TMC4

Summary

TMC4 (transmembrane channel like 4, HGNC:22998) is a protein-coding gene on chromosome 19q13.42, encoding Voltage-gated chloride channel TMC4 (Q7Z404). Voltage-gated chloride channel involved in high-concentration salt taste sensation.

Enables voltage-gated chloride channel activity. Predicted to be involved in sensory perception of salty taste. Located in extracellular exosome.

Source: NCBI Gene 147798 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 137 total
• MANE Select transcript: NM_144686

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22998
Approved symbol	TMC4
Name	transmembrane channel like 4
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000167608
Ensembl biotype	protein_coding
OMIM	617181
Entrez	147798

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 19 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000446291, ENST00000476013, ENST00000495398, ENST00000497518, ENST00000611183, ENST00000613492, ENST00000613723, ENST00000615945, ENST00000617472, ENST00000619895, ENST00000883973, ENST00000883974, ENST00000883975, ENST00000883976, ENST00000883977, ENST00000883978, ENST00000883979, ENST00000883980, ENST00000883981, ENST00000883982, ENST00000883983, ENST00000927552, ENST00000927553, ENST00000927554, ENST00000957112, ENST00000957113

RefSeq mRNA: 2 — MANE Select: NM_144686 NM_001145303, NM_144686

CCDS: CCDS12882, CCDS46174

Canonical transcript exons

ENST00000612564 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.74.

FANTOM5 (CAGE): breadth broad, TPM avg 5.3131 / max 168.7729, expressed in 431 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182596	4.9070	426
182597	0.2295	148
182595	0.1766	121

Top tissues by expression

134 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.74	gold quality
mucosa of transverse colon	UBERON:0004991	98.22	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.11	gold quality
duodenum	UBERON:0002114	97.27	gold quality
body of pancreas	UBERON:0001150	96.61	gold quality
left lobe of thyroid gland	UBERON:0001120	96.30	gold quality
thyroid gland	UBERON:0002046	96.12	gold quality
metanephros cortex	UBERON:0010533	96.06	gold quality
right lobe of thyroid gland	UBERON:0001119	95.77	gold quality
pituitary gland	UBERON:0000007	94.92	gold quality
rectum	UBERON:0001052	94.74	gold quality
saliva-secreting gland	UBERON:0001044	94.69	gold quality
minor salivary gland	UBERON:0001830	94.52	gold quality
gall bladder	UBERON:0002110	94.48	gold quality
adenohypophysis	UBERON:0002196	94.16	gold quality
prostate gland	UBERON:0002367	93.92	gold quality
adult mammalian kidney	UBERON:0000082	93.76	gold quality
lower esophagus mucosa	UBERON:0035834	92.96	gold quality
pancreas	UBERON:0001264	92.72	gold quality
transverse colon	UBERON:0001157	92.12	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.65	gold quality
small intestine	UBERON:0002108	91.59	gold quality
kidney	UBERON:0002113	91.44	gold quality
cortex of kidney	UBERON:0001225	91.16	gold quality
fallopian tube	UBERON:0003889	91.02	gold quality
body of stomach	UBERON:0001161	90.97	gold quality
stomach	UBERON:0000945	90.23	gold quality
upper lobe of left lung	UBERON:0008952	89.58	gold quality
esophagus mucosa	UBERON:0002469	88.09	gold quality
lung	UBERON:0002048	87.97	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.98
E-GEOD-99795	no	29.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting TMC4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-6808-3P	94.13	65.24	516
HSA-MIR-11400	94.03	67.12	81

Literature-anchored findings (GeneRIF, showing 2)

• Report no association between the TMC4 rs641738 variant and the development and severity of NAFLD in individuals of European descent. (PMID:26850495)
• This study explored the role of rs641738 C/T located in TMC4 exon 1 (p.Gly17Glu) and 500 bases- downstream of MBOAT7 gene (TMC4/MBOAT7), in the genetic risk for developing nonalcoholic fatty liver disease (NAFLD). No evidence was found of association between rs641738 and either NAFLD (Cochran-Armitage test for trend, p = 0.529) or the disease severity (p = 0.61). (PMID:29572551)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmc4	ENSDARG00000031757
mus_musculus	Tmc4	ENSMUSG00000019734
rattus_norvegicus	Tmc4	ENSRNOG00000059741
caenorhabditis_elegans		WBGENE00015177
caenorhabditis_elegans		WBGENE00020490

Paralogs (7): TMC5 (ENSG00000103534), TMC6 (ENSG00000141524), TMC2 (ENSG00000149488), TMC1 (ENSG00000165091), TMC8 (ENSG00000167895), TMC7 (ENSG00000170537), TMC3 (ENSG00000188869)

Protein

Protein identifiers

Voltage-gated chloride channel TMC4 — Q7Z404 (reviewed: Q7Z404)

Alternative names: Transmembrane channel-like protein 4

All UniProt accessions (4): A0A087WT65, A0A087WVI4, A0A087WXY6, C9JFU4

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-gated chloride channel involved in high-concentration salt taste sensation. Depolarization induced by high NaCl concentration may trigger the activation of TMC4-mediated chloride influx into taste bud cells, helping the return to resting potential. Also allows permeation of organic anions including gluconate, but their current amplitudes at positive potentials are less than that of chloride. Involved in pH and temperature-dependent modulation of salty taste.

Subcellular location. Membrane.

Similarity. Belongs to the TMC family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q7Z404-2	1	yes
Q7Z404-1	2
Q7Z404-3	3

RefSeq proteins (2): NP_001138775, NP_653287* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012496	TMC_dom	Domain
IPR038900	TMC	Family

Pfam: PF07810

Catalyzed reactions (Rhea), 1 shown:

• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (31 total): topological domain 10, transmembrane region 9, sequence conflict 4, splice variant 3, sequence variant 2, chain 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z404-F1	79.05	0.39

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (1): 107

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 88 (showing top): GOBP_INORGANIC_ANION_TRANSPORT, GOBP_CHLORIDE_TRANSPORT, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, IK3_01, GOBP_TRANSMEMBRANE_TRANSPORT, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, GOMF_VOLTAGE_GATED_MONOATOMIC_ANION_CHANNEL_ACTIVITY, GOMF_GATED_CHANNEL_ACTIVITY, GOMF_PASSIVE_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_MONOATOMIC_ANION_CHANNEL_ACTIVITY, GOMF_VOLTAGE_GATED_CHLORIDE_CHANNEL_ACTIVITY, GOMF_MONOATOMIC_ANION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, DODD_NASOPHARYNGEAL_CARCINOMA_DN

GO Biological Process (0):

GO Molecular Function (2): voltage-gated chloride channel activity (GO:0005247), mechanosensitive monoatomic ion channel activity (GO:0008381)

GO Cellular Component (3): plasma membrane (GO:0005886), extracellular exosome (GO:0070062), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chloride channel activity	1
voltage-gated monoatomic anion channel activity	1
monoatomic ion channel activity	1
gated channel activity	1
membrane	1
cell periphery	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

548 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMC4	MBOAT7	Q96N66	815
TMC4	TM6SF2	Q9BZW4	728
TMC4	PNPLA3	Q9NST1	696
TMC4	HSD17B13	Q7Z5P4	642
TMC4	MAP6D1	Q9H9H5	474
TMC4	PAXBP1	Q9Y5B6	461
TMC4	COMTD1	Q86VU5	460
TMC4	DISP2	A7MBM2	453
TMC4	DUS2	Q9NX74	452
TMC4	LPCAT4	Q643R3	444
TMC4	COPRS	Q9NQ92	442
TMC4	CAMK1G	Q96NX5	421
TMC4	HEATR4	Q86WZ0	415
TMC4	PODXL2	Q9NZ53	412
TMC4	MDN1	Q9NU22	411

IntAct

6 interactions, top by confidence:

A	B	Type	Score
TMC4	MARCHF6	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
LDLRAD1	ZNF316	psi-mi:“MI:0914”(association)	0.350
LYPD3	NEMP1	psi-mi:“MI:0914”(association)	0.350
FLT1	MTCL2	psi-mi:“MI:0914”(association)	0.350

BioGRID (31): TMC4 (Protein-RNA), TUSC5 (Two-hybrid), MS4A13 (Two-hybrid), ANO6 (Affinity Capture-MS), TPCN1 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), ANO5 (Affinity Capture-MS), RBMXL1 (Affinity Capture-MS), SLC12A4 (Affinity Capture-MS), TMEM179B (Affinity Capture-MS), FZD2 (Affinity Capture-MS), PKD2 (Affinity Capture-MS), SLC12A6 (Affinity Capture-MS), NDRG3 (Affinity Capture-MS), MARCH6 (Affinity Capture-MS)

ESM2 similar proteins: A1L504, A2A6C4, A5D7M7, A6NH21, A8WCG0, B0BNG2, D3ZI76, E9PY61, J3QMI4, O15554, O75908, O77759, O89109, P0C8N6, P51811, Q14DK4, Q1HG43, Q3TD49, Q496Z4, Q49LS0, Q49LS1, Q49LS5, Q49LS8, Q5GH56, Q5GH64, Q5GH72, Q5PQL3, Q5T1A1, Q5XK03, Q60850, Q6PRD1, Q7RTS5, Q7RTS6, Q7TN58, Q7TN60, Q7TQ65, Q7Z403, Q7Z404, Q80SX5, Q80UF9

Diamond homologs: A0A0U1QT59, E7FFT2, F1QFU0, F1QZE9, Q32NZ6, Q496Z4, Q4R7U0, Q5M7W4, Q6UXY8, Q7TN58, Q7TQ65, Q7Z402, Q7Z404, Q8C428, Q8IU68, Q8R4P4, Q8R4P5, Q8TDI7, Q8TDI8, Q11069, Q5YCC5, D3KZG3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

137 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	97
Likely benign	12
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2233 predictions. Top by Δscore:

Variant	Effect	Δscore
19:54160462:CTCA:C	donor_loss	1.0000
19:54160463:TCA:T	donor_loss	1.0000
19:54160464:CA:C	donor_loss	1.0000
19:54160465:ACCG:A	donor_loss	1.0000
19:54160466:CCGT:C	donor_gain	1.0000
19:54162671:A:AC	donor_gain	1.0000
19:54162672:C:CC	donor_gain	1.0000
19:54162672:CTTT:C	donor_gain	1.0000
19:54163029:TCACC:T	donor_loss	1.0000
19:54163030:CA:C	donor_loss	1.0000
19:54163031:A:AC	donor_gain	1.0000
19:54163032:C:CC	donor_gain	1.0000
19:54163155:CGGTC:C	acceptor_gain	1.0000
19:54163156:GGTCC:G	acceptor_loss	1.0000
19:54163160:C:CC	acceptor_gain	1.0000
19:54164403:C:CA	donor_gain	1.0000
19:54164411:T:TA	donor_gain	1.0000
19:54165415:GCAC:G	donor_loss	1.0000
19:54165418:CCT:C	donor_loss	1.0000
19:54165562:CCGAG:C	acceptor_gain	1.0000
19:54165563:CGAGC:C	acceptor_gain	1.0000
19:54165564:GAG:G	acceptor_gain	1.0000
19:54165565:AG:A	acceptor_gain	1.0000
19:54165567:C:CC	acceptor_gain	1.0000
19:54165567:CTG:C	acceptor_loss	1.0000
19:54165568:T:A	acceptor_loss	1.0000
19:54169518:T:TA	donor_gain	1.0000
19:54169536:C:CA	donor_gain	1.0000
19:54169562:T:TA	donor_gain	1.0000
19:54169563:C:A	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000096184 (19:54170655 A>T), RS1000142983 (19:54161482 G>A), RS1000249856 (19:54167297 C>T), RS1000292410 (19:54173303 G>A,C,T), RS1000309888 (19:54172812 C>T), RS1000341988 (19:54172523 G>A), RS1000697066 (19:54171536 G>A), RS1001083684 (19:54173468 C>A), RS1001191748 (19:54167776 T>C), RS1001246921 (19:54161542 T>G), RS1001306327 (19:54173653 A>C), RS1001569486 (19:54173891 G>A), RS1002252855 (19:54173652 CAAGG>C), RS1002374668 (19:54163073 T>C), RS1002376684 (19:54162462 A>G)

Disease associations

OMIM: gene MIM:617181 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST008758_80	Pre-treatment viral load in HIV-1 infection	2.000000e-16
GCST009652_31	Serum alkaline phosphatase levels	8.000000e-16
GCST011353_4	Serum alkaline phosphatase levels	3.000000e-10
GCST012020_545	Serum metabolite levels	2.000000e-14
GCST012020_546	Serum metabolite levels	2.000000e-21
GCST012020_547	Serum metabolite levels	2.000000e-13
GCST012232_36	Lipoprotein (a) levels	7.000000e-10
GCST90002398_94	Neutrophil count	1.000000e-09
GCST90002400_97	Plateletcrit	6.000000e-23
GCST90002402_572	Platelet count	1.000000e-18
GCST90002407_636	White blood cell count	5.000000e-09
GCST90013406_136	Liver enzyme levels (alkaline phosphatase)	3.000000e-59

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0010125	viral load
EFO:0004533	alkaline phosphatase measurement
EFO:0006925	lipoprotein A measurement
EFO:0004833	neutrophil count
EFO:0007985	platelet crit
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs626283	MBOAT7, TMC4		0.00	0
rs641738	MBOAT7, TMC4		0.00	0

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Calcitriol	affects cotreatment, increases expression	2
Nickel	decreases expression	2
Valproic Acid	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
diethyl phthalate	decreases expression, increases abundance	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
tobacco tar	decreases expression	1
benzo(e)pyrene	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, decreases reaction	1
monoethyl phthalate	decreases expression, increases abundance	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Coumestrol	affects cotreatment, decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Hydrogen Peroxide	affects expression	1
Lipopolysaccharides	decreases expression, decreases reaction	1
Methapyrilene	decreases methylation	1
Ozone	affects expression, increases abundance	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Testosterone	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	affects expression	1
Acrylamide	increases expression	1
S-Nitrosoglutathione	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_YA81	IDG-HEK293T-TMC4-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.