TMC1 — transmembrane channel like 1

15 sources retrieved · Most recent: April 2026 · Index updated 3 months ago

62PubMed Papers

#7,521 · top 39% of 19K genes

22Diseases

top 6%

0Drugs

174Pathogenic Variants

top 8%

OMIM Disease GeneIon ChannelTransporterVariant-RichExperimental GO EvidenceSwiss-Prot Reviewed

plasma membranecalcium channel activityvoltage-gated calcium channel activitystereociliumautosomal recessive nonsyndromic hearing loss 7autosomal dominant nonsyndromic hearing loss 36deafnessautosomal dominant nonsyndromic hearing loss

AI Summary

TMC1 (transmembrane channel-like 1) encodes a pore-forming subunit of the mechanotransducer (MET) ion channel complex essential for auditory and vestibular sensory transduction. Located at the tips of stereocilia in cochlear and vestibular hair cells, TMC1 directly senses mechanical stimuli and mediates calcium and cation influx 1 2. The protein functions as a mechanically gated ion channel activated by tension in tip-links connecting adjacent stereocilia; recent studies overcame previous technical barriers by demonstrating that membrane-localized TMC1 responds robustly to mechanical stimuli in heterologous cells and exhibits stretch-activated currents 1 3. TMC1 operates within a larger MET complex including auxiliary proteins LHFPL5, TMIE, CIB2/3, TOMT, and PCDH15, and functions redundantly with TMC2 in mechanotransduction 3. Pathogenic TMC1 variants cause nonsyndromic hearing loss, including both autosomal dominant (DFNA36) and recessive (DFNB7) forms, with TMC1 identified as a high-frequency deafness gene in multiple populations 4. Additionally, heterozygous TMC1 variants contribute to age-related hearing loss severity 5, and TMC1 was identified as a promising candidate for gene therapy interventions 6. Recent evidence indicates TMC1 also functions in vestibular mechanotransduction through interactions with mechanosensitive signaling proteins 7.

Sources cited

Human TMC1 and TMC2 are mechanically gated ion channels that respond to poking stimuli with stretch-activated currents and single-channel activity; deafness-related TMC1 mutations alter reversal potential

PMID: 39674179

TMC1 and TMC2 proteins are pore-forming subunits of mechanosensitive ion channels; purified proteins reconstituted in liposomes possess ion channel activity and respond to mechanical pressure

PMID: 31761710

TMC1/2 are mechanically gated ion channels in auditory mechanotransduction; expressed at stereocilia tips; recent in vitro studies confirmed TMC1/2 are mechanically activated ion channels

PMID: 40280017

TMC1 is among the most common deafness genes in a Chinese cohort of deaf children; detected in multiple cases with pathogenic variants

PMID: 36597107

Ultrarare heterozygous TMC1 pathogenic variants underlie severe presbycusis; TMC1:p.(Asn327Ile) variant was established as a mouse model for monogenic presbycusis

PMID: 33229591

TMC1 was identified as a promising candidate gene for hearing loss gene therapy based on favorable evaluation criteria including gene size, cochlear degradation timing, and efficacy in mouse models

PMID: 39951658

TMC1 is a representative molecular target shared between hearing loss and neurodegenerative processes, involved in auditory and neurodegenerative pathways

PMID: 40499729

TMC1 functions in vestibular mechanotransduction; LPHN2 converts force stimuli into increased open probability of TMC1 in utricular hair cells

PMID: 39966628

Disease Associations22

autosomal recessive nonsyndromic hearing loss 7Open Targets

0.77Strong

autosomal dominant nonsyndromic hearing loss 36Open Targets

0.75Strong

deafnessOpen Targets

0.70Moderate

autosomal dominant nonsyndromic hearing lossOpen Targets

0.68Moderate

hearing loss, autosomal recessiveOpen Targets

0.64Moderate

nonsyndromic genetic hearing lossOpen Targets

0.63Moderate

Rare genetic deafnessOpen Targets

0.55Moderate

Hearing impairmentOpen Targets

0.47Moderate

Sensorineural hearing impairmentOpen Targets

0.40Moderate

Non-syndromic genetic deafnessOpen Targets

0.39Weak

hearing lossOpen Targets

0.39Weak

Abnormality of the earOpen Targets

0.34Weak

ear malformationOpen Targets

0.34Weak

Delayed speech and language developmentOpen Targets

0.33Weak

Moderate intellectual disabilityOpen Targets

0.33Weak

MutismOpen Targets

0.30Weak

liver diseaseOpen Targets

0.27Weak

tooth diseaseOpen Targets

0.27Weak

EpiphoraOpen Targets

0.27Weak

sensorineural hearing lossOpen Targets

0.27Weak

Deafness, autosomal dominant, 36UniProt

Deafness, autosomal recessive, 7UniProt

Pathogenic Variants174

NM_138691.3(TMC1):c.1165C>T (p.Arg389Ter)Pathogenic

Rare genetic deafness|not provided|Autosomal recessive nonsyndromic hearing loss 7|Autosomal dominant nonsyndromic hearing loss 36;Autosomal recessive nonsyndromic hearing loss 7

★★☆☆2026→ Residue 389

NM_138691.3(TMC1):c.884+1G>APathogenic

not provided|Autosomal recessive nonsyndromic hearing loss 7

★★☆☆2026

NM_138691.3(TMC1):c.1763+3A>GPathogenic

★★☆☆2026

NM_138691.3(TMC1):c.1166G>A (p.Arg389Gln)Pathogenic

not provided|Nonsyndromic genetic hearing loss|Autosomal recessive nonsyndromic hearing loss 7;Autosomal dominant nonsyndromic hearing loss 36

★★☆☆2025→ Residue 389

NM_138691.3(TMC1):c.1764G>A (p.Trp588Ter)Pathogenic

not provided|Autosomal dominant nonsyndromic hearing loss 36;Autosomal recessive nonsyndromic hearing loss 7|Inborn genetic diseases

★★☆☆2025→ Residue 588

NM_138691.3(TMC1):c.332G>A (p.Trp111Ter)Pathogenic

not provided

★★☆☆2025→ Residue 111

NM_138691.3(TMC1):c.64+2T>APathogenic

Autosomal recessive nonsyndromic hearing loss 7|not provided

★★☆☆2025

NM_138691.3(TMC1):c.1714G>C (p.Asp572His)Pathogenic

Autosomal dominant nonsyndromic hearing loss 36|Monogenic hearing loss|not provided

★★☆☆2025→ Residue 572

NM_138691.3(TMC1):c.674C>T (p.Pro225Leu)Likely pathogenic

Rare genetic deafness|not provided|Autosomal dominant nonsyndromic hearing loss 36;Autosomal recessive nonsyndromic hearing loss 7

★★☆☆2025→ Residue 225

NM_138691.3(TMC1):c.2050G>C (p.Asp684His)Pathogenic

not provided|TMC1-related disorder|Autosomal dominant nonsyndromic hearing loss 36;Autosomal recessive nonsyndromic hearing loss 7|Autosomal recessive nonsyndromic hearing loss 7

★★☆☆2025→ Residue 684

NM_138691.3(TMC1):c.589G>A (p.Gly197Arg)Pathogenic

not provided|Nonsyndromic genetic hearing loss

★★☆☆2025→ Residue 197

NM_138691.3(TMC1):c.1405-2A>TLikely pathogenic

not provided|Autosomal recessive nonsyndromic hearing loss 7;Autosomal dominant nonsyndromic hearing loss 36

★★☆☆2025

NM_138691.3(TMC1):c.1534C>T (p.Arg512Ter)Pathogenic

not provided|Autosomal recessive nonsyndromic hearing loss 7|Autosomal dominant nonsyndromic hearing loss 36;Autosomal recessive nonsyndromic hearing loss 7

★★☆☆2025→ Residue 512

NM_138691.3(TMC1):c.100C>T (p.Arg34Ter)Pathogenic

Autosomal recessive nonsyndromic hearing loss 7|Rare genetic deafness|not provided|Hearing loss, autosomal recessive|Autosomal dominant nonsyndromic hearing loss 36|Autosomal recessive nonsyndromic hearing loss 7;Autosomal dominant nonsyndromic hearing loss 36

★★☆☆2025→ Residue 34

NM_138691.3(TMC1):c.2030T>C (p.Ile677Thr)Pathogenic

not provided|Autosomal dominant nonsyndromic hearing loss 36;Autosomal recessive nonsyndromic hearing loss 7|Autosomal recessive nonsyndromic hearing loss 7

★★☆☆2025→ Residue 677

NM_138691.3(TMC1):c.582G>A (p.Trp194Ter)Pathogenic

not provided

★★☆☆2025→ Residue 194

NM_138691.3(TMC1):c.2130-1delPathogenic

not provided

★★☆☆2025

NM_138691.3(TMC1):c.236+1G>TPathogenic

not provided

★★☆☆2025

NM_138691.3(TMC1):c.1810C>T (p.Arg604Ter)Pathogenic

Hearing loss, autosomal recessive|not provided|Autosomal dominant nonsyndromic hearing loss 36;Autosomal recessive nonsyndromic hearing loss 7

★★☆☆2025→ Residue 604

NM_138691.3(TMC1):c.741+1G>APathogenic

Rare genetic deafness|not provided|Autosomal recessive nonsyndromic hearing loss 7

★★☆☆2025

Tissue Expression6 tissues

Brain

100%

Heart

53%

Ovary

40%

Liver

11%

Lung

Bone Marrow

Gene Interaction Network6 neighbors

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Structure1 PDB hit

Preparing viewer…

PDB8XOQ · 2.41 Å · X-ray

View on RCSB

ConstraintgnomAD v4.1

LOEUFⓘ

0.91LoF Tolerant

pLIⓘ

0.00Tolerant

Observed/Expected LoF0.75 [0.62–0.91]

Rankings3 dim

Where TMC1 stands among ~20K protein-coding genes

#7,517of 20,598
Most Researched62
#427of 5,509
Most Pathogenic Variants174 · top 10%
#8,353of 17,882
Most Constrained (LOEUF)0.91