Erythrokeratodermia variabilis et progressiva 2

disease

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Also known as EKVP2

Summary

Erythrokeratodermia variabilis et progressiva 2 (MONDO:0033012) is a disease caused by GJB4 (GenCC Strong), with 1 cohort gene.

At a glance

Causal gene: GJB4 (GenCC Strong)
Cohort genes: 1
ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	erythrokeratodermia variabilis et progressiva 2
Mondo ID	MONDO:0033012
OMIM	617524
DOID	DOID:0080248
UMLS	C4479618
MedGen	1379712
GARD	0018588
Is cancer (heuristic)	no

Also known as: EKVP2

Data availability: 19 ClinVar variants · 4 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 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

19 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 4 pathogenic, 3 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
5005	NM_153212.3(GJB4):c.411C>A (p.Phe137Leu)	GJB4	Pathogenic	no assertion criteria provided
5006	NM_153212.3(GJB4):c.253A>C (p.Thr85Pro)	GJB4	Pathogenic	criteria provided, single submitter
5007	NM_153212.3(GJB4):c.35G>A (p.Gly12Asp)	GJB4	Pathogenic	no assertion criteria provided
5009	NM_153212.3(GJB4):c.566T>A (p.Phe189Tyr)	GJB4	Pathogenic	no assertion criteria provided
5004	NM_153212.3(GJB4):c.409T>C (p.Phe137Leu)	GJB4	Likely pathogenic	criteria provided, single submitter
1608519	NM_153212.3(GJB4):c.178T>G (p.Cys60Gly)	GJB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522773	NM_153212.3(GJB4):c.386G>A (p.Trp129Ter)	GJB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
774579	NM_153212.3(GJB4):c.384G>A (p.Trp128Ter)	GJB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2507391	NM_153212.3(GJB4):c.121G>A (p.Glu41Lys)	GJB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2596632	NM_153212.3(GJB4):c.7T>C (p.Trp3Arg)	GJB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2886525	NM_153212.3(GJB4):c.94C>T (p.Arg32Cys)	GJB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3064469	NM_153212.3(GJB4):c.1del (p.Met1*)	GJB4	Uncertain significance	criteria provided, single submitter
3068622	NM_153212.3(GJB4):c.507C>A (p.Cys169Ter)	GJB4	Uncertain significance	criteria provided, single submitter
3340337	NM_153212.3(GJB4):c.64C>T (p.Arg22Cys)	GJB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779698	NM_153212.3(GJB4):c.542del (p.Thr181fs)	GJB4	Uncertain significance	criteria provided, single submitter
4078771	NM_153212.3(GJB4):c.199G>A (p.Glu67Lys)	GJB4	Uncertain significance	criteria provided, single submitter
5008	NM_153212.3(GJB4):c.65G>A (p.Arg22His)	GJB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
195421	NM_153212.3(GJB4):c.153del (p.Phe51fs)	GJB4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
783282	NM_153212.3(GJB4):c.238C>T (p.Gln80Ter)	GJB4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
GJB4	Strong	Autosomal dominant	erythrokeratodermia variabilis et progressiva 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJB4	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
GJB4	HGNC:4286	ENSG00000189433	Q9NTQ9	Gap junction beta-4 protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJB4	Gap junction beta-4 protein	Structural component of gap junctions.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GJB4	Other/Unknown	no		Connexin, Connexin-30.3, Connexin_N

Expression context

Cohort genes with no expression data: 0.

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
skin of abdomen	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJB4	70	tissue_specific	yes	skin of abdomen, zone of skin, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJB4	469

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJB4	Q9NTQ9	78.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Gap junction assembly	1	292.8×	0.003	GJB4

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gap junction-mediated intercellular transport	1	2808.7×	0.001	GJB4
olfactory behavior	1	1872.4×	0.001	GJB4
sensory perception of smell	1	156.0×	0.009	GJB4
cell-cell signaling	1	69.6×	0.014	GJB4

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
GJB4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	1	GJB4

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)
GJB4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: GJB4