Palmoplantar keratoderma, epidermolytic

Summary

Palmoplantar keratoderma, epidermolytic (MONDO:0968949) is a disease with 3 cohort genes. The dominant Reactome pathway is Formation of the cornified envelope (3 cohort genes).

At a glance

• Cohort genes: 3
• ClinVar variants: 80

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	palmoplantar keratoderma, epidermolytic
Mondo ID	MONDO:0968949
OMIM	144200
DOID	DOID:0080223
UMLS	C1721006
MedGen	354561
GARD	0027034
Is cancer (heuristic)	no

Data availability: 80 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (7): 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

Subtypes (2): epidermolytic palmoplantar keratoderma, 1, palmoplantar keratoderma, epidermolytic, 2

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

80 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 15 conflicting classifications of pathogenicity, 13 benign/likely benign, 5 benign, 3 pathogenic/likely pathogenic, 3 likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
432078	NM_006121.4(KRT1):c.1453C>T (p.Leu485Phe)	KRT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2997	NM_000226.4(KRT9):c.487C>T (p.Arg163Trp)	KRT9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3001	NM_000226.4(KRT9):c.488G>A (p.Arg163Gln)	KRT9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687438	NM_000226.4(KRT9):c.500A>C (p.Tyr167Ser)	KRT9	Likely pathogenic	criteria provided, single submitter
3000	NM_000226.4(KRT9):c.483T>A (p.Asn161Lys)	KRT9	Likely pathogenic	criteria provided, multiple submitters, no conflicts
587419	NM_005557.4(KRT16):c.539C>T (p.Ala180Val)	KRT16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3006	NM_000226.4(KRT9):c.470T>C (p.Met157Thr)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323115	NM_000226.4(KRT9):c.1594G>A (p.Gly532Ser)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323117	NM_000226.4(KRT9):c.1560C>T (p.Tyr520=)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323123	NM_000226.4(KRT9):c.1394T>G (p.Phe465Cys)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323127	NM_000226.4(KRT9):c.1125C>T (p.His375=)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323131	NM_000226.4(KRT9):c.1011C>T (p.Asn337=)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323138	NM_000226.4(KRT9):c.286G>A (p.Gly96Ser)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
66145	NM_000226.4(KRT9):c.1216T>C (p.Cys406Arg)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
889267	NM_000226.4(KRT9):c.1869C>T (p.Ser623=)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890014	NM_000226.4(KRT9):c.697C>T (p.Arg233Cys)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891512	NM_000226.4(KRT9):c.1290C>T (p.Ile430=)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891574	NM_000226.4(KRT9):c.250A>G (p.Ser84Gly)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891760	NM_000226.4(KRT9):c.1120C>T (p.Arg374Trp)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891761	NM_000226.4(KRT9):c.1119C>T (p.Leu373=)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323110	NM_000226.4(KRT9):c.*230T>C	KRT9	Uncertain significance	criteria provided, single submitter
323111	NM_000226.4(KRT9):c.*181G>A	KRT9	Uncertain significance	criteria provided, single submitter
323112	NM_000226.4(KRT9):c.*103C>G	KRT9	Uncertain significance	criteria provided, single submitter
323113	NM_000226.4(KRT9):c.1839C>T (p.Tyr613=)	KRT9	Uncertain significance	criteria provided, single submitter
323118	NM_000226.4(KRT9):c.1520G>T (p.Gly507Val)	KRT9	Uncertain significance	criteria provided, multiple submitters, no conflicts
323119	NM_000226.4(KRT9):c.1519G>C (p.Gly507Arg)	KRT9	Uncertain significance	criteria provided, multiple submitters, no conflicts
323121	NM_000226.4(KRT9):c.1405G>A (p.Gly469Arg)	KRT9	Uncertain significance	criteria provided, single submitter
323124	NM_000226.4(KRT9):c.1336C>T (p.Arg446Trp)	KRT9	Uncertain significance	criteria provided, single submitter
323125	NM_000226.4(KRT9):c.1315C>T (p.Leu439Phe)	KRT9	Uncertain significance	criteria provided, single submitter
323128	NM_000226.4(KRT9):c.1096A>G (p.Ser366Gly)	KRT9	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT1	Orphanet:2199	Epidermolytic palmoplantar keratoderma
KRT1	Orphanet:281139	Annular epidermolytic ichthyosis
KRT1	Orphanet:281190	Congenital reticular ichthyosiform erythroderma
KRT1	Orphanet:312	Autosomal dominant epidermolytic ichthyosis
KRT1	Orphanet:50942	Striate palmoplantar keratoderma
KRT1	Orphanet:530838	KRT1-related diffuse nonepidermolytic keratoderma
KRT1	Orphanet:538574	Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome
KRT1	Orphanet:79503	Ichthyosis hystrix of Curth-Macklin
KRT16	Orphanet:2199	Epidermolytic palmoplantar keratoderma
KRT16	Orphanet:2309	Pachyonychia congenita
KRT16	Orphanet:448264	Isolated focal non-epidermolytic palmoplantar keratoderma
KRT9	Orphanet:2199	Epidermolytic palmoplantar keratoderma

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT1	HGNC:6412	ENSG00000167768	P04264	Keratin, type II cytoskeletal 1	clinvar
KRT16	HGNC:6423	ENSG00000186832	P08779	Keratin, type I cytoskeletal 16	clinvar
KRT9	HGNC:6447	ENSG00000171403	P35527	Keratin, type I cytoskeletal 9	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT1	Keratin, type II cytoskeletal 1	May regulate the activity of kinases such as PKC and SRC via binding to integrin beta-1 (ITB1) and the receptor of activated protein C kinase 1 (RACK1).
KRT16	Keratin, type I cytoskeletal 16	Epidermis-specific type I keratin that plays a key role in skin.
KRT9	Keratin, type I cytoskeletal 9	May serve an important special function either in the mature palmar and plantar skin tissue or in the morphogenetic program of the formation of these tissues.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRT1	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
KRT16	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom
KRT9	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mammalian vulva	1
skin of hip	1
upper leg skin	1
gingiva	1
gingival epithelium	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
penis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT1	177	tissue_specific	marker	mammalian vulva, upper leg skin, skin of hip
KRT16	176	broad	marker	gingival epithelium, gingiva, lower esophagus mucosa
KRT9	59	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, penis

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT1	2,716
KRT16	2,175
KRT9	1,635

Intra-cohort edges

A	B	Sources
KRT1	KRT16	intact
KRT1	KRT9	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRT1	P04264	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT16	P08779	74.26
KRT9	P35527	66.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 evidence-associated genes (3 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 3 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	3	87.8×	1e-05	KRT1, KRT16, KRT9
Keratinization	3	55.7×	3e-05	KRT1, KRT16, KRT9
Developmental Biology	3	14.5×	0.001	KRT1, KRT16, KRT9
Regulation of FXIIa and plasma kallikrein activity	1	380.7×	0.007	KRT1
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	92.8×	0.021	KRT1
Developmental Cell Lineages	1	74.6×	0.022	KRT1
FXIIa activates plasma kallikrein-kinin system	1	57.7×	0.025	KRT1
Innate Immune System	1	8.5×	0.138	KRT1
Neutrophil degranulation	1	7.7×	0.138	KRT1
Immune System	1	4.3×	0.214	KRT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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	3	240.7×	2e-06	KRT1, KRT16, KRT9
establishment of skin barrier	2	303.6×	2e-04	KRT1, KRT16
morphogenesis of an epithelium	2	229.3×	2e-04	KRT16, KRT9
keratinization	2	156.0×	3e-04	KRT1, KRT16
keratinocyte migration	1	802.5×	0.005	KRT16
complement activation, lectin pathway	1	561.7×	0.007	KRT1
protein heterotetramerization	1	351.1×	0.008	KRT1
cornification	1	351.1×	0.008	KRT1
hair cycle	1	312.1×	0.008	KRT16
fibrinolysis	1	280.9×	0.008	KRT1
skin development	1	147.8×	0.013	KRT9
regulation of angiogenesis	1	140.4×	0.013	KRT1
keratinocyte differentiation	1	82.6×	0.020	KRT16
epidermis development	1	70.2×	0.022	KRT9
epithelial cell differentiation	1	58.5×	0.025	KRT9
negative regulation of inflammatory response	1	45.7×	0.028	KRT1
cytoskeleton organization	1	44.2×	0.028	KRT16
response to oxidative stress	1	43.5×	0.028	KRT1
negative regulation of cell migration	1	37.2×	0.031	KRT16
inflammatory response	1	12.6×	0.085	KRT16
spermatogenesis	1	11.7×	0.087	KRT9
innate immune response	1	11.2×	0.087	KRT16

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
KRT1	0	0
KRT16	0	0
KRT9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	KRT1, KRT16, KRT9

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KRT1	0	—
KRT16	0	—
KRT9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.