TMC1

Chr 9ADAR

transmembrane channel like 1

Also known as: DFNA36, DFNB11, DFNB7

NCBI Gene: 117531ENSG00000165091UniProt: Q8TDI8OMIM: 606706

TMC1 encodes a pore-forming subunit of the mechanotransducer channel complex located at stereocilia tips in cochlear hair cells, where it mediates auditory sensory transduction by responding to mechanical tension and transporting calcium and monovalent cations. Mutations cause both progressive postlingual hearing loss and profound prelingual deafness with autosomal recessive inheritance. The gene is extremely intolerant to loss-of-function variants (pLI approaching 1), indicating that complete protein loss is likely incompatible with normal development.

GeneReviewsOMIMResearchSummary from RefSeq, UniProt
MultiplemechanismAD/ARLOEUF 0.972 OMIM phenotypes
Clinical Summary— TMC1
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Gene-Disease Validity (ClinGen)
nonsyndromic genetic hearing loss · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
Explore recent and relevant literature in Research Assistant →
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GeneReview available — TMC1
Authoritative clinical overview · Recommended first read
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.97LOEUF
pLI 0.000
Z-score 1.69
OE 0.74 (0.56–0.97)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.86Z-score
OE missense 0.88 (0.81–0.96)
350 obs / 398.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.74 (0.56–0.97)
0≤0.351.4
Missense OE0.88 (0.81–0.96)
0≤0.61.4
Synonymous OE1.03
0≤1.21.6
LoF obs/exp: 35 / 47.6Missense obs/exp: 350 / 398.2Syn Z: -0.26
DN
0.7326th %ile
GOF
0.81top 10%
LOF
0.2679th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFTwo different missense mutations, p.D572N and p.D572H, affecting the same nucleotide and codon of the TMC1 gene were earlier reported to cause autosomal dominant hearing impairment at locus DFNA36 in two North American families.PMID:19180119

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

TMC1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Tmc Reliance Is Biased by the Hair Cell Subtype and Position Within the Ear
Zhu S et al.·Front Cell Dev Biol
2021
Genetic correction of induced pluripotent stem cells from a DFNA36 patient results in morphologic and functional recovery of derived hair cell-like cells
Luo Y et al.·Stem Cell Res Ther
2024Functional
The cytosolic N-terminal region of heterologously-expressed transmembrane channel-like protein 1 (TMC1) can be cleaved in HEK293 cells
Yamaguchi S et al.·PLoS One
2023
Clinical and Genetic Characteristics of Finnish Patients with Autosomal Recessive and Dominant Non-Syndromic Hearing Loss Due to Pathogenic TMC1 Variants
Kraatari-Tiri M et al.·J Clin Med
2022Cohort
Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing
Ballesteros A et al.·Sci Adv
2022
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Identification and characterization of a novel p. S390C variant in TMC1 in an autosomal recessive family with non-syndromic hearing loss.
Dong H et al.·Acta Otolaryngol
2026
Dual Genetic Diagnosis of Prader-Willi Syndrome and TMC1-Related Severe Congenital Hearing Loss: Diagnostic Challenges and Cochlear Implant Outcomes.
Samara P et al.·Diagnostics (Basel)
2026Open Access
Altered Pore Composition and Flexibility in a Deafness-Associated TMC1 Variant: Insights from Molecular Dynamics Simulations.
Zamboni D et al.·ACS Chem Neurosci
2025Open Access
Identification of druggable binding sites and small molecules as modulators of TMC1.
De-la-Torre P et al.·Commun Biol
2025Open Access
TMC1 and TMC2 function as the mechano-electrical transduction ion channel in hearing.
Deng S et al.·Curr Opin Neurobiol
2025
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients