Erythrokeratodermia variabilis et progressiva 1

Summary

Erythrokeratodermia variabilis et progressiva 1 (MONDO:0033010) is a disease caused by GJB3 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: GJB3 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 83

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	erythrokeratodermia variabilis et progressiva 1
Mondo ID	MONDO:0033010
OMIM	133200
DOID	DOID:0111195
UMLS	C4551486
MedGen	1633225
GARD	0025782
Is cancer (heuristic)	no

Also known as: EKVP1

Data availability: 83 ClinVar variants · 8 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 1

Related subtypes (7): transgrediens et progrediens palmoplantar keratoderma, erythrokeratodermia variabilis et progressiva 7, erythrokeratodermia variabilis et progressiva 6, erythrokeratodermia variabilis et progressiva 2, erythrokeratodermia variabilis et progressiva 3, erythrokeratodermia variabilis et progressiva 4, erythrokeratodermia variabilis et progressiva 5

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

83 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 18 benign, 15 conflicting classifications of pathogenicity, 6 benign/likely benign, 5 pathogenic, 4 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
6482	NM_024009.3(GJB3):c.34G>C (p.Gly12Arg)	GJB3	Pathogenic	no assertion criteria provided
6483	NM_024009.3(GJB3):c.35G>A (p.Gly12Asp)	GJB3	Pathogenic	criteria provided, single submitter
6484	NM_024009.3(GJB3):c.256T>A (p.Cys86Ser)	GJB3	Pathogenic	no assertion criteria provided
6489	NM_024009.3(GJB3):c.125G>C (p.Arg42Pro)	GJB3	Pathogenic	no assertion criteria provided
6491	NM_024009.3(GJB3):c.101T>C (p.Leu34Pro)	GJB3	Pathogenic	criteria provided, single submitter
1175309	NM_001099287.2(NIPAL4):c.649C>G (p.Pro217Ala)	NIPAL4	Likely pathogenic	no assertion criteria provided
163536	NM_024009.3(GJB3):c.652_663del (p.Leu218_Asp221del)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178351	NM_024009.3(GJB3):c.479G>A (p.Arg160His)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179376	NM_024009.3(GJB3):c.293G>A (p.Arg98His)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289016	NM_024009.3(GJB3):c.499G>A (p.Val167Met)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297191	NM_024009.3(GJB3):c.223C>T (p.Arg75Cys)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
46083	NM_024009.3(GJB3):c.340G>A (p.Ala114Thr)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6485	NM_024009.3(GJB3):c.547G>A (p.Glu183Lys)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6493	NM_024009.3(GJB3):c.580G>A (p.Ala194Thr)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
873945	NM_024009.3(GJB3):c.317G>A (p.Arg106His)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
874892	NM_024009.3(GJB3):c.647G>A (p.Arg216Gln)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875775	NM_024009.3(GJB3):c.-3G>A	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875776	NM_024009.3(GJB3):c.61G>A (p.Gly21Arg)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876774	NM_024009.3(GJB3):c.126C>T (p.Arg42=)	GJB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876777	NM_024009.3(GJB3):c.316C>T (p.Arg106Cys)	GJB3	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
1310993	NM_024009.3(GJB3):c.670C>T (p.Arg224Ter)	GJB3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2580940	NM_024009.3(GJB3):c.371A>G (p.His124Arg)	GJB3	Uncertain significance	criteria provided, single submitter
297180	NM_024009.3(GJB3):c.-399G>A	GJB3	Uncertain significance	criteria provided, single submitter
297181	NM_024009.3(GJB3):c.-398C>G	GJB3	Uncertain significance	criteria provided, single submitter
297182	NM_024009.3(GJB3):c.-383G>A	GJB3	Uncertain significance	criteria provided, single submitter
297183	NM_024009.3(GJB3):c.-307T>C	GJB3	Uncertain significance	criteria provided, single submitter
297184	NM_024009.3(GJB3):c.-231G>A	GJB3	Uncertain significance	criteria provided, single submitter
297185	NM_024009.3(GJB3):c.-177G>A	GJB3	Uncertain significance	criteria provided, single submitter
297186	NM_024009.3(GJB3):c.-159T>C	GJB3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 7 · 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
GJB3	Strong	Autosomal dominant	erythrokeratodermia variabilis et progressiva 1	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJB3	Orphanet:139512	Neuropathy with hearing impairment
GJB3	Orphanet:317	Erythrokeratodermia variabilis
GJB3	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB3	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
NIPAL4	Orphanet:313	Lamellar ichthyosis
NIPAL4	Orphanet:79394	Congenital ichthyosiform erythroderma
GJB4	Orphanet:317	Erythrokeratodermia variabilis

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
GJB3	HGNC:4285	ENSG00000188910	O75712	Gap junction beta-3 protein	gencc,clinvar
NIPAL4	HGNC:28018	ENSG00000172548	Q0D2K0	Magnesium transporter NIPA4	clinvar
GJB4	HGNC:4286	ENSG00000189433	Q9NTQ9	Gap junction beta-4 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJB3	Gap junction beta-3 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
NIPAL4	Magnesium transporter NIPA4	Acts as a Mg(2+) transporter.
GJB4	Gap junction beta-4 protein	Structural component of gap junctions.

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)
GJB3	Other/Unknown	no		Connexin, Connexin31, Connexin_N
NIPAL4	Other/Unknown	no		Mg_trans_NIPA, EmrE-like
GJB4	Other/Unknown	no		Connexin, Connexin-30.3, Connexin_N

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
skin of abdomen	3
skin of leg	3
upper arm skin	2
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJB3	183	broad	marker	skin of abdomen, skin of leg, upper arm skin
NIPAL4	165	broad	marker	upper arm skin, skin of abdomen, skin of leg
GJB4	70	tissue_specific	yes	skin of abdomen, zone of skin, skin of leg

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJB3	782
NIPAL4	540
GJB4	469

Intra-cohort edges

A	B	Sources
GJB3	GJB4	string_interaction
GJB4	NIPAL4	string_interaction

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJB3	O75712	79.29
NIPAL4	Q0D2K0	78.91
GJB4	Q9NTQ9	78.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Gap junction assembly	2	195.2×	1e-04	GJB3, GJB4
Miscellaneous transport and binding events	1	146.4×	0.010	NIPAL4
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	92.8×	0.011	GJB3

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
gap junction-mediated intercellular transport	1	936.2×	0.003	GJB4
olfactory behavior	1	624.1×	0.003	GJB4
cell-cell signaling	2	46.4×	0.003	GJB3, GJB4
magnesium ion transport	1	401.2×	0.004	NIPAL4
placenta development	1	147.8×	0.008	GJB3
sensory perception of smell	1	52.0×	0.019	GJB4

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
GJB3	0	0
NIPAL4	0	0
GJB4	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	GJB3, NIPAL4, GJB4

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)
GJB3	0	—
NIPAL4	0	—
GJB4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.