Erythrokeratodermia variabilis et progressiva 3

Summary

Erythrokeratodermia variabilis et progressiva 3 (MONDO:0033013) is a disease caused by GJA1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GJA1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	erythrokeratodermia variabilis et progressiva 3
Mondo ID	MONDO:0033013
OMIM	617525
DOID	DOID:0080249
UMLS	C4479619
MedGen	1380593
GARD	0018589
Is cancer (heuristic)	no

Also known as: EKVP3

Data availability: 10 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 3

Related subtypes (7): transgrediens et progrediens palmoplantar keratoderma, erythrokeratodermia variabilis et progressiva 7, erythrokeratodermia variabilis et progressiva 6, erythrokeratodermia variabilis et progressiva 1, erythrokeratodermia variabilis et progressiva 2, 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

10 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
203469	NM_000165.5(GJA1):c.131C>T (p.Ala44Val)	GJA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
435323	NM_000165.5(GJA1):c.119C>T (p.Ala40Val)	GJA1	Pathogenic	criteria provided, multiple submitters, no conflicts
16991	NM_000165.5(GJA1):c.1127G>A (p.Arg376Gln)	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1050474	NM_000165.5(GJA1):c.932del (p.Ala311fs)	GJA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1206770	NM_000165.5(GJA1):c.1039C>A (p.Leu347Ile)	GJA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
203468	NM_000165.5(GJA1):c.681A>T (p.Glu227Asp)	GJA1	Uncertain significance	criteria provided, single submitter
2185470	NM_000165.5(GJA1):c.826G>A (p.Ala276Thr)	GJA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3592998	NM_000165.5(GJA1):c.305A>T (p.Lys102Met)	GJA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779697	NM_000165.5(GJA1):c.137G>C (p.Gly46Ala)	GJA1	Uncertain significance	criteria provided, single submitter
4796597	NM_000165.5(GJA1):c.488C>G (p.Ser163Cys)	GJA1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · 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
GJA1	Strong	Autosomal dominant	erythrokeratodermia variabilis et progressiva 3	25

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJA1	Orphanet:1010	Autosomal dominant palmoplantar keratoderma and congenital alopecia
GJA1	Orphanet:1522	Craniometaphyseal dysplasia
GJA1	Orphanet:2248	Hypoplastic left heart syndrome
GJA1	Orphanet:2710	Oculodentodigital dysplasia
GJA1	Orphanet:317	Erythrokeratodermia variabilis
GJA1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJA1	Orphanet:93404	Syndactyly type 3

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
GJA1	HGNC:4274	ENSG00000152661	P17302	Gap junction alpha-1 protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJA1	Gap junction alpha-1 protein	Structural component of the gap junction, a specialized intercellular structure consisting of a cluster of closely packed pairs of transmembrane channels, the connexons, that allow passage of small molecules and electrical signals between…

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)
GJA1	Other/Unknown	no		Connexin, Connexin43, Connexin_N

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
dorsal motor nucleus of vagus nerve	1
hair follicle	1
lateral globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJA1	292	ubiquitous	marker	lateral globus pallidus, dorsal motor nucleus of vagus nerve, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJA1	4,942

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJA1	P17302	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Oligomerization of connexins into connexons	1	3806.7×	1e-03	GJA1
Transport of connexins along the secretory pathway	1	3806.7×	1e-03	GJA1
Regulation of gap junction activity	1	3806.7×	1e-03	GJA1
SARS-CoV-2 targets PDZ proteins in cell-cell junction	1	2284.0×	0.001	GJA1
Formation of annular gap junctions	1	1038.2×	0.002	GJA1
Gap junction degradation	1	951.7×	0.002	GJA1
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	671.8×	0.002	GJA1
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	543.8×	0.003	GJA1
Gap junction assembly	1	292.8×	0.004	GJA1
RHOJ GTPase cycle	1	200.3×	0.005	GJA1
RHOQ GTPase cycle	1	181.3×	0.006	GJA1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
microtubule-based transport	1	16852.0×	9e-04	GJA1
positive regulation of mesodermal cell differentiation	1	16852.0×	9e-04	GJA1
negative regulation of gonadotropin secretion	1	8426.0×	0.001	GJA1
positive regulation of morphogenesis of an epithelium	1	5617.3×	0.001	GJA1
cell communication by electrical coupling	1	4213.0×	0.001	GJA1
negative regulation of trophoblast cell migration	1	2407.4×	0.002	GJA1
gap junction assembly	1	2106.5×	0.002	GJA1
glutamate secretion	1	1685.2×	0.002	GJA1
atrial cardiac muscle cell action potential	1	1685.2×	0.002	GJA1
export across plasma membrane	1	1685.2×	0.002	GJA1
cell communication by electrical coupling involved in cardiac conduction	1	1404.3×	0.002	GJA1
cardiac conduction system development	1	1053.2×	0.002	GJA1
bone remodeling	1	936.2×	0.002	GJA1
xenobiotic transport	1	842.6×	0.003	GJA1
positive regulation of stem cell proliferation	1	526.6×	0.004	GJA1
establishment of mitotic spindle orientation	1	481.5×	0.004	GJA1
maintenance of blood-brain barrier	1	481.5×	0.004	GJA1
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.004	GJA1
cellular response to amyloid-beta	1	391.9×	0.004	GJA1
bone development	1	276.3×	0.005	GJA1
monoatomic ion transmembrane transport	1	208.1×	0.007	GJA1
positive regulation of cold-induced thermogenesis	1	163.6×	0.008	GJA1
negative regulation of cell growth	1	144.0×	0.009	GJA1
intracellular protein localization	1	104.7×	0.012	GJA1
heart development	1	78.8×	0.015	GJA1
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.016	GJA1
cell-cell signaling	1	69.6×	0.016	GJA1
positive regulation of gene expression	1	38.7×	0.028	GJA1
spermatogenesis	1	35.2×	0.029	GJA1
signal transduction	1	16.1×	0.062	GJA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GJA1	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJA1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GJA1	4	Binding:4

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

1 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)
KANAMYCIN	4	GJA1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJA1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.