TMEM168

Summary

TMEM168 (transmembrane protein 168, HGNC:25826) is a protein-coding gene on chromosome 7q31.1, encoding Transmembrane protein 168 (Q9H0V1). Plays a key role in maintaining the cardiac electrical stability by modulating cell surface expression of SCN5A.

Enables sodium channel regulator activity. Predicted to act upstream of or within regulation of ubiquitin-dependent protein catabolic process and regulation of voltage-gated sodium channel activity. Located in nuclear membrane and transport vesicle.

Source: NCBI Gene 64418 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Brugada syndrome (Disputed, ClinGen)
• Clinical variants (ClinVar): 93 total
• MANE Select transcript: NM_022484

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25826
Approved symbol	TMEM168
Name	transmembrane protein 168
Location	7q31.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp564C012, FLJ13576
Ensembl gene	ENSG00000146802
Ensembl biotype	protein_coding
Entrez	64418

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 21 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000312814, ENST00000418785, ENST00000441474, ENST00000447395, ENST00000449743, ENST00000454074, ENST00000480969, ENST00000863807, ENST00000863808, ENST00000863809, ENST00000863810, ENST00000863811, ENST00000863812, ENST00000863813, ENST00000863814, ENST00000912412, ENST00000912413, ENST00000912414, ENST00000942635, ENST00000942636, ENST00000942637, ENST00000942638

RefSeq mRNA: 2 — MANE Select: NM_022484 NM_001287497, NM_022484

CCDS: CCDS5757

Canonical transcript exons

ENST00000312814 — 5 exons

Exon	Start	End
ENSE00000977382	112772781	112773055
ENSE00001150219	112762377	112767744
ENSE00001250523	112783698	112784953
ENSE00001653801	112790160	112790393
ENSE00003607326	112775176	112775318

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 94.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.2429 / max 114.8289, expressed in 1786 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85769	12.1915	1786
85770	0.0514	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of sigmoid colon	UBERON:0004993	94.93	gold quality
hair follicle	UBERON:0002073	94.31	gold quality
colonic mucosa	UBERON:0000317	94.30	gold quality
secondary oocyte	CL:0000655	94.25	gold quality
upper leg skin	UBERON:0004262	93.76	gold quality
skin of hip	UBERON:0001554	93.38	gold quality
corpus epididymis	UBERON:0004359	92.83	gold quality
tibia	UBERON:0000979	92.60	gold quality
superficial temporal artery	UBERON:0001614	92.18	gold quality
choroid plexus epithelium	UBERON:0003911	92.16	gold quality
oocyte	CL:0000023	92.15	gold quality
cauda epididymis	UBERON:0004360	92.11	gold quality
rectum	UBERON:0001052	91.71	gold quality
jejunal mucosa	UBERON:0000399	91.29	gold quality
oral cavity	UBERON:0000167	91.00	gold quality
visceral pleura	UBERON:0002401	90.74	gold quality
caput epididymis	UBERON:0004358	90.32	gold quality
urethra	UBERON:0000057	90.30	gold quality
endometrium	UBERON:0001295	90.22	gold quality
pleura	UBERON:0000977	90.09	gold quality
superior surface of tongue	UBERON:0007371	90.01	gold quality
calcaneal tendon	UBERON:0003701	89.99	gold quality
parietal pleura	UBERON:0002400	89.87	gold quality
penis	UBERON:0000989	89.65	gold quality
esophagus squamous epithelium	UBERON:0006920	89.65	gold quality
oviduct epithelium	UBERON:0004804	89.59	gold quality
placenta	UBERON:0001987	89.57	gold quality
parotid gland	UBERON:0001831	89.35	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.23	gold quality
seminal vesicle	UBERON:0000998	89.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.09
E-MTAB-4850	no	220.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

205 targeting TMEM168, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3658	99.96	73.87	4379

Literature-anchored findings (GeneRIF, showing 3)

• Data suggested that siRNA-TMEM168 (siTMEM168) prevented viability of U87 and U373 cells, induced cell cycle arrest (G0/G1 phase) and promoted apoptosis, and the mechanisms involved in blocking Wnt/beta-catenin pathway, as evidenced by reducing expression of beta-catenin, C-myc, cyclin D1, and survivin. (PMID:30940290)
• Identification of transmembrane protein 168 mutation in familial Brugada syndrome. (PMID:32175648)
• Transmembrane protein 168 mutation reduces cardiomyocyte cell surface expression of Nav1.5 through alphaB-crystallin intracellular dynamics. (PMID:34086898)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem168b	ENSDARG00000062168
danio_rerio	tmem168a	ENSDARG00000068705
mus_musculus	Tmem168	ENSMUSG00000029569
rattus_norvegicus	Tmem168	ENSRNOG00000057290

Protein

Protein identifiers

Transmembrane protein 168 — Q9H0V1 (reviewed: Q9H0V1)

All UniProt accessions (4): Q9H0V1, C9IZT1, C9JVE9, H7C268

UniProt curated annotations — full annotation on UniProt →

Function. Plays a key role in maintaining the cardiac electrical stability by modulating cell surface expression of SCN5A. May play a role in the modulation of anxiety behavior by regulating GABAergic neuronal system in the nucleus accumbens.

Subcellular location. Nucleus membrane.

Induction. Overexpressed in glioblastoma multiforme (GBM) patients.

Similarity. Belongs to the TMEM168 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H0V1-1	1	yes
Q9H0V1-2	2

RefSeq proteins (2): NP_001274426, NP_071929* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029713	TMEM168	Family

UniProt features (21 total): transmembrane region 11, sequence conflict 4, glycosylation site 3, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0V1-F1	83.47	0.35

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 (3): 111, 533, 598

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 170 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, TGCACTT_MIR519C_MIR519B_MIR519A, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, AAGCCAT_MIR135A_MIR135B, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CTATGCA_MIR153, ONKEN_UVEAL_MELANOMA_UP, GOBP_REGULATION_OF_CATABOLIC_PROCESS, DODD_NASOPHARYNGEAL_CARCINOMA_UP, TGCCTTA_MIR124A, GOBP_REGULATION_OF_PROTEOLYSIS, GOBP_PROTEIN_CATABOLIC_PROCESS

GO Biological Process (1): regulation of ubiquitin-dependent protein catabolic process (GO:2000058)

GO Molecular Function (1): sodium channel regulator activity (GO:0017080)

GO Cellular Component (4): transport vesicle (GO:0030133), nuclear membrane (GO:0031965), nucleus (GO:0005634), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ubiquitin-dependent protein catabolic process	1
regulation of protein catabolic process	1
sodium channel activity	1
ion channel regulator activity	1
endomembrane system	1
cytoplasmic vesicle	1
nucleus	1
nuclear envelope	1
organelle membrane	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

486 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM168	CCDC70	Q6NSX1	495
TMEM168	NDC1	Q9BTX1	493
TMEM168	TMEM140	Q9NV12	454
TMEM168	GPR85	P60893	438
TMEM168	ZMYND19	Q96E35	431
TMEM168	PPP1R3A	Q16821	429
TMEM168	SAMTOR	Q1RMZ1	389
TMEM168	MRPL57	Q9BQC6	388
TMEM168	ARMCX2	Q7L311	388
TMEM168	MDFIC	Q9P1T7	386
TMEM168	TFEC	O14948	384
TMEM168	IFRD1	O00458	382
TMEM168	TTC14	Q96N46	377
TMEM168	CCDC28A	Q8IWP9	373
TMEM168	RSRC2	Q7L4I2	372

IntAct

15 interactions, top by confidence:

A	B	Type	Score
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
TMEM168	CRKL	psi-mi:“MI:0915”(physical association)	0.490
CRKL	TMEM168	psi-mi:“MI:0915”(physical association)	0.490
TMEM168	GTF2IRD1	psi-mi:“MI:0915”(physical association)	0.400
NETO2	TIA1	psi-mi:“MI:0914”(association)	0.350
ATP2B2	GPR89A	psi-mi:“MI:0914”(association)	0.350
	BTAF1	psi-mi:“MI:0914”(association)	0.350
	FAM20B	psi-mi:“MI:0914”(association)	0.350
ATP2B2	ESYT2	psi-mi:“MI:0914”(association)	0.350
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350
MFSD14A	FAM171A2	psi-mi:“MI:0914”(association)	0.350
PIGP	TMEM168	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): TMEM168 (Two-hybrid), TMEM168 (Affinity Capture-MS), TMEM168 (Affinity Capture-MS), TMEM168 (Affinity Capture-MS), TMEM168 (Affinity Capture-MS), TMEM168 (Affinity Capture-MS), TMEM168 (Affinity Capture-MS), TMEM168 (Proximity Label-MS), TMEM168 (Proximity Label-MS), TMEM168 (Affinity Capture-MS), TMEM168 (Affinity Capture-MS), TMEM168 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), TMEM168 (Affinity Capture-Western), TMEM168 (Affinity Capture-MS)

ESM2 similar proteins: A0A494BZU4, A0A7H0DND7, A0JNG0, A2T345, A4IIV4, C4QM85, E7F594, G5EDX4, O02051, O45306, P0DP42, P0DST5, P0DST6, P21061, P24763, P34362, P34363, P53053, Q09282, Q0II41, Q10907, Q11071, Q11085, Q13571, Q20249, Q297K8, Q2KHT4, Q2KJA5, Q32KQ5, Q5DC12, Q5GH77, Q5PQM0, Q5RD28, Q5REZ0, Q5TAH2, Q61168, Q6AXT9, Q6GV27, Q6GV28, Q7K1V5

Diamond homologs: A0JNG0, Q1LUD1, Q5PQM0, Q5RD28, Q7ZY86, Q91VX9, Q9H0V1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1171 predictions. Top by Δscore:

Variant	Effect	Δscore
7:112772840:T:C	donor_gain	0.9900
7:112775319:C:CC	acceptor_gain	0.9900
7:112784825:TGTA:T	donor_gain	0.9900
7:112790544:T:TA	donor_gain	0.9900
7:112767396:C:A	donor_gain	0.9800
7:112767538:G:C	donor_gain	0.9800
7:112772839:A:AC	donor_gain	0.9800
7:112773056:C:CC	acceptor_gain	0.9800
7:112784854:CG:C	donor_gain	0.9800
7:112789398:T:C	acceptor_gain	0.9800
7:112767373:T:TA	donor_gain	0.9700
7:112767745:C:CC	acceptor_gain	0.9700
7:112772839:AT:A	donor_gain	0.9700
7:112773061:G:GC	acceptor_gain	0.9700
7:112775315:TTGG:T	acceptor_gain	0.9700
7:112775987:T:TC	acceptor_gain	0.9700
7:112784868:A:C	donor_gain	0.9700
7:112784883:T:TA	donor_gain	0.9700
7:112790492:G:C	donor_gain	0.9700
7:112767395:T:TA	donor_gain	0.9600
7:112767743:ACCTG:A	acceptor_loss	0.9600
7:112767744:CCT:C	acceptor_loss	0.9600
7:112767745:CT:C	acceptor_loss	0.9600
7:112767746:T:G	acceptor_loss	0.9600
7:112773061:G:C	acceptor_gain	0.9600
7:112784823:CATG:C	donor_gain	0.9600
7:112784866:TA:T	donor_gain	0.9600
7:112784867:AA:A	donor_gain	0.9600
7:112767424:TC:T	donor_gain	0.9500
7:112767425:CC:C	donor_gain	0.9500

AlphaMissense

4568 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:112767210:A:G	L694P	0.999
7:112767427:A:G	W622R	0.999
7:112767427:A:T	W622R	0.999
7:112767517:A:G	W592R	0.999
7:112767517:A:T	W592R	0.999
7:112767597:G:T	A565E	0.999
7:112767637:A:G	W552R	0.999
7:112767637:A:T	W552R	0.999
7:112772793:A:G	W512R	0.999
7:112772793:A:T	W512R	0.999
7:112775203:G:T	A415D	0.999
7:112775204:C:G	A415P	0.999
7:112767207:A:T	V695D	0.998
7:112767210:A:T	L694H	0.998
7:112767216:A:G	F692S	0.998
7:112767478:A:G	W605R	0.998
7:112767478:A:T	W605R	0.998
7:112767598:C:G	A565P	0.998
7:112767672:A:G	L540P	0.998
7:112772816:C:T	G504E	0.998
7:112772817:C:A	G504W	0.998
7:112772823:A:C	Y502D	0.998
7:112772826:A:C	Y501D	0.998
7:112775209:C:T	G413E	0.998
7:112775210:C:G	G413R	0.998
7:112775210:C:T	G413R	0.998
7:112784072:A:G	W252R	0.998
7:112784072:A:T	W252R	0.998
7:112784335:C:T	G164E	0.998
7:112784336:C:G	G164R	0.998

dbSNP variants (sampled 300 via entrez): RS1000288077 (7:112785675 A>T), RS1000355479 (7:112768343 A>G), RS1000412152 (7:112785958 A>C,G), RS1000505659 (7:112778111 T>A,C,G), RS1000690226 (7:112775614 A>C), RS1000723260 (7:112767038 C>T), RS1000757340 (7:112765937 G>A), RS1000828907 (7:112773098 A>G), RS1000947090 (7:112787155 GAAACA>G), RS1001007720 (7:112787374 C>A), RS1001180002 (7:112768229 T>C), RS1001189060 (7:112772474 T>C), RS1001229588 (7:112764247 C>A), RS1001381173 (7:112787522 C>A,G,T), RS1001464217 (7:112786327 G>A)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Brugada syndrome	Disputed	AD

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	3
cobaltous chloride	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, affects cotreatment	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases methylation	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Copper	affects binding, increases expression	1
Coumestrol	increases expression	1
Doxorubicin	affects expression	1
Ethyl Methanesulfonate	increases expression	1
Plant Extracts	increases expression, affects cotreatment	1
Quercetin	decreases expression	1
Selenium	decreases expression	1
Testosterone	increases expression	1
Valproic Acid	decreases methylation	1
Cyclosporine	increases expression	1
Paclitaxel	affects response to substance	1

Clinical trials (associated diseases)

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