Epidermodysplasia verruciformis, susceptibility to, 1

Summary

Epidermodysplasia verruciformis, susceptibility to, 1 (MONDO:0100045) is a disease caused by TMC6 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: TMC6 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermodysplasia verruciformis, susceptibility to, 1
Mondo ID	MONDO:0100045
OMIM	226400
UMLS	C4722564
MedGen	1648341
Is cancer (heuristic)	no

Also known as: epidermodysplasia verruciformis 1 · EV1

Data availability: 31 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › epidermodysplasia verruciformis, susceptibility to › epidermodysplasia verruciformis, susceptibility to, 1

Related subtypes (4): epidermodysplasia verruciformis, susceptibility to, 2, epidermodysplasia verruciformis, susceptibility to, 3, epidermodysplasia verruciformis, susceptibility to, 4, epidermodysplasia verruciformis, susceptibility to, 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

31 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 6 conflicting classifications of pathogenicity, 5 pathogenic, 2 likely benign, 1 likely pathogenic, 1 benign/likely benign, 1 risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
4748	NM_001127198.5(TMC6):c.280C>T (p.Arg94Ter)	TMC6	Pathogenic	criteria provided, multiple submitters, no conflicts
4750	NM_001127198.5(TMC6):c.744C>A (p.Tyr248Ter)	TMC6	Pathogenic	criteria provided, single submitter
4751	NM_001127198.5(TMC6):c.892-2A>T	TMC6	Pathogenic	criteria provided, single submitter
582588	NM_001127198.5(TMC6):c.748_1082+56del	TMC6	Pathogenic	criteria provided, single submitter
456001	NC_000017.11:g.(?78137697)(78137834_?)del	TMC8	Pathogenic	criteria provided, single submitter
3583084	NM_001127198.5(TMC6):c.634-3_654del	TMC6	Likely pathogenic	criteria provided, single submitter
4749	NM_001127198.5(TMC6):c.1726G>T (p.Glu576Ter)	TMC6	risk factor	no assertion criteria provided
526236	NM_001127198.5(TMC6):c.1214G>A (p.Arg405His)	LOC130061785	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626187	NM_001127198.5(TMC6):c.633+8C>T	LOC130061786	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
790929	NM_001127198.5(TMC6):c.2384C>T (p.Pro795Leu)	TMC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
456021	NM_152468.5(TMC8):c.1168G>A (p.Val390Ile)	TMC8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
456026	NM_152468.5(TMC8):c.1982C>T (p.Pro661Leu)	TMC8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
526232	NM_152468.5(TMC8):c.1364G>A (p.Arg455Gln)	TMC8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626188	NM_152468.5(TMC8):c.149+4G>T	LOC130061792	Uncertain significance	criteria provided, multiple submitters, no conflicts
626189	NM_152468.5(TMC8):c.1525A>G (p.Ile509Val)	LOC130061795	Uncertain significance	criteria provided, multiple submitters, no conflicts
1005756	NM_001127198.5(TMC6):c.1175C>T (p.Thr392Met)	TMC6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1383285	NM_001127198.5(TMC6):c.1097T>G (p.Phe366Cys)	TMC6	Uncertain significance	criteria provided, multiple submitters, no conflicts
565521	NM_001127198.5(TMC6):c.73T>C (p.Tyr25His)	TMC6	Uncertain significance	criteria provided, multiple submitters, no conflicts
626186	NM_001127198.5(TMC6):c.2354G>C (p.Arg785Thr)	TMC6	Uncertain significance	criteria provided, multiple submitters, no conflicts
654892	NM_001127198.5(TMC6):c.1729A>G (p.Lys577Glu)	TMC6	Uncertain significance	criteria provided, single submitter
656239	NM_001127198.5(TMC6):c.1972T>G (p.Phe658Val)	TMC6	Uncertain significance	criteria provided, single submitter
659827	NM_001127198.5(TMC6):c.2407del (p.Gln803fs)	TMC6	Uncertain significance	criteria provided, single submitter
640919	NM_152468.5(TMC8):c.2161C>G (p.Pro721Ala)	TMC8	Uncertain significance	criteria provided, single submitter
651801	NM_152468.5(TMC8):c.1206C>G (p.Asp402Glu)	TMC8	Uncertain significance	criteria provided, single submitter
651874	NM_152468.5(TMC8):c.1065C>G (p.Phe355Leu)	TMC8	Uncertain significance	criteria provided, single submitter
656770	NM_152468.5(TMC8):c.1665-8C>G	TMC8	Uncertain significance	criteria provided, single submitter
827990	NM_152468.5(TMC8):c.2120G>A (p.Gly707Glu)	TMC8	Uncertain significance	criteria provided, single submitter
992546	NM_152468.5(TMC8):c.1325C>T (p.Ala442Val)	TMC8	Uncertain significance	criteria provided, single submitter
1596866	NM_001127198.5(TMC6):c.536+14del	TMC6	Likely benign	criteria provided, multiple submitters, no conflicts
456016	NM_001127198.5(TMC6):c.704A>G (p.Lys235Arg)	TMC6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
TMC6	Definitive	Autosomal recessive	epidermodysplasia verruciformis, susceptibility to, 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMC6	Orphanet:302	Inherited epidermodysplasia verruciformis
TMC8	Orphanet:302	Inherited epidermodysplasia verruciformis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMC6	HGNC:18021	ENSG00000141524	Q7Z403	Transmembrane channel-like protein 6	gencc,clinvar
TMC8	HGNC:20474	ENSG00000167895	Q8IU68	Transmembrane channel-like protein 8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMC6	Transmembrane channel-like protein 6	Acts as a regulatory protein involved in the regulation of numerous cellular processes.
TMC8	Transmembrane channel-like protein 8	Acts as a regulatory protein involved in the regulation of numerous cellular processes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMC6	Other/Unknown	no		TMC_dom, TMC
TMC8	Other/Unknown	no		TMC_dom, TMC

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
C1 segment of cervical spinal cord	1
lymph node	1
spleen	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMC6	274	ubiquitous	marker	granulocyte, C1 segment of cervical spinal cord, lymph node
TMC8	209	broad	marker	granulocyte, spleen, vermiform appendix

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMC6	2,052
TMC8	1,271

Intra-cohort edges

A	B	Sources
TMC6	TMC8	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMC8	Q8IU68	76.77
TMC6	Q7Z403	72.56

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Neutrophil degranulation	1	23.1×	0.043	TMC6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intracellular zinc ion homeostasis	2	481.5×	3e-05	TMC6, TMC8
protein stabilization	2	66.9×	9e-04	TMC6, TMC8
regulation of extrinsic apoptotic signaling pathway via death domain receptors	1	1203.7×	0.002	TMC8
regulation of tumor necrosis factor-mediated signaling pathway	1	351.1×	0.005	TMC8
negative regulation of protein binding	1	312.1×	0.005	TMC8
negative regulation of protein-containing complex assembly	1	227.7×	0.006	TMC8
negative regulation of canonical NF-kappaB signal transduction	1	86.0×	0.013	TMC8
positive regulation of apoptotic process	1	28.4×	0.035	TMC8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
TMC6	0	0
TMC8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	TMC6, TMC8

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TMC6	0	—
TMC8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.