TMC8
Chr 17ARtransmembrane channel like 8
Also known as: EV2, EVER2, EVIN2
Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin. EV is caused by mutations in either of two adjacent genes located on chromosome 17q25.3. Both of these genes encode integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 8 predicted transmembrane domains and 3 leucine zipper motifs. [provided by RefSeq, Jul 2008]
Primary Disease Associations & Inheritance
{Epidermodysplasia verruciformis, susceptibility to, 2}MIM #618231
AR
Clinical Summary— TMC8
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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
31 Pathogenic / Likely Pathogenic· 205 VUS of 485 total submissions
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.12LOEUF
pLI 0.000
Z-score 1.01
OE 0.81 (0.59–1.12)
Highly tolerant — LoF variants common in population
Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.57Z-score
OE missense 0.92 (0.85–1.00)
380 obs / 412.3 exp
Mild missense constraint
Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.81 (0.59–1.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.85–1.00)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 25 / 31.1Missense obs/exp: 380 / 412.3Syn Z: 0.26
ClinVar Variant Classifications
485 submitted variants in ClinVar
Classification Summary
Pathogenic24
Likely Pathogenic7
VUS205
Likely Benign215
Benign34
24
Pathogenic
7
Likely Pathogenic
205
VUS
215
Likely Benign
34
Benign
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 19 | 0 | 5 | 0 | 24 |
Likely Pathogenic | 7 | 0 | 0 | 0 | 7 |
VUS | 2 | 185 | 16 | 2 | 205 |
Likely Benign | 0 | 3 | 104 | 108 | 215 |
Benign | 0 | 0 | 33 | 1 | 34 |
| Total | 28 | 188 | 158 | 111 | 485 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TMC8 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
Gene2Phenotype Curations
TMC8-related epidermodysplasia verruciformis
definitiveGene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org
OMIM — Genotype-Phenotype Relationships
1 OMIM entry
TRANSMEMBRANE CHANNEL-LIKE PROTEIN 8; TMC8
MIM #605829 · *
Autosomal recessive
External Resources
Links to major genomics databases and tools
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
Monogenic etiologies of persistent human papillomavirus infections: A comprehensive systematic review.
Biglari S et al.·Genet Med
2024Review
Novel TMC8 splice site mutation in epidermodysplasia verruciformis and review of HPV infections in patients with the disease.
Imahorn E et al.·J Eur Acad Dermatol Venereol
2017Case report
Expression of a TMC6-TMC8-CIB1 heterotrimeric complex in lymphocytes is regulated by each of the components.
Wu CJ et al.·J Biol Chem
2020
Contribution of TMC6 and TMC8 (EVER1 and EVER2) variants to cervical cancer susceptibility.
Castro FA et al.·Int J Cancer
2012
A coding variant in TMC8 (EVER2) is associated with high risk HPV infection and head and neck cancer risk.
Liang C et al.·PLoS One
2015
Re-evaluation of epidermodysplasia verruciformis: Reconciling more than 90 years of debate.
Przybyszewska J et al.·J Am Acad Dermatol
2017Review
TMC8 mutation in a Turkish family with epidermodysplasia verruciformis including laryngeal papilloma and recurrent skin carcinoma.
Esenboga S et al.·J Cosmet Dermatol
2022Case report
Whole transcriptome-based skin virome profiling in typical epidermodysplasia verruciformis reveals α-, β-, and γ-HPV infections.
Saeidian AH et al.·JCI Insight
2023
A TMC8 splice variant causes epidermodysplasia verruciformis in a Pakistani family.
Xiong X et al.·Clin Exp Dermatol
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
No evidence for restriction of Beta-HPV8 gene expression by epidermodysplasia verruciformis susceptibility genes CIB1, TMC6, or TMC8 in keratinocytes.
Rehm TM et al.·Tumour Virus Res
2025Open Access
MmuPV1 infection of Tmc6/Ever1 or Tmc8/Ever2 deficient FVB mice as a model of βHPV in typical epidermodysplasia verruciformis.
Wong M et al.·PLoS Pathog
2025Open AccessFunctional
Establishment of a human induced pluripotent stem cell line, KMUGMCi005-A, from a patient with Epidermodysplasia verruciformis (EV) bearing homozygous splicing donor site mutation in the TMC8 gene.
Ura H et al.·Stem Cell Res
2022
Risk of penile tumor development in Caucasian individuals is independent of the coding variant rs7208422 in the TMC8 (EVER2) gene.
Stoehr R et al.·Mol Clin Oncol
2021
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
Case of epidermodysplasia verruciformis with a novel mutation of TMC8.
Ushida M et al.·J Dermatol
2021
Epidermodysplasia verruciformis with squamous cell carcinomas and the identification of a novel TMC8 mutation.
Kuriyama Y et al.·J Dermatol
2023
Comprehensive co-expression analysis reveals TMC8 as a prognostic immune-associated gene in head and neck squamous cancer
Lin B et al.·Oncol Lett
2021
Construction of a risk model associated with tryptophan metabolism and identification of related molecular subtypes in laryngeal squamous cell carcinoma
Liu F et al.·Front Genet
2025Functional
Pan-Cancer Analysis Reveals the Signature of TMC Family of Genes as a Promising Biomarker for Prognosis and Immunotherapeutic Response
Song J et al.·Front Immunol
2021
Identification and Splicing Characterization of Novel TMC6 and TMC8 Variants Associated With Epidermodysplasia Verruciformis in Three Chinese Families
Wang R et al.·Front Genet
2021
General Features and Novel Gene Signatures That Identify Epstein-Barr Virus-Associated Epithelial Cancers
Heawchaiyaphum C et al.·Cancers (Basel)
2021
Top 7 full-text resultsSearch PubTator3 ↗
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools