paginated sample, class counts are floors:

4 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17002	NM_004004.6(GJB2):c.71G>A (p.Trp24Ter)	GJB2	Pathogenic	reviewed by expert panel
17004	NM_004004.6(GJB2):c.35del (p.Gly12fs)	GJB2	Pathogenic	reviewed by expert panel
17011	NM_004004.6(GJB2):c.223C>T (p.Arg75Trp)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17027	NM_004004.6(GJB2):c.224G>A (p.Arg75Gln)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17029	NM_004004.6(GJB2):c.-23+1G>A	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
373942	NM_001942.4(DSG1):c.604G>T (p.Glu202Ter)	DSG1	Likely pathogenic	no assertion criteria provided
374188	NM_001942.4(DSG1):c.1176T>G (p.Tyr392Ter)	DSG1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 12 · 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
KLF4	Strong	Autosomal dominant	hereditary palmoplantar keratoderma	2
COL14A1	Supportive	Autosomal dominant	punctate palmoplantar keratoderma type 1	2
COL20A1	Limited	Autosomal dominant	hereditary palmoplantar keratoderma
SACK1G	Limited	Autosomal recessive	hereditary palmoplantar keratoderma

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL14A1	Orphanet:79501	Punctate palmoplantar keratoderma type 1
DSG1	Orphanet:369992	Severe dermatitis-multiple allergies-metabolic wasting syndrome
DSG1	Orphanet:369999	Diffuse palmoplantar keratoderma with painful fissures
DSG1	Orphanet:370002	Focal palmoplantar keratoderma with joint keratoses
DSG1	Orphanet:50942	Striate palmoplantar keratoderma
GJB2	Orphanet:166286	Porokeratotic eccrine ostial and dermal duct nevus
GJB2	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
GJB2	Orphanet:2698	Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome
GJB2	Orphanet:477	KID syndrome
GJB2	Orphanet:494	Keratoderma hereditarium mutilans
GJB2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL20A1	HGNC:14670	ENSG00000101203	Q9P218	Collagen alpha-1(XX) chain	gencc
COL14A1	HGNC:2191	ENSG00000187955	Q05707	Collagen alpha-1(XIV) chain	gencc
SACK1G	HGNC:32554	ENSG00000188522	A6ND36	Protein FAM83G	gencc
KLF4	HGNC:6348	ENSG00000136826	O43474	Krueppel-like factor 4	gencc
DSG1	HGNC:3048	ENSG00000134760	Q02413	Desmoglein-1	clinvar
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL20A1	Collagen alpha-1(XX) chain	Probable collagen protein.
COL14A1	Collagen alpha-1(XIV) chain	Plays an adhesive role by integrating collagen bundles.
SACK1G	Protein FAM83G	Substrate for type I BMP receptor kinase involved in regulation of some target genes of the BMP signaling pathway.
KLF4	Krueppel-like factor 4	Transcription factor; can act both as activator and as repressor.
DSG1	Desmoglein-1	Component of intercellular desmosome junctions.
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.33

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
Antibody/Immunoglobulin	2	9.7×	0.048
Transcription factor	1	1.4×	0.758
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL20A1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Collagen
COL14A1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Collagen
SACK1G	Other/Unknown	no		SACK1, FAM83
KLF4	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
DSG1	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Desmosomal_cadherin
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingival epithelium	2
upper arm skin	2
penis	2
skin of hip	2
upper leg skin	2
anterior cingulate cortex	1
left testis	1
right testis	1
descending thoracic aorta	1
popliteal artery	1
right coronary artery	1
skin of leg	1
gingiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL20A1	133	tissue_specific	marker	right testis, left testis, anterior cingulate cortex
COL14A1	245	broad	marker	descending thoracic aorta, right coronary artery, popliteal artery
SACK1G	183	ubiquitous	marker	upper arm skin, gingival epithelium, skin of leg
KLF4	290	ubiquitous	marker	upper leg skin, skin of hip, penis
DSG1	152	tissue_specific	marker	upper arm skin, upper leg skin, skin of hip
GJB2	196	broad	marker	gingival epithelium, gingiva, penis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL14A1	1,991
DSG1	1,643
GJB2	1,391
COL20A1	975
SACK1G	387
KLF4	316

Intra-cohort edges

A	B	Sources
COL14A1	COL20A1	biogrid_interaction

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB2	P29033	24
COL20A1	Q9P218	4
KLF4	O43474	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COL14A1	Q05707	74.06
DSG1	Q02413	62.93
SACK1G	A6ND36	59.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 6 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Collagen chain trimerization	2	103.8×	0.004	COL20A1, COL14A1
Collagen biosynthesis and modifying enzymes	2	68.2×	0.005	COL20A1, COL14A1
Oligomerization of connexins into connexons	1	761.3×	0.009	GJB2
Transport of connexins along the secretory pathway	1	761.3×	0.009	GJB2
Apoptotic cleavage of cell adhesion proteins	1	207.6×	0.024	DSG1
Positive Regulation of CDH1 Gene Transcription	1	190.3×	0.024	KLF4
FOXO-mediated transcription of cell cycle genes	1	134.3×	0.025	KLF4
Synthesis, secretion, and deacylation of Ghrelin	1	120.2×	0.025	KLF4
Transport of connexons to the plasma membrane	1	108.8×	0.025	GJB2
Transcriptional regulation of pluripotent stem cells	1	108.8×	0.025	KLF4
FOXO-mediated transcription	1	67.2×	0.034	KLF4
Gap junction assembly	1	58.6×	0.034	GJB2
Peptide hormone metabolism	1	54.4×	0.034	KLF4
RND3 GTPase cycle	1	51.9×	0.034	DSG1
RND2 GTPase cycle	1	51.9×	0.034	DSG1
Assembly of collagen fibrils and other multimeric structures	1	40.1×	0.042	COL14A1
Collagen degradation	1	35.1×	0.045	COL14A1
Adipogenesis	1	31.3×	0.047	KLF4
Transcriptional regulation of white adipocyte differentiation	1	25.9×	0.054	KLF4
Formation of the cornified envelope	1	17.6×	0.075	DSG1
Keratinization	1	11.1×	0.111	DSG1
Neutrophil degranulation	1	4.6×	0.238	DSG1
RNA Polymerase II Transcription	1	4.5×	0.238	KLF4
Gene expression (Transcription)	1	3.6×	0.282	KLF4
Generic Transcription Pathway	1	3.0×	0.313	KLF4
Developmental Biology	1	2.9×	0.313	KLF4
Metabolism of proteins	1	2.5×	0.344	KLF4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of cell growth involved in cardiac muscle cell development	1	3370.4×	0.009	COL14A1
negative regulation of leukocyte adhesion to arterial endothelial cell	1	3370.4×	0.009	KLF4
negative regulation of muscle hyperplasia	1	1685.2×	0.009	KLF4
mesodermal cell fate determination	1	1123.5×	0.009	KLF4
post-embryonic camera-type eye development	1	842.6×	0.009	KLF4
regulation of blastocyst development	1	842.6×	0.009	KLF4
negative regulation of chemokine (C-X-C motif) ligand 2 production	1	842.6×	0.009	KLF4
post-embryonic hemopoiesis	1	561.7×	0.009	KLF4
positive regulation of hemoglobin biosynthetic process	1	561.7×	0.009	KLF4
epidermis morphogenesis	1	561.7×	0.009	KLF4
negative regulation of response to cytokine stimulus	1	561.7×	0.009	KLF4
gap junction-mediated intercellular transport	1	561.7×	0.009	GJB2
cell-cell adhesion	2	40.6×	0.009	COL14A1, DSG1
regulation of axon regeneration	1	481.5×	0.009	KLF4
ventricular cardiac muscle tissue development	1	421.3×	0.009	COL14A1
gap junction assembly	1	421.3×	0.009	GJB2
cellular response to laminar fluid shear stress	1	421.3×	0.009	KLF4
negative regulation of heterotypic cell-cell adhesion	1	374.5×	0.010	KLF4
epidermal cell differentiation	1	337.0×	0.011	KLF4
cellular response to endothelin	1	280.9×	0.012	KLF4
defense response to tumor cell	1	259.3×	0.012	KLF4
negative regulation of interleukin-8 production	1	198.3×	0.014	KLF4
positive regulation of protein metabolic process	1	198.3×	0.014	KLF4
negative regulation of cell migration involved in sprouting angiogenesis	1	198.3×	0.014	KLF4
maternal process involved in female pregnancy	1	187.2×	0.014	DSG1
positive regulation of sprouting angiogenesis	1	134.8×	0.019	KLF4
negative regulation of smooth muscle cell proliferation	1	124.8×	0.020	KLF4
positive regulation of telomere maintenance	1	102.1×	0.022	KLF4
response to progesterone	1	99.1×	0.022	DSG1
calcium-dependent cell-cell adhesion	1	96.3×	0.022	DSG1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GJB2	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DSG1	1	2
GJB2	1	4
COL20A1	0	0
COL14A1	0	0
SACK1G	0	0
KLF4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJB2
MOLIBRESIB	2	DSG1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DSG1	8	Binding:8
GJB2	5	Binding:5
COL14A1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
KANAMYCIN	4	GJB2
MOLIBRESIB	2	DSG1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJB2
B	Phased (≥1) drug, not yet approved	1	DSG1
C	Druggable family + PDB, no drug	1	COL20A1
D	Druggable family + AlphaFold only, no drug	1	COL14A1
E	Difficult family or no structure, no drug	2	SACK1G, KLF4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COL20A1	0	—
COL14A1	1	—
SACK1G	0	—
KLF4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.