Isolated focal non-epidermolytic palmoplantar keratoderma

Summary

Isolated focal non-epidermolytic palmoplantar keratoderma (MONDO:0014622) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 202

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated focal non-epidermolytic palmoplantar keratoderma
Mondo ID	MONDO:0014622
OMIM	616400
Orphanet	448264
DOID	DOID:0111708, DOID:0111711
UMLS	C4225339
MedGen	895056
GARD	0017781
Is cancer (heuristic)	no

Also known as: FNEPPK2 · palmoplantar keratoderma, nonepidermolytic, focal 2 · palmoplantar keratoderma, nonepidermolytic, focal type 2

Data availability: 202 ClinVar variants · 3 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 › focal palmoplantar keratoderma › isolated focal non-epidermolytic palmoplantar keratoderma

Related subtypes (11): hereditary painful callosities, palmoplantar keratoderma-esophageal carcinoma syndrome, focal palmoplantar and gingival keratoderma, tyrosinemia type II, hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome, palmoplantar keratoderma, nonepidermolytic, focal 1, nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome, wooly hair-palmoplantar keratoderma syndrome, pachyonychia congenita, focal palmoplantar keratoderma with joint keratoses, striate palmoplantar keratoderma

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

202 retrieved; paginated sample, class counts are floors:

95 benign, 73 uncertain significance, 14 benign/likely benign, 12 conflicting classifications of pathogenicity, 5 likely benign, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
192256	NM_145068.4(TRPV3):c.2017C>T (p.Leu673Phe)	TRPV3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
192257	NM_145068.4(TRPV3):c.1739A>C (p.Gln580Pro)	TRPV3	Pathogenic	no assertion criteria provided
803297	NM_145068.4(TRPV3):c.1703G>T (p.Gly568Val)	TRPV3	Pathogenic	criteria provided, single submitter
322763	NM_145068.4(TRPV3):c.1659G>A (p.Leu553=)	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
322764	NM_145068.4(TRPV3):c.1654G>A (p.Val552Met)	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
322765	NM_145068.4(TRPV3):c.1622T>C (p.Leu541Ser)	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
322771	NM_145068.4(TRPV3):c.1401+9G>T	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
740462	NM_145068.4(TRPV3):c.1971G>A (p.Leu657=)	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
756130	NM_145068.4(TRPV3):c.955C>T (p.Arg319Cys)	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888891	NM_145068.4(TRPV3):c.1401+4C>T	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888952	NM_145068.4(TRPV3):c.540C>A (p.Asn180Lys)	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
889631	NM_145068.4(TRPV3):c.380T>C (p.Val127Ala)	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890513	NM_145068.4(TRPV3):c.2185C>T (p.Arg729Ter)	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890515	NM_145068.4(TRPV3):c.2078G>A (p.Arg693His)	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891073	NM_145068.4(TRPV3):c.1935G>T (p.Gln645His)	TRPV3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
322672	NM_145068.4(TRPV3):c.*3340C>G	SPATA22	Uncertain significance	criteria provided, single submitter
322675	NM_145068.4(TRPV3):c.*3295G>C	SPATA22	Uncertain significance	criteria provided, single submitter
322683	NM_145068.4(TRPV3):c.*3045G>T	SPATA22	Uncertain significance	criteria provided, single submitter
322684	NM_145068.4(TRPV3):c.*2895C>G	SPATA22	Uncertain significance	criteria provided, single submitter
322685	NM_145068.4(TRPV3):c.*2808C>T	SPATA22	Uncertain significance	criteria provided, single submitter
322688	NM_145068.4(TRPV3):c.*2671C>T	SPATA22	Uncertain significance	criteria provided, single submitter
322689	NM_145068.4(TRPV3):c.*2622G>T	SPATA22	Uncertain significance	criteria provided, single submitter
322691	NM_145068.4(TRPV3):c.*2490T>C	SPATA22	Uncertain significance	criteria provided, single submitter
322693	NM_145068.4(TRPV3):c.*2365T>C	SPATA22	Uncertain significance	criteria provided, single submitter
322695	NM_145068.4(TRPV3):c.*2296T>C	SPATA22	Uncertain significance	criteria provided, single submitter
322706	NM_145068.4(TRPV3):c.*2019A>G	SPATA22	Uncertain significance	criteria provided, single submitter
322711	NM_145068.4(TRPV3):c.*1669G>A	SPATA22	Uncertain significance	criteria provided, single submitter
322712	NM_145068.4(TRPV3):c.*1625C>G	SPATA22	Uncertain significance	criteria provided, single submitter
322716	NM_145068.4(TRPV3):c.*1591G>C	SPATA22	Uncertain significance	criteria provided, single submitter
322724	NM_145068.4(TRPV3):c.*1218G>A	SPATA22	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 5 · 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
KRT16	Strong	Autosomal dominant	palmoplantar keratoderma, nonepidermolytic, focal 1	10
TRPV3	Strong	Autosomal dominant	mutilating palmoplantar keratoderma with periorificial keratotic plaques	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPV3	Orphanet:448264	Isolated focal non-epidermolytic palmoplantar keratoderma
TRPV3	Orphanet:659	Mutilating palmoplantar keratoderma with periorificial keratotic plaques
KRT16	Orphanet:2199	Epidermolytic palmoplantar keratoderma
KRT16	Orphanet:2309	Pachyonychia congenita
KRT16	Orphanet:448264	Isolated focal non-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
TRPV3	HGNC:18084	ENSG00000167723	Q8NET8	Transient receptor potential cation channel subfamily V member 3	gencc,clinvar
KRT16	HGNC:6423	ENSG00000186832	P08779	Keratin, type I cytoskeletal 16	gencc
SPATA22	HGNC:30705	ENSG00000141255	Q8NHS9	Spermatogenesis-associated protein 22	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRPV3	Transient receptor potential cation channel subfamily V member 3	Non-selective calcium permeant cation channel.
KRT16	Keratin, type I cytoskeletal 16	Epidermis-specific type I keratin that plays a key role in skin.
SPATA22	Spermatogenesis-associated protein 22	Meiosis-specific protein required for homologous recombination in meiosis I.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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
Ion channel	1	37.2×	0.053
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRPV3	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
KRT16	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom
SPATA22	Other/Unknown	no		Spata22

Expression context

Cohort genes with no expression data: 0.

3 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
skin of abdomen	1
skin of leg	1
sural nerve	1
gingiva	1
gingival epithelium	1
lower esophagus mucosa	1
left testis	1
right testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPV3	157	broad	marker	skin of leg, skin of abdomen, sural nerve
KRT16	176	broad	marker	gingival epithelium, gingiva, lower esophagus mucosa
SPATA22	161	tissue_specific	marker	sperm, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT16	2,175
TRPV3	931
SPATA22	912

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRPV3	Q8NET8	34

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT16	P08779	74.26
SPATA22	Q8NHS9	61.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 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
TRP channels	1	203.9×	0.020	TRPV3
Formation of the cornified envelope	1	43.9×	0.045	KRT16
Keratinization	1	27.9×	0.047	KRT16
Developmental Biology	1	7.2×	0.134	KRT16

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
negative regulation of hair cycle	1	5617.3×	0.004	TRPV3
spermatocyte division	1	2808.7×	0.004	SPATA22
meiotic DNA repair synthesis	1	1872.4×	0.004	SPATA22
keratinocyte migration	1	802.5×	0.006	KRT16
reproductive system development	1	802.5×	0.006	SPATA22
osmosensory signaling pathway	1	510.7×	0.007	TRPV3
response to temperature stimulus	1	510.7×	0.007	TRPV3
hair cycle	1	312.1×	0.009	KRT16
positive regulation of calcium ion import	1	312.1×	0.009	TRPV3
regulation of meiotic cell cycle	1	255.3×	0.009	SPATA22
homologous chromosome pairing at meiosis	1	200.6×	0.011	SPATA22
calcium ion import across plasma membrane	1	181.2×	0.011	TRPV3
establishment of skin barrier	1	151.8×	0.012	KRT16
morphogenesis of an epithelium	1	114.6×	0.015	KRT16
fertilization	1	104.0×	0.015	SPATA22
keratinocyte differentiation	1	82.6×	0.017	KRT16
intermediate filament organization	1	80.2×	0.017	KRT16
keratinization	1	78.0×	0.017	KRT16
calcium ion transmembrane transport	1	70.2×	0.018	TRPV3
cytoskeleton organization	1	44.2×	0.027	KRT16
actin filament organization	1	39.6×	0.029	TRPV3
negative regulation of cell migration	1	37.2×	0.029	KRT16
inflammatory response	1	12.6×	0.081	KRT16
innate immune response	1	11.2×	0.087	KRT16

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPV3	4	3
KRT16	0	0
SPATA22	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANNABINOL	3	TRPV3
TETRAHYDROCANNABIVARIN	2	TRPV3
CANNABIDIVARIN	2	TRPV3
CANNABIGEROL	2	TRPV3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TRPV3	55	Binding:52, Functional:3

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

4 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)
CANNABINOL	3	TRPV3
TETRAHYDROCANNABIVARIN	2	TRPV3
CANNABIDIVARIN	2	TRPV3
CANNABIGEROL	2	TRPV3

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	1	TRPV3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	KRT16, SPATA22

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)
KRT16	0	—
SPATA22	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.