Erythrokeratodermia variabilis et progressiva 6

Summary

Erythrokeratodermia variabilis et progressiva 6 (MONDO:0032801) is a disease caused by TRPM4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TRPM4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 93

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	erythrokeratodermia variabilis et progressiva 6
Mondo ID	MONDO:0032801
OMIM	618531
DOID	DOID:0080766
UMLS	C5193144
MedGen	1681026
GARD	0018672
Is cancer (heuristic)	no

Also known as: EKVP6

Data availability: 93 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 6

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

93 retrieved; paginated sample, class counts are floors:

71 uncertain significance, 10 conflicting classifications of pathogenicity, 5 likely benign, 4 benign, 1 pathogenic/likely pathogenic, 1 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
652587	NM_017636.4(TRPM4):c.3119T>C (p.Ile1040Thr)	TRPM4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
652588	NM_017636.4(TRPM4):c.3099C>G (p.Ile1033Met)	TRPM4	Pathogenic	no assertion criteria provided
1024940	NM_017636.4(TRPM4):c.735C>T (p.Gly245=)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038721	NM_017636.4(TRPM4):c.754C>T (p.Arg252Cys)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1462550	NM_017636.4(TRPM4):c.1885G>A (p.Glu629Lys)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1467291	NM_017636.4(TRPM4):c.2733G>A (p.Thr911=)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
241177	NM_017636.4(TRPM4):c.2740A>T (p.Lys914Ter)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
450673	NM_017636.4(TRPM4):c.635G>A (p.Arg212Gln)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
663529	NM_017636.4(TRPM4):c.634C>T (p.Arg212Trp)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
726551	NM_017636.4(TRPM4):c.3329-8C>G	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
894244	NM_017636.4(TRPM4):c.1466C>T (p.Pro489Leu)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
945762	NM_017636.4(TRPM4):c.338G>A (p.Arg113His)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014313	NM_017636.4(TRPM4):c.2894G>A (p.Arg965His)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1019328	NM_017636.4(TRPM4):c.2932A>G (p.Ile978Val)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1047141	NM_017636.4(TRPM4):c.3062T>A (p.Val1021Glu)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1054189	NM_017636.4(TRPM4):c.1261C>T (p.Arg421Trp)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1059247	NM_017636.4(TRPM4):c.2915T>A (p.Leu972Gln)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1061455	NM_017636.4(TRPM4):c.2778+1G>A	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1061618	NM_017636.4(TRPM4):c.650C>T (p.Pro217Leu)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1316165	NM_017636.4(TRPM4):c.1603G>T (p.Glu535Ter)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1316349	NM_017636.4(TRPM4):c.2738A>G (p.Asn913Ser)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1317234	NM_017636.4(TRPM4):c.994C>T (p.Arg332Ter)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1320916	NM_017636.4(TRPM4):c.1212C>A (p.Asn404Lys)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1321648	NM_017636.4(TRPM4):c.749G>A (p.Arg250His)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1328064	NM_017636.4(TRPM4):c.2992G>A (p.Gly998Ser)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1346243	NM_017636.4(TRPM4):c.865G>A (p.Glu289Lys)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1370326	NM_017636.4(TRPM4):c.858G>A (p.Thr286=)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1372874	NM_017636.4(TRPM4):c.1263+2T>G	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1379870	NM_017636.4(TRPM4):c.845AGA[1] (p.Lys283del)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1407010	NM_017636.4(TRPM4):c.3339_3342del (p.Ser1114fs)	TRPM4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
TRPM4	Strong	Autosomal dominant	erythrokeratodermia variabilis et progressiva 6	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPM4	Orphanet:130	Brugada syndrome
TRPM4	Orphanet:316	Progressive symmetric erythrokeratodermia
TRPM4	Orphanet:871	Hereditary progressive cardiac conduction defect

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
TRPM4	HGNC:17993	ENSG00000130529	Q8TD43	Transient receptor potential cation channel subfamily M member 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRPM4	Transient receptor potential cation channel subfamily M member 4	Calcium-activated selective cation channel that mediates membrane depolarization.

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRPM4	Ion channel	yes		Ion_trans_dom, TRPM_SLOG, TRPM

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
apex of heart	1
mucosa of transverse colon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPM4	201	ubiquitous	marker	mucosa of transverse colon, rectum, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRPM4	1,217

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRPM4	Q8TD43	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
TRP channels	1	407.9×	0.004	TRPM4
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	278.5×	0.004	TRPM4

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
positive regulation of atrial cardiac muscle cell action potential	1	16852.0×	9e-04	TRPM4
positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization	1	16852.0×	9e-04	TRPM4
membrane depolarization during Purkinje myocyte cell action potential	1	5617.3×	0.001	TRPM4
membrane depolarization during bundle of His cell action potential	1	5617.3×	0.001	TRPM4
regulation of T cell cytokine production	1	4213.0×	0.001	TRPM4
membrane depolarization during AV node cell action potential	1	3370.4×	0.001	TRPM4
metal ion transport	1	1872.4×	0.002	TRPM4
regulation of ventricular cardiac muscle cell action potential	1	1404.3×	0.003	TRPM4
positive regulation of adipose tissue development	1	1053.2×	0.003	TRPM4
dendritic cell chemotaxis	1	991.3×	0.003	TRPM4
negative regulation of bone mineralization	1	936.2×	0.003	TRPM4
obsolete inorganic cation transmembrane transport	1	936.2×	0.003	TRPM4
cellular response to ATP	1	887.0×	0.003	TRPM4
positive regulation of heart rate	1	702.2×	0.003	TRPM4
monoatomic cation transmembrane transport	1	624.1×	0.003	TRPM4
sodium ion import across plasma membrane	1	624.1×	0.003	TRPM4
positive regulation of vasoconstriction	1	601.9×	0.003	TRPM4
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	374.5×	0.004	TRPM4
regulation of heart rate by cardiac conduction	1	374.5×	0.004	TRPM4
protein sumoylation	1	324.1×	0.004	TRPM4
positive regulation of fat cell differentiation	1	300.9×	0.004	TRPM4
negative regulation of osteoblast differentiation	1	295.6×	0.004	TRPM4
protein homotetramerization	1	237.3×	0.005	TRPM4
calcium ion transmembrane transport	1	210.7×	0.006	TRPM4
calcium-mediated signaling	1	183.2×	0.006	TRPM4
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.007	TRPM4
positive regulation of cytosolic calcium ion concentration	1	117.0×	0.009	TRPM4
adaptive immune response	1	84.3×	0.012	TRPM4
positive regulation of cell population proliferation	1	33.6×	0.030	TRPM4

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPM4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TRPM4	14	Binding:13, Functional:1

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	1	TRPM4
D	Druggable family + AlphaFold only, no drug	0
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)
TRPM4	14	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.