TMEM181

Summary

TMEM181 (transmembrane protein 181, HGNC:20958) is a protein-coding gene on chromosome 6q25.3, encoding Transmembrane protein 181 (Q9P2C4). Mediates action of cytolethal distending toxins (CDT), which are secreted by many pathogenic bacteria.

The TMEM181 gene encodes a putative G protein-coupled receptor expressed on the cell surface (Carette et al., 2009 [PubMed 19965467]; Wollscheid et al., 2009 [PubMed 19349973]).

Source: NCBI Gene 57583 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 110 total
• MANE Select transcript: NM_001376852

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20958
Approved symbol	TMEM181
Name	transmembrane protein 181
Location	6q25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000146433
Ensembl biotype	protein_coding
OMIM	613209
Entrez	57583

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 11 nonsense_mediated_decay, 6 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000367090, ENST00000684151, ENST00000714113, ENST00000714114, ENST00000714115, ENST00000714116, ENST00000714117, ENST00000714118, ENST00000714119, ENST00000714120, ENST00000714121, ENST00000714122, ENST00000714124, ENST00000714125, ENST00000714194, ENST00000714203, ENST00000714212, ENST00000714225, ENST00000714226, ENST00000714227

RefSeq mRNA: 7 — MANE Select: NM_001376852 NM_001376817, NM_001376850, NM_001376852, NM_001376854, NM_001376855, NM_001376856, NM_020823

CCDS: CCDS43520, CCDS94026

Canonical transcript exons

ENST00000684151 — 17 exons

Exon	Start	End
ENSE00000975838	158573420	158573523
ENSE00000975839	158580940	158580995
ENSE00000975840	158583954	158584044
ENSE00000975841	158585304	158585425
ENSE00000975842	158589672	158589782
ENSE00000975843	158605267	158605347
ENSE00000975844	158607244	158607343
ENSE00000975845	158608333	158608463
ENSE00000975846	158608659	158608750
ENSE00000975847	158623550	158623607
ENSE00000975848	158625104	158625206
ENSE00000975849	158625703	158625754
ENSE00000975852	158631323	158631389
ENSE00001443461	158629730	158629819
ENSE00001443462	158628408	158628490
ENSE00003920921	158560091	158560232
ENSE00004023154	158631810	158635429

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 98.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.6387 / max 398.7661, expressed in 1819 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70840	32.1521	1819
70841	3.3418	1482
70838	0.8540	258
70839	0.1667	94
70837	0.1241	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pylorus	UBERON:0001166	98.11	gold quality
cardia of stomach	UBERON:0001162	97.74	gold quality
saphenous vein	UBERON:0007318	97.43	gold quality
pericardium	UBERON:0002407	97.31	gold quality
ileal mucosa	UBERON:0000331	96.99	gold quality
tibial artery	UBERON:0007610	96.89	gold quality
popliteal artery	UBERON:0002250	96.88	gold quality
superior surface of tongue	UBERON:0007371	96.25	gold quality
trachea	UBERON:0003126	96.05	gold quality
medulla oblongata	UBERON:0001896	95.96	gold quality
mammary duct	UBERON:0001765	95.85	gold quality
epithelium of mammary gland	UBERON:0003244	95.65	gold quality
superior vestibular nucleus	UBERON:0007227	95.55	gold quality
jejunal mucosa	UBERON:0000399	95.31	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.19	gold quality
urethra	UBERON:0000057	94.97	gold quality
dorsal plus ventral thalamus	UBERON:0001897	94.71	gold quality
tongue	UBERON:0001723	94.57	gold quality
cauda epididymis	UBERON:0004360	94.49	gold quality
inferior vagus X ganglion	UBERON:0005363	94.48	gold quality
pons	UBERON:0000988	94.47	gold quality
subthalamic nucleus	UBERON:0001906	94.34	gold quality
nasal cavity epithelium	UBERON:0005384	94.34	gold quality
colonic mucosa	UBERON:0000317	94.14	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.06	gold quality
upper arm skin	UBERON:0004263	93.87	gold quality
vena cava	UBERON:0004087	93.59	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.58	gold quality
trigeminal ganglion	UBERON:0001675	93.53	gold quality
pharyngeal mucosa	UBERON:0000355	93.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

151 targeting TMEM181, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem181	ENSDARG00000045910
mus_musculus	Tmem181a	ENSMUSG00000038141
rattus_norvegicus	Tmem181	ENSRNOG00000018158
drosophila_melanogaster	CG13409	FBGN0038926

Protein

Protein identifiers

Transmembrane protein 181 — Q9P2C4 (reviewed: Q9P2C4)

All UniProt accessions (12): Q9P2C4, A0AAQ5BHF0, A0AAQ5BHG2, A0AAQ5BHJ8, A0AAQ5BHK1, A0AAQ5BHK4, A0AAQ5BHL1, A0AAQ5BHL6, A0AAQ5BHM7, A0AAQ5BHM8, A0AAQ5BHQ5, A0AAQ5BHT8

UniProt curated annotations — full annotation on UniProt →

Function. Mediates action of cytolethal distending toxins (CDT), which are secreted by many pathogenic bacteria. Expression level of TMEM181 is rate-limiting for intoxication.

Subunit / interactions. Interacts with cytolethal distending toxin.

Subcellular location. Membrane.

Similarity. Belongs to the TMEM181 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P2C4-2	2	yes
Q9P2C4-1	1

RefSeq proteins (7): NP_001363746, NP_001363779, NP_001363781, NP_001363783, NP_001363784, NP_001363785, NP_065874 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR040416	TMEM181	Family
IPR047843	WLS-like_TM	Domain
IPR054077	TMEM181_GOLD	Domain

Pfam: PF06664, PF21885

UniProt features (12 total): transmembrane region 9, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2C4-F1	78.28	0.23

Functional residue map

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

Post-translational modifications (1): 443

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 106 (showing top): chr6q25, GOMF_TOXIC_SUBSTANCE_BINDING, MEISSNER_NPC_HCP_WITH_H3K27ME3, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3, MIKKELSEN_NPC_HCP_WITH_H3K4ME3_AND_H3K27ME3, MIKKELSEN_MEF_HCP_WITH_H3K27ME3, SERVITJA_LIVER_HNF1A_TARGETS_UP, WAMUNYOKOLI_OVARIAN_CANCER_GRADES_1_2_UP, LIM_MAMMARY_STEM_CELL_DN, E2F5_TARGET_GENES, HMG20B_TARGET_GENES, KLF7_TARGET_GENES, MIER1_TARGET_GENES, PHF21A_TARGET_GENES, ZNF197_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (1): toxic substance binding (GO:0015643)

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1236 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM181	SGMS1	Q86VZ5	574
TMEM181	TULP4	Q9NRJ4	481
TMEM181	VN1R1	Q9GZP7	423
TMEM181	ALOXE3	Q9BYJ1	407
TMEM181	LSR	Q86X29	401
TMEM181	TOE1	Q96GM8	400
TMEM181	ALDH18A1	P54886	393
TMEM181	GPR107	Q5VW38	376
TMEM181	OR10A6	Q8NH74	375
TMEM181	GPRC5C	Q9NQ84	374
TMEM181	SYNGR2	O43760	368
TMEM181	ERAP2	Q6P179	368
TMEM181	DYNLT1	P63172	366
TMEM181	TAGAP	Q8N103	365
TMEM181	TMEM165	Q9HC07	359

IntAct

25 interactions, top by confidence:

A	B	Type	Score
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
DPEP1	ILVBL	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
	ESYT2	psi-mi:“MI:0914”(association)	0.350
DPEP1	TMEM120B	psi-mi:“MI:0914”(association)	0.350
	NPC1	psi-mi:“MI:0914”(association)	0.350
KLRC3	RNF13	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
ENTPD7	TMEM120B	psi-mi:“MI:0914”(association)	0.350
SCN3B	A2ML1	psi-mi:“MI:0914”(association)	0.350
SPPL2B	HAS3	psi-mi:“MI:0914”(association)	0.350
TSPAN3	SCAMP3	psi-mi:“MI:0914”(association)	0.350
FPR2	SCAMP3	psi-mi:“MI:0914”(association)	0.350
TSPAN17	MGST3	psi-mi:“MI:0914”(association)	0.350
TSPAN18	ITGA6	psi-mi:“MI:0914”(association)	0.350
SCN3B	NBAS	psi-mi:“MI:0914”(association)	0.350
VSIG4	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC25A37	RAB30	psi-mi:“MI:0914”(association)	0.350
SLC12A9	PGRMC1	psi-mi:“MI:0914”(association)	0.350
SLC19A2	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC39A7	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (30): TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-RNA), TMEM181 (Affinity Capture-RNA), TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS)

ESM2 similar proteins: A0JNC1, A0PK00, A1L2R7, A2BIE7, A3KNK1, A6QPF8, A7XZ53, A8DZH4, D3ZEH5, O35052, O95427, P98191, Q05B45, Q0VFK3, Q17QL9, Q1LY80, Q28CY9, Q3TA38, Q5BL21, Q5EAX9, Q5EAY8, Q5FWV6, Q5HZE2, Q5RET6, Q5U239, Q5ZMP3, Q63ZG0, Q68EY2, Q6DD44, Q6DE21, Q6ZMG9, Q7ZUA6, Q8BXA5, Q8C172, Q8C1E7, Q8CIF6, Q8NBJ9, Q8WVP7, Q91XU8, Q92903

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	93
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3505 predictions. Top by Δscore:

Variant	Effect	Δscore
6:158536849:G:GT	donor_gain	1.0000
6:158573414:CCCCA:C	acceptor_loss	1.0000
6:158573415:CCCAG:C	acceptor_loss	1.0000
6:158573416:CCAG:C	acceptor_loss	1.0000
6:158573417:CA:C	acceptor_loss	1.0000
6:158573418:A:AG	acceptor_gain	1.0000
6:158573418:AGG:A	acceptor_loss	1.0000
6:158573419:G:GG	acceptor_gain	1.0000
6:158573521:GAG:G	donor_gain	1.0000
6:158573522:AG:A	donor_loss	1.0000
6:158573523:GG:G	donor_loss	1.0000
6:158573524:G:GG	donor_gain	1.0000
6:158585299:TGTA:T	acceptor_loss	1.0000
6:158585300:GTA:G	acceptor_loss	1.0000
6:158585301:TAGA:T	acceptor_loss	1.0000
6:158585302:A:AC	acceptor_loss	1.0000
6:158585302:A:AG	acceptor_gain	1.0000
6:158585303:G:GG	acceptor_gain	1.0000
6:158585303:GA:G	acceptor_gain	1.0000
6:158585303:GAA:G	acceptor_gain	1.0000
6:158585303:GAAA:G	acceptor_gain	1.0000
6:158585423:GGG:G	donor_gain	1.0000
6:158585424:GG:G	donor_gain	1.0000
6:158585424:GGG:G	donor_gain	1.0000
6:158585425:GG:G	donor_gain	1.0000
6:158585426:G:GA	donor_loss	1.0000
6:158585427:T:A	donor_loss	1.0000
6:158585428:G:GG	donor_loss	1.0000
6:158589671:GAAAT:G	acceptor_gain	1.0000
6:158589778:TCACA:T	donor_gain	1.0000

AlphaMissense

3117 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:158607263:T:C	L335P	0.999
6:158607271:T:C	F338L	0.999
6:158607273:T:A	F338L	0.999
6:158607273:T:G	F338L	0.999
6:158607286:T:A	W343R	0.999
6:158607286:T:C	W343R	0.999
6:158607288:G:C	W343C	0.998
6:158607288:G:T	W343C	0.998
6:158607304:T:A	W349R	0.998
6:158607304:T:C	W349R	0.998
6:158608431:T:A	W395R	0.998
6:158608431:T:C	W395R	0.998
6:158631356:T:C	M576T	0.998
6:158629764:C:A	N546K	0.997
6:158629764:C:G	N546K	0.997
6:158631337:G:C	D570H	0.997
6:158631357:G:A	M576I	0.997
6:158631357:G:C	M576I	0.997
6:158631357:G:T	M576I	0.997
6:158607272:T:C	F338S	0.996
6:158608680:T:C	F413L	0.996
6:158608682:C:A	F413L	0.996
6:158608682:C:G	F413L	0.996
6:158631350:T:C	F574S	0.996
6:158631356:T:A	M576K	0.996
6:158631359:T:C	L577P	0.996
6:158625709:G:T	R492M	0.995
6:158629795:T:C	S557P	0.995
6:158629799:C:A	P558Q	0.995
6:158631350:T:G	F574C	0.995

dbSNP variants (sampled 300 via entrez): RS1000044765 (6:158585151 C>A), RS1000082599 (6:158543029 C>A), RS1000091114 (6:158620564 C>T), RS1000096705 (6:158584905 T>A), RS1000123494 (6:158633198 CG>C), RS1000135376 (6:158630207 C>T), RS1000162384 (6:158574478 A>G), RS1000183166 (6:158536926 G>T), RS1000240742 (6:158614949 C>A,T), RS1000250598 (6:158535219 G>C,T), RS1000280386 (6:158545994 C>A,G,T), RS1000285244 (6:158609258 G>A,C), RS1000302886 (6:158535413 C>A,T), RS1000314645 (6:158614746 C>T), RS1000317657 (6:158568566 C>G,T)

Disease associations

OMIM: gene MIM:613209 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006065_10	Glaucoma (primary open-angle)	8.000000e-09
GCST006412_61	Intraocular pressure	7.000000e-10
GCST009725_89	Intraocular pressure	1.000000e-06
GCST009726_11	Glaucoma	7.000000e-06
GCST010396_55	Gut microbiota (bacterial taxa, hurdle binary method)	8.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Tretinoin	decreases expression, increases expression	2
triphenyl phosphate	affects expression	1
sodium arsenite	increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
K 7174	increases expression	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Cadmium	increases abundance, increases expression	1
Coumestrol	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Methapyrilene	increases methylation	1
Thiram	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Cyclosporine	decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1

Clinical trials (associated diseases)

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