Erythrokeratodermia variabilis et progressiva 4

disease

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Also known as EKVP4

Summary

Erythrokeratodermia variabilis et progressiva 4 (MONDO:0033014) is a disease caused by KDSR (GenCC Definitive), with 1 cohort gene.

At a glance

Causal gene: KDSR (GenCC Definitive)
Cohort genes: 1
ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	erythrokeratodermia variabilis et progressiva 4
Mondo ID	MONDO:0033014
OMIM	617526
DOID	DOID:0080250
UMLS	C4479620
MedGen	1372799
GARD	0018590
Is cancer (heuristic)	no

Also known as: EKVP4 · erythrokeratodermia variabilis et progressiva 4

Data availability: 7 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 › diffuse palmoplantar keratoderma › erythrokeratodermia variabilis › erythrokeratodermia variabilis et progressiva 4

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:

3 likely pathogenic, 3 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
427789	NM_002035.4(KDSR):c.164_166del (p.Gln55_Gly56delinsArg)	KDSR	Pathogenic	no assertion criteria provided
427790	NM_002035.4(KDSR):c.256-2A>C	KDSR	Pathogenic	no assertion criteria provided
427792	NM_002035.4(KDSR):c.557A>T (p.Tyr186Phe)	KDSR	Pathogenic	no assertion criteria provided
2572585	NM_002035.4(KDSR):c.544G>A (p.Gly182Ser)	KDSR	Likely pathogenic	criteria provided, single submitter
3067941	NM_002035.4(KDSR):c.190C>T (p.Arg64Ter)	KDSR	Likely pathogenic	criteria provided, single submitter
427791	NM_002035.4(KDSR):c.879G>A (p.Gln293=)	KDSR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1300062	NM_002035.4(KDSR):c.261G>A (p.Val87=)	KDSR	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
KDSR	Definitive	Autosomal recessive	erythrokeratodermia variabilis et progressiva 4	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KDSR	Orphanet:316	Progressive symmetric erythrokeratodermia
KDSR	Orphanet:317	Erythrokeratodermia variabilis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KDSR	HGNC:4021	ENSG00000119537	Q06136	3-ketodihydrosphingosine reductase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KDSR	3-ketodihydrosphingosine reductase	Catalyzes the reduction of 3’-oxosphinganine (3-ketodihydrosphingosine/KDS) to sphinganine (dihydrosphingosine/DHS), the second step of de novo sphingolipid biosynthesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KDSR	Enzyme (other)	yes	1.1.1.102	SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
buccal mucosa cell	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KDSR	287	ubiquitous	marker	endothelial cell, buccal mucosa cell, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KDSR	1,419

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KDSR	Q06136	95.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 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
Sphingolipid de novo biosynthesis	1	285.5×	0.012	KDSR
Sphingolipid metabolism	1	167.9×	0.012	KDSR
Metabolism of lipids	1	31.6×	0.042	KDSR
Metabolism	1	11.6×	0.086	KDSR

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
3-keto-sphinganine metabolic process	1	16852.0×	2e-04	KDSR
glycosphingolipid biosynthetic process	1	601.9×	0.003	KDSR
ceramide biosynthetic process	1	421.3×	0.003	KDSR
sphingolipid biosynthetic process	1	358.6×	0.003	KDSR

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
KDSR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KDSR	1.1.1.102	3-dehydrosphinganine reductase

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	1	KDSR
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KDSR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: KDSR