TMEM175

Summary

TMEM175 (transmembrane protein 175, HGNC:28709) is a protein-coding gene on chromosome 4p16.3, encoding Endosomal/lysosomal proton channel TMEM175 (Q9BSA9). Proton-activated proton channel that catalyzes proton efflux from endosomes and lysosomes to maintain a steady-state pH.

Enables arachidonate binding activity; potassium ion leak channel activity; and proton channel activity. Involved in lysosomal lumen pH elevation; potassium ion transmembrane transport; and proton transmembrane transport. Located in endosome membrane and lysosome. Is active in lysosomal membrane.

Source: NCBI Gene 84286 — RefSeq curated summary.

At a glance

• GWAS associations: 38
• Clinical variants (ClinVar): 131 total — 2 pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_032326

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28709
Approved symbol	TMEM175
Name	transmembrane protein 175
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC4618
Ensembl gene	ENSG00000127419
Ensembl biotype	protein_coding
OMIM	616660
Entrez	84286

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 20 protein_coding, 8 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000264771, ENST00000438836, ENST00000452360, ENST00000502513, ENST00000504180, ENST00000504505, ENST00000504744, ENST00000504850, ENST00000505734, ENST00000506669, ENST00000507319, ENST00000508204, ENST00000509508, ENST00000510493, ENST00000513682, ENST00000513952, ENST00000514453, ENST00000514546, ENST00000515492, ENST00000515740, ENST00000515876, ENST00000622959, ENST00000904683, ENST00000904684, ENST00000904685, ENST00000904686, ENST00000949493, ENST00000949494, ENST00000949495, ENST00000949496, ENST00000949497, ENST00000949498

RefSeq mRNA: 7 — MANE Select: NM_032326 NM_001297423, NM_001297424, NM_001297425, NM_001297426, NM_001297427, NM_001297428, NM_032326

CCDS: CCDS3341, CCDS75087, CCDS75088

Canonical transcript exons

ENST00000264771 — 11 exons

Exon	Start	End
ENSE00002053317	932460	932540
ENSE00003490837	947709	947892
ENSE00003503138	951682	951717
ENSE00003507634	952367	952450
ENSE00003568039	953190	953354
ENSE00003602440	955405	955483
ENSE00003611371	951207	951258
ENSE00003619645	950421	950518
ENSE00003632571	955755	955890
ENSE00003655081	957824	958656
ENSE00003663111	948116	948154

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 97.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.5301 / max 193.3725, expressed in 1811 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46529	21.1899	1810
46528	0.3401	155

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	97.87	gold quality
cerebellar hemisphere	UBERON:0002245	97.55	gold quality
cerebellar cortex	UBERON:0002129	97.43	gold quality
granulocyte	CL:0000094	97.06	gold quality
adenohypophysis	UBERON:0002196	96.95	gold quality
right frontal lobe	UBERON:0002810	96.29	gold quality
cerebellum	UBERON:0002037	96.17	gold quality
pituitary gland	UBERON:0000007	95.83	gold quality
apex of heart	UBERON:0002098	95.75	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.40	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.28	gold quality
spleen	UBERON:0002106	94.86	gold quality
right lobe of thyroid gland	UBERON:0001119	94.57	gold quality
right lobe of liver	UBERON:0001114	94.55	gold quality
right adrenal gland cortex	UBERON:0035827	94.53	gold quality
left lobe of thyroid gland	UBERON:0001120	94.46	gold quality
anterior cingulate cortex	UBERON:0009835	94.41	gold quality
right adrenal gland	UBERON:0001233	94.39	gold quality
nerve	UBERON:0001021	94.32	gold quality
tibial nerve	UBERON:0001323	94.32	gold quality
nucleus accumbens	UBERON:0001882	94.18	gold quality
spinal cord	UBERON:0002240	94.15	gold quality
body of pancreas	UBERON:0001150	94.07	gold quality
putamen	UBERON:0001874	93.95	gold quality
metanephros cortex	UBERON:0010533	93.93	gold quality
left adrenal gland	UBERON:0001234	93.89	gold quality
hypothalamus	UBERON:0001898	93.80	gold quality
left adrenal gland cortex	UBERON:0035825	93.80	gold quality
right uterine tube	UBERON:0001302	93.66	gold quality
amygdala	UBERON:0001876	93.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.56
E-MTAB-6058	no	34.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting TMEM175, 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-10523-5P	99.91	69.22	2038
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-4751	98.80	64.95	525
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-6764-3P	98.44	67.64	1153
HSA-MIR-6824-3P	98.44	67.62	1154
HSA-MIR-3169	96.40	67.58	698
HSA-MIR-4740-5P	96.25	67.96	726

Literature-anchored findings (GeneRIF, showing 8)

• Data indicated that GBA and TMEM175/GAK significantly alter age at onset in PD. (PMID:25914293)
• TMEM175 deficiency impairs lysosomal and mitochondrial function and increases alpha-synuclein aggregation. (PMID:28193887)
• structure of TMEM175 represents a novel architecture of a tetrameric cation channel whose ion selectivity mechanism appears to be distinct from that of the classical K(+) channel family (PMID:28723891)
• Data suggest that the TMEM175 p.M393T variant is responsible for the main signal in the chromosome 4p16.3 locus therefore conferring risk for Parkinson disease through its phosphorylation of alpha-synuclein. (PMID:31261387)
• Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting glucosylceramidase activity. (PMID:31658403)
• Gating and selectivity mechanisms for the lysosomal K(+) channel TMEM175. (PMID:32228865)
• A growth-factor-activated lysosomal K(+) channel regulates Parkinson’s pathology. (PMID:33505021)
• Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel. (PMID:37390818)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem175	ENSDARG00000076376
mus_musculus	Tmem175	ENSMUSG00000013495
rattus_norvegicus	Tmem175	ENSRNOG00000000044

Protein

Protein identifiers

Endosomal/lysosomal proton channel TMEM175 — Q9BSA9 (reviewed: Q9BSA9)

Alternative names: Potassium channel TMEM175, Transmembrane protein 175

All UniProt accessions (10): Q9BSA9, D6RAJ5, D6RAU7, D6RBE5, D6RCD9, D6RDY8, D6RHV8, D6RIZ2, E7ETE6, F6UWG6

UniProt curated annotations — full annotation on UniProt →

Function. Proton-activated proton channel that catalyzes proton efflux from endosomes and lysosomes to maintain a steady-state pH. Activated at low pH (under pH 4.6) by luminal side protons: selectively mediates lysosomal proton release from lysosomes, eliciting a proton leak that balances V-ATPase activity to maintain pH homeostasis. Regulation of lumenal pH stability is required for autophagosome-lysosome fusion. Also acts as a potassium channel at higher pH, regulating potassium conductance in endosomes and lysosomes. Constitutes the pore-forming subunit of the lysoK(GF) complex, a complex activated by extracellular growth factors. The lysoK(GF) complex is composed of TMEM175 and AKT (AKT1, AKT2 or AKT3), a major target of growth factor receptors: in the complex, TMEM175 channel is opened by conformational changes by AKT, leading to its activation. The lysoK(GF) complex is required to protect neurons against stress-induced damage.

Subunit / interactions. Homodimer. Interacts with AKT (AKT1, AKT2 or AKT3); leading to formation of the lysoK(GF) complex, which activates the channel. Interacts with LAMP1; inhibiting the proton channel activity of TMEM175. Interacts with LAMP2; inhibiting the proton channel activity of TMEM175.

Subcellular location. Endosome membrane. Lysosome membrane.

Tissue specificity. Widely expressed.

Disease relevance. Parkinson disease (PARK) [MIM:168600] A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. Disease susceptibility may be associated with variants affecting the gene represented in this entry. TMEM175 defects result in unstable lysosomal pH, leading to decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance by the lysosome and decreased mitochondrial respiration.

Activity regulation. Active at low pH (under pH 4.6): proton channel activity is activated by luminal side protons. Polyunsaturated fatty acids, such as arachidonic acid, also activate the channel activity. Proton channel activity is directly inhibited by LAMP1 or LAMP2, facilitating lysosomal acidification. Channel activity is activated following interaction with AKT (AKT1, AKT2 or AKT3): interaction promotes activation from closed to an open state. Activation by AKT is independent of AKT serine/threonine-protein kinase activity.

Domain organisation. Composed of two modules of six transmembranes, forming a homodimer with a tetrameric architecture. The six transmembrane regions of each module are tightly packed within each subunit without undergoing domain swapping. Forms a central ion-conduction pore lined by the side chains of the pore-lining helices. Conserved isoleucine residues (Ile-46 in the first module and Ile-271 in the second module) in the center of the pore serve as the gate in the closed conformation. In the widened channel in the open conformation, Ser-45 and Ile-46 in the first module (and Thr-274 and Ile-271 in the second module), establish a constriction essential for potassium selectivity.

Similarity. Belongs to the TMEM175 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BSA9-1	1	yes
Q9BSA9-2	2

RefSeq proteins (7): NP_001284352, NP_001284353, NP_001284354, NP_001284355, NP_001284356, NP_001284357, NP_115702* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010617	TMEM175-like	Family

Pfam: PF06736

Catalyzed reactions (Rhea), 2 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• H(+)(in) = H(+)(out) (RHEA:34979)

UniProt features (117 total): mutagenesis site 39, helix 25, topological domain 13, transmembrane region 12, region of interest 6, site 6, strand 5, turn 3, short sequence motif 2, sequence variant 2, chain 1, compositionally biased region 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
7UNL	ELECTRON MICROSCOPY	2.45
7UNM	ELECTRON MICROSCOPY	2.61
6WC9	ELECTRON MICROSCOPY	2.64
8DHM	ELECTRON MICROSCOPY	2.73
9VSQ	ELECTRON MICROSCOPY	2.74
9VSR	ELECTRON MICROSCOPY	2.92
6WCA	ELECTRON MICROSCOPY	3.03
6WCB	ELECTRON MICROSCOPY	3.17
6W8N	ELECTRON MICROSCOPY	3.2
6WCC	ELECTRON MICROSCOPY	3.24
6W8O	ELECTRON MICROSCOPY	3.4
8FYF	ELECTRON MICROSCOPY	3.4
9VSP	ELECTRON MICROSCOPY	3.4
8VIC	ELECTRON MICROSCOPY	3.48
7LF6	ELECTRON MICROSCOPY	3.5
8FY5	ELECTRON MICROSCOPY	3.5
8VIE	ELECTRON MICROSCOPY	3.52
6W8P	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BSA9-F1	81.77	0.44

Functional residue map

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

Catalytic / active sites (6): 46 (hydrophobic filter residue 1-1); 50 (hydrophobic filter residue 2-1); 53 (hydrophobic filter residue 3-1); 271 (hydrophobic filter residue 1-2); 275 (hydrophobic filter residue 2-2); 278 (hydrophobic filter residue 3-2)

Post-translational modifications (1): 6

Mutagenesis-validated functional residues (39):

Position	Phenotype
35	impaired potassium channel activity.
38	does not affect proton and potassium channel activity.
39	impaired potassium channel activity.
40	impaired potassium channel activity.
41	abolished proton permeability without altering potassium permeability.
41	impaired potassium channel activity.
45–49	decreased selectivity for potassium ion; when associated with a-274.
45	reduced potassium channel activity without altering proton channel activity.
45	decreased selectivity for potassium ion.
46	decreased channel activity.
46	abolished proton and potassium channel activity; when associated with m-271.
46	impaired selectivity; can conduct both k(+) and na(+); when associated with n-271.
49	decreased selectivity for potassium ion.
49	abolished potassium channel activity and decreased proton channel activity.
50	does not affect selectivity; when associated with a-275.
53	does not affect selectivity; when associated with a-278.
241	reduced channel activation, probably caused by decreased interaction with akt1; when associated with a-338.
271	decreased channel activity.
271	impaired selectivity; can conduct both k(+) and na(+); when associated with n-46.
271	abolished proton and potassium channel activity.
274	decreased selectivity for potassium ion. abolished proton and potassium channel activity. decreased selectivity for pota
274	abolished proton and potassium channel activity.
274	decreased selectivity for potassium ion.
275	does not affect selectivity; when associated with a-50.
278	does not affect selectivity; when associated with a-53.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 119 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, GOBP_MEMBRANE_FUSION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, CREBP1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_PHAGOLYSOSOME_ASSEMBLY, CREB_Q4, GOBP_PHAGOSOME_MATURATION, GOBP_ORGANELLE_MEMBRANE_FUSION, E4F1_Q6, chr4p16

GO Biological Process (9): obsolete regulation of lysosomal lumen pH (GO:0035751), lysosomal lumen pH elevation (GO:0035752), neuron cellular homeostasis (GO:0070050), potassium ion transmembrane transport (GO:0071805), phagosome-lysosome fusion (GO:0090385), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (5): potassium channel activity (GO:0005267), proton channel activity (GO:0015252), potassium ion leak channel activity (GO:0022841), arachidonate binding (GO:0050544), protein binding (GO:0005515)

GO Cellular Component (5): lysosome (GO:0005764), lysosomal membrane (GO:0005765), endosome (GO:0005768), endosome membrane (GO:0010008), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic cation transmembrane transport	2
monoatomic cation channel activity	2
intracellular pH elevation	1
cellular homeostasis	1
potassium ion transport	1
phagolysosome assembly	1
vesicle fusion	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
potassium ion transmembrane transporter activity	1
proton transmembrane transporter activity	1
potassium channel activity	1
leak channel activity	1
icosanoid binding	1
icosatetraenoic acid binding	1
binding	1
lytic vacuole	1
lysosome	1
lytic vacuole membrane	1
endomembrane system	1
cytoplasmic vesicle	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

528 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM175	GAK	O14976	728
TMEM175	SNCA	P37840	727
TMEM175	LRRK2	Q5S007	720
TMEM175	DGKQ	P52824	713
TMEM175	MCCC1	Q96RQ3	659
TMEM175	GBA1	P04062	605
TMEM175	ATP13A2	Q9NQ11	582
TMEM175	TMEM229B	Q8NBD8	570
TMEM175	TMEM230	Q96A57	563
TMEM175	RAB29	O14966	514
TMEM175	VPS13C	Q709C8	512
TMEM175	TMEM163	Q8TC26	507
TMEM175	NUCKS1	Q9H1E3	506
TMEM175	SYT11	Q9BT88	488
TMEM175	SYT12	Q8IV01	471

IntAct

10 interactions, top by confidence:

A	B	Type	Score
TMEM175	SAR1B	psi-mi:“MI:0915”(physical association)	0.400
TMEM175	GPR37	psi-mi:“MI:0915”(physical association)	0.370
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TNFRSF10C	SLC22A23	psi-mi:“MI:0914”(association)	0.350
TMEM154	VPS26A	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): TMEM175 (Two-hybrid), TMEM175 (Affinity Capture-MS), TMEM175 (Affinity Capture-MS), TMEM175 (Affinity Capture-MS), TMEM175 (Affinity Capture-MS), TMEM175 (Affinity Capture-MS), SAR1B (Affinity Capture-MS), TMEM175 (Affinity Capture-MS), TMEM175 (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A1A4P6, A1A5B4, A5PK40, A6NDV4, A6NFX1, A6NGC4, A6QL84, A6QLK4, B1AWJ5, B6ID01, E1BY51, P58749, Q2TA01, Q2YDG0, Q32PG7, Q3T9M1, Q4R7X9, Q5HZE5, Q5JZQ7, Q5R6H1, Q5RBY7, Q60HE8, Q6AY05, Q6AYM9, Q6PHN7, Q6TCG5, Q6UX01, Q6UXD7, Q7RTT9, Q7Z403, Q80ZE4, Q8CE47, Q8R139, Q8TBR7, Q96FZ5, Q96HE8, Q96S97, Q9BSA9, Q9BZW5, Q9CQC4

Diamond homologs: A0A086F3E3, A5PN43, K9UJK2, Q32PG7, Q5ZKY0, Q6AY05, Q9BSA9, Q9CXY1, S5VBU1, E4TN31

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	96
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1047903	GRCh37/hg19 4p16.3(chr4:388344-3872380)	Pathogenic
58014	GRCh38/hg38 4p16.3-16.2(chr4:85149-4596207)x3	Pathogenic

SpliceAI

2240 predictions. Top by Δscore:

Variant	Effect	Δscore
4:950417:CCA:C	acceptor_loss	1.0000
4:950418:CAG:C	acceptor_loss	1.0000
4:950419:A:AG	acceptor_gain	1.0000
4:950420:G:A	acceptor_loss	1.0000
4:950420:G:GA	acceptor_gain	1.0000
4:950420:GC:G	acceptor_gain	1.0000
4:950420:GCA:G	acceptor_gain	1.0000
4:950420:GCAGT:G	acceptor_gain	1.0000
4:951196:A:AG	acceptor_gain	1.0000
4:951196:AAAT:A	acceptor_gain	1.0000
4:951197:A:G	acceptor_gain	1.0000
4:951197:AAT:A	acceptor_gain	1.0000
4:951198:AT:A	acceptor_gain	1.0000
4:951199:T:A	acceptor_gain	1.0000
4:951199:T:G	acceptor_gain	1.0000
4:951202:TTTA:T	acceptor_loss	1.0000
4:951204:TAGG:T	acceptor_loss	1.0000
4:951205:A:AG	acceptor_gain	1.0000
4:951206:G:GG	acceptor_gain	1.0000
4:951206:GGTT:G	acceptor_gain	1.0000
4:951254:ACCTG:A	donor_gain	1.0000
4:951255:CCTG:C	donor_gain	1.0000
4:951256:CTG:C	donor_gain	1.0000
4:951256:CTGG:C	donor_loss	1.0000
4:951257:TG:T	donor_gain	1.0000
4:951257:TGG:T	donor_loss	1.0000
4:951258:GG:G	donor_gain	1.0000
4:951259:G:GG	donor_gain	1.0000
4:951260:T:A	donor_loss	1.0000
4:953351:CTTGG:C	donor_loss	1.0000

AlphaMissense

3250 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:955841:A:C	S265R	0.998
4:955843:C:A	S265R	0.998
4:955843:C:G	S265R	0.998
4:947857:A:C	S40R	0.997
4:947859:T:A	S40R	0.997
4:947859:T:G	S40R	0.997
4:947882:C:A	A48D	0.997
4:958140:A:C	S387R	0.997
4:958142:C:A	S387R	0.997
4:958142:C:G	S387R	0.997
4:950481:T:C	F85L	0.996
4:950483:T:A	F85L	0.996
4:950483:T:G	F85L	0.996
4:950502:T:A	W92R	0.996
4:950502:T:C	W92R	0.996
4:957930:T:C	F317L	0.996
4:957932:C:A	F317L	0.996
4:957932:C:G	F317L	0.996
4:958269:A:C	S430R	0.996
4:958271:C:A	S430R	0.996
4:958271:C:G	S430R	0.996
4:951710:C:A	P124H	0.994
4:955857:C:A	A270D	0.994
4:957951:T:A	W324R	0.994
4:957951:T:C	W324R	0.994
4:955845:A:T	D266V	0.993
4:955866:C:A	A273D	0.993
4:955872:T:C	L275P	0.993
4:958116:A:C	S379R	0.993
4:958118:C:A	S379R	0.993

dbSNP variants (sampled 300 via entrez): RS1000020000 (4:949751 C>T), RS1000128699 (4:954283 A>G), RS1000154536 (4:942005 A>G), RS1000189512 (4:953941 C>T), RS1000191417 (4:958273 T>C), RS1000540578 (4:936889 G>A), RS1000713429 (4:941507 C>T), RS1000780266 (4:946421 C>T), RS10008187 (4:947229 C>G,T), RS1000873965 (4:952002 A>G), RS1000894244 (4:951014 G>C), RS1001045128 (4:943171 T>C), RS1001057931 (4:935140 T>G), RS1001185759 (4:932388 C>G,T), RS1001189865 (4:956403 C>T)

Disease associations

OMIM: gene MIM:616660 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): fetal growth restriction (MONDO:0005030), renal hypoplasia (MONDO:0019637)

Orphanet (1): Renal hypoplasia (Orphanet:93101)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000089	Renal hypoplasia

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST002544_16	Parkinson’s disease	1.000000e-43
GCST002560_18	Type 2 diabetes	7.000000e-06
GCST003129_30	Primary biliary cholangitis	9.000000e-12
GCST004902_45	Parkinson’s disease	1.000000e-50
GCST005334_4	Limited cutaneous systemic scleroderma	2.000000e-06
GCST005336_3	Systemic sclerosis	2.000000e-06
GCST007780_3	Parkinson’s disease (age of onset)	1.000000e-08
GCST008074_122	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-11
GCST008074_159	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-09
GCST008075_193	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	8.000000e-08
GCST008075_87	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	6.000000e-07
GCST008083_124	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-09
GCST008083_6	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-11
GCST008084_100	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-07
GCST008084_167	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-08
GCST008085_182	HDL cholesterol levels in current drinkers	1.000000e-06
GCST008087_128	Triglyceride levels in current drinkers	5.000000e-10
GCST008087_30	Triglyceride levels in current drinkers	1.000000e-07
GCST009325_45	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	1.000000e-69
GCST009512_6	Parkinson’s disease	3.000000e-07
GCST010049_9	Parkinson’s disease	7.000000e-06
GCST010991_38	Parkinson’s disease	1.000000e-11
GCST012431_3	Parkinson’s disease	6.000000e-11
GCST90013445_23	Type 1 diabetes	6.000000e-09
GCST90013445_37	Type 1 diabetes	6.000000e-09
GCST90020024_1235	A body shape index	3.000000e-08
GCST90020024_1236	A body shape index	3.000000e-10
GCST90020024_1237	A body shape index	3.000000e-12
GCST90020025_1041	Waist-to-hip ratio adjusted for BMI	4.000000e-10
GCST90020025_1043	Waist-to-hip ratio adjusted for BMI	4.000000e-13

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:1001017	limited scleroderma
EFO:0004847	age at onset
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D005317	Fetal Growth Retardation	C12.050.703.277.370; C16.300.390; C23.550.393.450

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Benzo(a)pyrene	affects expression, affects methylation	3
bisphenol A	decreases methylation, increases expression	2
(+)-JQ1 compound	increases expression	2
Air Pollutants	increases abundance, increases expression, affects response to substance	2
Aflatoxin B1	increases methylation	2
OTX015	increases expression	1
mivebresib	increases expression	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
jinfukang	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	1
Atrazine	decreases expression	1
Copper	affects binding, increases expression	1
Disulfiram	affects binding, increases expression	1
Doxorubicin	increases expression	1
Nitrogen Oxides	increases abundance, affects response to substance	1
Smoke	increases abundance, increases expression	1
Tunicamycin	increases expression	1
Thapsigargin	increases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1
Particulate Matter	affects response to substance, increases abundance	1

Cellosaurus cell lines

16 cell lines: 9 cancer cell line, 6 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2IS	Abcam HeLa TMEM175 KO	Cancer cell line	Female
CVCL_D8CN	Ubigene A-549 TMEM175 KO	Cancer cell line	Male
CVCL_D8X8	Ubigene HCT 116 TMEM175 KO	Cancer cell line	Male
CVCL_D9UE	Ubigene HEK293 TMEM175 KO	Transformed cell line	Female
CVCL_E0RB	Ubigene HeLa TMEM175 KO	Cancer cell line	Female
CVCL_E1C6	Ubigene SH-SY5Y TMEM175 KO	Cancer cell line	Female
CVCL_E1DV	Ubigene U2OS TMEM175 KO	Cancer cell line	Female
CVCL_E6KZ	TD-28	Induced pluripotent stem cell	Female
CVCL_E6L0	TD-28 corrected	Induced pluripotent stem cell	Female
CVCL_E6LT	3123	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00347867	PHASE4	UNKNOWN	Viagra for the Treatment of IUGR
NCT00909974	PHASE4	COMPLETED	Effect of Prenatal Nutritional Supplementation on Birth Outcome in Hounde District, Burkina Faso
NCT01352234	PHASE4	COMPLETED	Comparison of Doses of Acetylsalicylic Acid in Women With Previous History of Preeclampsia
NCT01390051	PHASE4	COMPLETED	Can Low Molecular Weight Heparin During Pregnancy With Intrauterine Growth Restriction Increase Birth Weight?
NCT01695070	PHASE4	COMPLETED	Melatonin to Prevent Brain Injury in Unborn Growth Restricted Babies
NCT03674606	PHASE4	COMPLETED	Trial of Early Screening Test for Pre-eclampsia and Growth Restriction
NCT04051567	PHASE4	UNKNOWN	Low-dose Aspirin for Prevention of Adverse Pregnancy Outcomes in Twin Pregnancies
NCT05029778	PHASE4	UNKNOWN	Arginine + Citrulline as a Supplement for Weight Gain in Fetus With a Decrease in Their Growth Curve
NCT05800938	PHASE4	COMPLETED	The Effect of Oral Isosorbide Mononitrate Therapy on Umbilical Artery Doppler Resistance Index in Pregnancies With Intrauterine Growth Restriction: Prospective Randomized Control Trial
NCT07171086	PHASE4	NOT_YET_RECRUITING	AI-POCUS for Maternal and Neonatal Health in Ethiopia
NCT00174252	PHASE3	COMPLETED	Study Aimed At Improving Height With Genotonorm In Children Born Little And/Or Light With Growth Retardation At The Age
NCT00197340	PHASE3	COMPLETED	Antepartum Chronic Epidural Therapy (ACET) to Improve Blood Flow to the Uterus, Placenta and Baby in Pre-Eclampsia and Intrauterine Growth Restriction
NCT00452491	PHASE3	COMPLETED	MAXOMAT ® in the Treatment of Severe Early Onset Intrauterine Growth Retardation on Pre-pubertal Children
NCT01073605	PHASE3	COMPLETED	Genotropin Treatment in Short Prepubertal Children With Intra-Uterine Growth Retardation
NCT02336243	PHASE3	UNKNOWN	A Randomized Trial of Docosahexaenoic Acid Supplementation During Pregnancy to Prevent Deep Placentation Disorders
NCT02590536	PHASE3	COMPLETED	A Trial Evaluating the Role of Sildenafil in the Treatment of Fetal Growth Restriction
NCT02672566	PHASE3	COMPLETED	Low-molecular-weight Heparin in Constituted Vascular Intrauterine Growth Restriction
NCT03177824	PHASE3	UNKNOWN	Sildenafil Citrate for Treatment of Growth-restricted Fetuses
NCT03230162	PHASE3	UNKNOWN	Sildenafil Versus Low Molecular Weight Heparin in Fetal Growth Restriction Treatment
NCT03324139	PHASE3	COMPLETED	Treatment of Intrauterine Growth Restriction With Low Molecular Heparin.
NCT03669185	PHASE3	UNKNOWN	Pentaerithrityl Tetranitrate (PETN) for Secondary Prevention of Intrauterine Growth Restriction
NCT04084990	PHASE3	TERMINATED	Sleep Apnea and Fetal Growth Restriction
NCT04356326	PHASE3	RECRUITING	Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy
NCT04557475	PHASE3	WITHDRAWN	Transplacental Aspirin Therapy for Early Onset Fetal Growth Restriction
NCT04762992	PHASE3	ENROLLING_BY_INVITATION	LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)
NCT05253781	PHASE3	COMPLETED	Low Dose Aspirin for Preventing Intrauterine Growth Restriction and Preeclampsia in Sickle Cell Pregnancy (PIPSICKLE)
NCT05651347	PHASE3	RECRUITING	Antenatal Melatonin Supplementation for Neuroprotection in Fetal Growth Restriction
NCT05774236	PHASE3	COMPLETED	Cook´s Balloon Versus Dinoprostone for Labor Induction of Term Pregnancies With Fetal Growth Restriction
NCT06497959	PHASE3	RECRUITING	Study of Placental Vascularization Using Contrast Ultrasound
NCT02280031	PHASE2	COMPLETED	Effect of Low Dose Aspirin on Birthweight in Twins: The GAP Trial.
NCT02425436	PHASE2	COMPLETED	Role of Ginkgo Biloba Extract in IUGR
NCT02678221	PHASE2	UNKNOWN	Sildenafil Citrate for the Management of Asymmetrical Intrauterine Growth Restriction
NCT02696577	PHASE2	COMPLETED	The Effect of Omega 3 on Pregnancy Complicated by Asymmetrical Intrauterine Growth Restriction
NCT07098975	PHASE2	RECRUITING	Statin Intervention for Severe Early-Onset Placental Insufficiency. (STATIN-PRE Trial)
NCT04508751	PHASE1	COMPLETED	PED NEONAT 20-000599 Fetal Body Composition
NCT06565728	PHASE1	COMPLETED	Vitamin D Versus Sildenafil Citrate in Fetal Growth Restriction
NCT07549295	PHASE1	ENROLLING_BY_INVITATION	Melatonin and Perinatal Outcomes in MVM-Related Fetal Growth Restriction (MIMVMFGR)
NCT01107782	PHASE2/PHASE3	UNKNOWN	Sildenafil and Uteroplacental Perfusion
NCT02277132	PHASE2/PHASE3	TERMINATED	The Dutch STRIDER (Sildenafil TheRapy In Dismal Prognosis Early-onset Fetal Growth Restriction)
NCT02442492	PHASE2/PHASE3	TERMINATED	Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction