TMEM165

Summary

TMEM165 (transmembrane protein 165, HGNC:30760) is a protein-coding gene on chromosome 4q12, encoding Putative divalent cation/proton antiporter TMEM165 (Q9HC07). Putative divalent cation:proton antiporter that exchanges calcium or manganese ions for protons across the Golgi membrane. It is a selective cancer dependency (DepMap: 10.8% of cell lines).

This gene encodes a predicted transmembrane protein with a perinuclear Golgi-like distribution in fibroblasts. Mutations in this gene are associated with the autosomal recessive disorder congenital disorder of glycosylation, type IIk. Knockdown of this gene’s expression causes decreased sialylation in HEK cells and suggests this gene plays a role in terminal Golgi glycosylation. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55858 — RefSeq curated summary.

At a glance

• Gene–disease (curated): TMEM165-congenital disorder of glycosylation (Definitive, GenCC)
• GWAS associations: 21
• Clinical variants (ClinVar): 176 total — 5 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 10.8% of screened cell lines
• MANE Select transcript: NM_018475

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30760
Approved symbol	TMEM165
Name	transmembrane protein 165
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	TMPT27, TPARL, GDT1, SLC64A1
Ensembl gene	ENSG00000134851
Ensembl biotype	protein_coding
OMIM	614726
Entrez	55858

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 8 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000381334, ENST00000502797, ENST00000506103, ENST00000506198, ENST00000508404, ENST00000508561, ENST00000509575, ENST00000511710, ENST00000514070, ENST00000514904, ENST00000515591, ENST00000608091, ENST00000882548, ENST00000882549, ENST00000882550, ENST00000882551, ENST00000954721

RefSeq mRNA: 1 — MANE Select: NM_018475 NM_018475

CCDS: CCDS3499

Canonical transcript exons

ENST00000381334 — 6 exons

Exon	Start	End
ENSE00001220922	55425376	55426175
ENSE00002063104	55395957	55396396
ENSE00003468973	55424538	55424643
ENSE00003478530	55417072	55417247
ENSE00003543724	55417803	55417985
ENSE00003576511	55411614	55411839

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.1051 / max 554.2903, expressed in 1827 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47697	43.2292	1824
47695	4.8759	1012

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	99.03	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.74	gold quality
spinal cord	UBERON:0002240	98.37	gold quality
mucosa of stomach	UBERON:0001199	97.96	gold quality
right lung	UBERON:0002167	97.94	gold quality
inferior vagus X ganglion	UBERON:0005363	97.91	gold quality
upper lobe of left lung	UBERON:0008952	97.88	gold quality
upper lobe of lung	UBERON:0008948	97.73	gold quality
palpebral conjunctiva	UBERON:0001812	97.66	gold quality
subthalamic nucleus	UBERON:0001906	97.59	gold quality
cartilage tissue	UBERON:0002418	97.55	gold quality
monocyte	CL:0000576	97.43	gold quality
lateral globus pallidus	UBERON:0002476	97.43	gold quality
left adrenal gland	UBERON:0001234	97.36	gold quality
gingival epithelium	UBERON:0001949	97.35	gold quality
body of pancreas	UBERON:0001150	97.33	gold quality
left uterine tube	UBERON:0001303	97.33	gold quality
left adrenal gland cortex	UBERON:0035825	97.30	gold quality
esophagus mucosa	UBERON:0002469	97.22	gold quality
vagina	UBERON:0000996	97.21	gold quality
calcaneal tendon	UBERON:0003701	97.16	gold quality
ectocervix	UBERON:0012249	97.10	gold quality
mononuclear cell	CL:0000842	97.09	gold quality
tibia	UBERON:0000979	97.08	gold quality
epithelium of nasopharynx	UBERON:0001951	97.08	gold quality
endometrium	UBERON:0001295	97.05	gold quality
ascending aorta	UBERON:0001496	97.05	gold quality
minor salivary gland	UBERON:0001830	97.05	gold quality
right adrenal gland	UBERON:0001233	97.01	gold quality
thoracic aorta	UBERON:0001515	97.01	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	1514.53
E-HCAD-35	yes	89.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

65 targeting TMEM165, 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-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3671	99.90	73.04	3897
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 15)

• we identified TMEM165 (also named TPARL) as a gene involved in congenital disorders of glycosylation (CDG). (PMID:22683087)
• Defects in TMEM165 affect both Ca2+ and pH homeostasis. (PMID:23569283)
• Congenital Disorders of Glycosylation disease-causing mutations of TMEM165 changes subcellular localization of the protein. (PMID:23575229)
• Antisense oligonucleotide-mediated pseudoexon skipping used in a Golgi-resident protein, a promising treatment option for a specific TMEM165-congenital disorders of glycosylation. (PMID:24720419)
• Study not only provides novel insights into the molecular causes of glycosylation defects observed in TMEM165-deficient cells but also suggests that TMEM165 is a key determinant for the regulation of Golgi Mn(2+) homeostasis. (PMID:27008884)
• This manuscript is a review of the current state of knowledge on TMEM165 deficiencies in Congenital Disorders of Glycosylation as well as new data on function of TMEM165 and some speculative models on TMEM165/Golgi functions are discussed. (PMID:27401145)
• The finding of numerous splice variants could lead to a family of TMEM165 isoforms. (PMID:28088503)
• Data indicate the Golgi protein transmembrane protein 165 (TMEM165) as a manganese-sensitive protein in mammalian cells. (PMID:28270545)
• High TMEM165 expression is associated with hepatocellular carcinoma. (PMID:30015898)
• The results show the crucial importance of two conserved motifs of TMEM165 (E-x-G-D-K-[TF] and E-x-G-D-R-[SQ]) and underline the contribution of some specific amino acids in both Golgi glycosylation and Mn(2+) sensitivity. (PMID:31351090)
• Fetal bovine serum impacts the observed N-glycosylation defects in TMEM165 KO HEK cells. (PMID:31415112)
• TMEM165 was constitutively degraded in lysosomes in the absence of SPCA1. (PMID:31652305)
• The human Golgi protein TMEM165 transports calcium and manganese in yeast and bacterial cells. (PMID:32047108)
• Serum bikunin isoforms in congenital disorders of glycosylation and linkeropathies. (PMID:32700771)
• Insights into the regulation of cellular Mn[2+] homeostasis via TMEM165. (PMID:37062452)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem165	ENSDARG00000034600
mus_musculus	Tmem165	ENSMUSG00000029234
rattus_norvegicus	Tmem165	ENSRNOG00000002199
drosophila_melanogaster	CG42542	FBGN0260659
caenorhabditis_elegans		WBGENE00021847

Protein

Protein identifiers

Putative divalent cation/proton antiporter TMEM165 — Q9HC07 (reviewed: Q9HC07)

Alternative names: Transmembrane protein 165, Transmembrane protein PT27, Transmembrane protein TPARL

All UniProt accessions (5): D6RBL0, D6RD79, Q9HC07, V9GY93, V9GYC8

UniProt curated annotations — full annotation on UniProt →

Function. Putative divalent cation:proton antiporter that exchanges calcium or manganese ions for protons across the Golgi membrane. Mediates the reversible transport of calcium or manganese to the Golgi lumen driven by the proton gradient and possibly the membrane potential generated by V-ATPase. Provides calcium or manganese cofactors to resident Golgi enzymes and contributes to the maintenance of an acidic luminal Golgi pH required for proper functioning of the secretory pathway. Promotes Ca(2+) storage within the Golgi lumen of the mammary epithelial cells to be then secreted into milk. The transport mechanism and stoichiometry remains to be elucidated.

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Ubiquitously expressed.

Disease relevance. Congenital disorder of glycosylation 2K (CDG2K) [MIM:614727] An autosomal recessive disorder with a variable phenotype. Affected individuals show psychomotor retardation and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Congenital disorders of glycosylation are caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins and a wide variety of clinical features. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the GDT1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HC07-1	1	yes
Q9HC07-2	2

RefSeq proteins (1): NP_060945* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001727	GDT1-like	Family
IPR049555	GDT1-like_CS	Conserved_site

Pfam: PF01169

Catalyzed reactions (Rhea), 2 shown:

• Ca(2+)(in) + n H(+)(out) = Ca(2+)(out) + n H(+)(in) (RHEA:76631)
• Mn(2+)(in) + n H(+)(out) = Mn(2+)(out) + n H(+)(in) (RHEA:76635)

UniProt features (27 total): topological domain 7, transmembrane region 6, sequence variant 4, mutagenesis site 3, compositionally biased region 2, signal peptide 1, chain 1, region of interest 1, coiled-coil region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HC07-F1	76.36	0.47

Functional residue map

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

Mutagenesis-validated functional residues (3):

Position	Phenotype
124	alters subcellular location.
127	no effect on subcellular location.
209–210	no effect on subcellular location.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 293 (showing top): GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, TTTGTAG_MIR520D, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOCC_TRANS_GOLGI_NETWORK, ONKEN_UVEAL_MELANOMA_UP, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOTZMANN_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_DN, LIAO_METASTASIS, GOBP_REGULATION_OF_PH

GO Biological Process (10): protein N-linked glycosylation (GO:0006487), calcium ion transport (GO:0006816), manganese ion transport (GO:0006828), intracellular calcium ion homeostasis (GO:0006874), Golgi calcium ion homeostasis (GO:0032468), Golgi calcium ion transport (GO:0032472), obsolete regulation of lysosomal lumen pH (GO:0035751), calcium ion transmembrane transport (GO:0070588), manganese ion transmembrane transport (GO:0071421), metal ion transport (GO:0030001)

GO Molecular Function (4): manganese ion transmembrane transporter activity (GO:0005384), calcium ion transmembrane transporter activity (GO:0015085), antiporter activity (GO:0015297), metal ion transmembrane transporter activity (GO:0046873)

GO Cellular Component (7): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), Golgi apparatus (GO:0005794), endosome membrane (GO:0010008), trans-Golgi network membrane (GO:0032588), cis-Golgi network membrane (GO:0033106), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
bounding membrane of organelle	3
metal ion transport	2
Golgi apparatus	2
calcium ion transport	2
monoatomic cation transmembrane transport	2
glycoprotein biosynthetic process	1
transition metal ion transport	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
intracellular calcium ion homeostasis	1
manganese ion transport	1
monoatomic cation transport	1
transition metal ion transmembrane transporter activity	1
manganese ion transmembrane transport	1
metal ion transmembrane transporter activity	1
calcium ion transmembrane transport	1
secondary active transmembrane transporter activity	1
monoatomic cation transmembrane transporter activity	1
lysosome	1
lytic vacuole membrane	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endosome	1
cytoplasmic vesicle membrane	1
trans-Golgi network	1
organelle membrane	1
cis-Golgi network	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1162 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM165	TM9SF2	Q99805	607
TMEM165	ALG2	Q9H553	582
TMEM165	GOSR1	O95249	568
TMEM165	SLC10A7	Q0GE19	559
TMEM165	ATP2C1	P98194	534
TMEM165	GOLIM4	O00461	527
TMEM165	PIGO	Q8TEQ8	513
TMEM165	UNC50	Q53HI1	502
TMEM165	SRD5A3	Q9H8P0	480
TMEM165	PDCL2	Q8N4E4	480
TMEM165	CSNK1E	P49674	480
TMEM165	COG7	P83436	478
TMEM165	COG2	Q14746	478
TMEM165	PMM2	O15305	474
TMEM165	COG4	Q9H9E3	470

IntAct

78 interactions, top by confidence:

A	B	Type	Score
CNOT2	CNOT1	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
STX5	GOSR2	psi-mi:“MI:0914”(association)	0.670
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
VSIG1	TNPO2	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
PROM1	TMEM165	psi-mi:“MI:0915”(physical association)	0.370
REL	TMEM165	psi-mi:“MI:0915”(physical association)	0.370
AHSP	TMEM165	psi-mi:“MI:0915”(physical association)	0.370
Snw1	AKR7A2	psi-mi:“MI:0914”(association)	0.350
SMC6	IFT88	psi-mi:“MI:0914”(association)	0.350
Rab5c		psi-mi:“MI:0914”(association)	0.350
Prkci	LLGL2	psi-mi:“MI:0914”(association)	0.350
Klhl21	DERL1	psi-mi:“MI:0914”(association)	0.350
CDK1	CHEK1	psi-mi:“MI:0914”(association)	0.350
USP43	DKFZP586J0619	psi-mi:“MI:0914”(association)	0.350
Evpl	RAD9A	psi-mi:“MI:0914”(association)	0.350
CDK2AP1	MTA3	psi-mi:“MI:0914”(association)	0.350
GPATCH8	FDX1	psi-mi:“MI:0914”(association)	0.350
Tubg1	ZC3H18	psi-mi:“MI:0914”(association)	0.350
SMC3	NEURL4	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (139): TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), TMEM165 (Two-hybrid)

ESM2 similar proteins: A0A365, A0QHM5, A0QX51, A1E9V4, A1EA38, A1KIW9, A2AKQ0, A2VE55, A4FIS6, B8ZR76, F1QGW6, P06247, P0C315, P0C316, P20461, P41091, P49020, P53033, P60161, P60162, P65263, P81795, P9WK98, P9WK99, Q15363, Q15B89, Q1KXS9, Q2KHU8, Q2MI71, Q2MIF8, Q2VEF0, Q33C02, Q3C1M5, Q49KW8, Q4VZI6, Q5HZM6, Q5R797, Q5RIC0, Q5ZHS1, Q5ZMS3

Diamond homologs: A2YXC7, A2ZE50, B8AAM2, B9G125, P38301, P52875, P52876, Q10320, Q2R2Z4, Q2R4J1, Q4V899, Q5NAY7, Q6ZIB9, Q93Y38, Q94AX5, Q9C6M1, Q9HC07, Q9P7Q0, Q9SX28, Q9T0H9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	74
Likely benign	66
Benign	17

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
2768393	NM_018475.5(TMEM165):c.747G>A (p.Trp249Ter)	Pathogenic
3246588	NC_000004.11:g.(?55124936)(57786056_?)del	Pathogenic
35518	NM_018475.5(TMEM165):c.792+182G>A	Pathogenic
35519	NM_018475.5(TMEM165):c.377G>A (p.Arg126His)	Pathogenic
35521	NM_018475.5(TMEM165):c.910G>A (p.Gly304Arg)	Pathogenic
4845777	NM_018475.5(TMEM165):c.919del (p.Val307fs)	Likely pathogenic

SpliceAI

3211 predictions. Top by Δscore:

Variant	Effect	Δscore
4:55411613:GA:G	acceptor_gain	1.0000
4:55411613:GAAA:G	acceptor_gain	1.0000
4:55411837:CAGGT:C	donor_loss	1.0000
4:55411838:AGGTG:A	donor_loss	1.0000
4:55411839:GGTG:G	donor_loss	1.0000
4:55411840:GTG:G	donor_loss	1.0000
4:55411841:T:A	donor_loss	1.0000
4:55417245:G:GT	donor_gain	1.0000
4:55417245:GAA:G	donor_gain	1.0000
4:55417248:G:GG	donor_gain	1.0000
4:55438277:ATTAC:A	donor_loss	1.0000
4:55438278:TTAC:T	donor_loss	1.0000
4:55438279:TAC:T	donor_loss	1.0000
4:55438280:A:C	donor_loss	1.0000
4:55442435:ATCTG:A	donor_gain	1.0000
4:55442436:T:C	donor_gain	1.0000
4:55443839:C:CT	acceptor_gain	1.0000
4:55443839:C:T	acceptor_gain	1.0000
4:55443894:CAT:C	acceptor_gain	1.0000
4:55443897:C:CC	acceptor_gain	1.0000
4:55443898:T:C	acceptor_gain	1.0000
4:55443899:T:C	acceptor_gain	1.0000
4:55444629:TTA:T	donor_loss	1.0000
4:55444630:TACC:T	donor_loss	1.0000
4:55444631:AC:A	donor_loss	1.0000
4:55444632:CCT:C	donor_loss	1.0000
4:55444794:CCATG:C	acceptor_gain	1.0000
4:55444795:CA:C	acceptor_gain	1.0000
4:55444796:A:AC	acceptor_gain	1.0000
4:55444796:A:C	acceptor_gain	1.0000

AlphaMissense

2072 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:55411737:G:C	D111H	1.000
4:55411738:A:C	D111A	1.000
4:55411738:A:T	D111V	1.000
4:55411746:T:C	F114L	1.000
4:55411748:T:A	F114L	1.000
4:55411748:T:G	F114L	1.000
4:55417081:G:A	G148D	1.000
4:55417146:T:C	F170L	1.000
4:55417148:T:A	F170L	1.000
4:55417148:T:G	F170L	1.000
4:55417149:G:C	G171R	1.000
4:55417150:G:A	G171D	1.000
4:55417945:A:C	D251A	1.000
4:55417945:A:G	D251G	1.000
4:55417945:A:T	D251V	1.000
4:55424560:G:A	G272D	1.000
4:55424572:G:A	G276E	1.000
4:55425390:G:C	G305R	1.000
4:55425399:T:C	F308L	1.000
4:55425401:T:A	F308L	1.000
4:55425401:T:G	F308L	1.000
4:55411714:T:A	V103D	0.999
4:55411725:T:C	S107P	0.999
4:55411729:A:C	E108A	0.999
4:55411729:A:T	E108V	0.999
4:55411730:A:C	E108D	0.999
4:55411730:A:T	E108D	0.999
4:55411734:G:C	G110R	0.999
4:55411735:G:A	G110D	0.999
4:55411738:A:G	D111G	0.999

dbSNP variants (sampled 300 via entrez): RS1000070451 (4:55440593 C>A,G), RS1000088900 (4:55433483 G>C), RS1000121491 (4:55433152 T>C), RS1000192407 (4:55418567 A>G), RS1000270209 (4:55407917 A>G), RS1000280217 (4:55412319 A>G), RS1000301006 (4:55425720 C>T), RS1000312726 (4:55421004 C>T), RS1000355221 (4:55412642 T>C), RS1000539211 (4:55395558 G>T), RS1000556197 (4:55415516 A>C,T), RS1000609543 (4:55438003 G>A), RS1000617950 (4:55414064 C>A,T), RS1000650630 (4:55422815 A>C,G), RS1000661831 (4:55422507 C>T)

Disease associations

OMIM: gene MIM:614726 | disease phenotypes: MIM:614727, MIM:606764, MIM:142623

GenCC curated gene-disease

Disease	Classification	Inheritance
TMEM165-congenital disorder of glycosylation	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
TMEM165-congenital disorder of glycosylation	Moderate	AR

Mondo (3): TMEM165-congenital disorder of glycosylation (MONDO:0013870), gastrointestinal stromal tumor (MONDO:0011719), Hirschsprung disease (MONDO:0018309)

Orphanet (3): TMEM165-CDG (Orphanet:314667), Gastrointestinal stromal tumor (Orphanet:44890), Hirschsprung disease (Orphanet:388)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000272	Malar flattening
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000705	Amelogenesis imperfecta
HP:0000939	Osteoporosis
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001324	Muscle weakness
HP:0001382	Joint hypermobility
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001873	Thrombocytopenia
HP:0001955	Unexplained fevers
HP:0002240	Hepatomegaly
HP:0002500	Abnormal cerebral white matter morphology
HP:0002656	Epiphyseal dysplasia
HP:0002751	Kyphoscoliosis
HP:0003236	Elevated circulating creatine kinase concentration
HP:0004322	Short stature
HP:0005484	Secondary microcephaly
HP:0005575	Hemolytic-uremic syndrome
HP:0011800	Midface retrusion
HP:0031956	Elevated circulating aspartate aminotransferase concentration
HP:0031964	Elevated circulating alanine aminotransferase concentration
HP:0100252	Diaphyseal dysplasia
HP:0100255	Metaphyseal dysplasia

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST005962_39	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-06
GCST007267_124	Systolic blood pressure	2.000000e-10
GCST010699_101	Brain morphology (min-P)	1.000000e-11
GCST010701_29	Cortical surface area (MOSTest)	2.000000e-31
GCST010702_108	Subcortical volume (MOSTest)	1.000000e-09
GCST010703_345	Brain morphology (MOSTest)	4.000000e-10
GCST012227_1028	Hip circumference adjusted for BMI	7.000000e-10
GCST90020024_701	A body shape index	7.000000e-12
GCST90020025_317	Waist-to-hip ratio adjusted for BMI	4.000000e-14
GCST90020025_319	Waist-to-hip ratio adjusted for BMI	8.000000e-19
GCST90020025_320	Waist-to-hip ratio adjusted for BMI	4.000000e-15
GCST90020025_322	Waist-to-hip ratio adjusted for BMI	2.000000e-25
GCST90020026_283	Hip index	7.000000e-16
GCST90020026_285	Hip index	3.000000e-11
GCST90020027_1892	Waist-hip index	8.000000e-15
GCST90020027_1894	Waist-hip index	1.000000e-19
GCST90020027_1895	Waist-hip index	4.000000e-15
GCST90020027_1897	Waist-hip index	2.000000e-26
GCST90020028_1930	Hip circumference adjusted for BMI	2.000000e-10
GCST90020028_1931	Hip circumference adjusted for BMI	1.000000e-12
GCST90020029_697	Waist circumference adjusted for body mass index	5.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0006335	systolic blood pressure
EFO:0004346	neuroimaging measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D046152	Gastrointestinal Stromal Tumors	C04.557.450.565.370; C06.301.371.308; C06.405.249.308
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067325 (SINGLE PROTEIN)

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1801260	CLOCK, TMEM165	4	-1.50	1	lithium
rs3736544	CLOCK, TMEM165		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC64 Golgi Ca²⁺/H⁺ exchangers

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.77	Kd	17.11	nM	CHEMBL5653589
7.77	ED50	17.11	nM	CHEMBL5653589
5.05	Kd	8832	nM	CHEMBL3752910
5.05	ED50	8832	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149611: Binding affinity to human TMEM165 incubated for 45 mins by Kinobead based pull down assay	kd	0.0171	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149611: Binding affinity to human TMEM165 incubated for 45 mins by Kinobead based pull down assay	kd	8.8316	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	3
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
nickel chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentabromodiphenyl ether	decreases expression	1
monomethylarsonous acid	increases expression	1
torcetrapib	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
Atrazine	decreases expression	1
Catechin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Nickel	increases expression	1
Quercetin	decreases expression	1
Ribonucleotides	affects binding	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	increases expression	1
Gold Compounds	increases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	increases expression	1
beta-Naphthoflavone	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652653	Binding	Binding affinity to human TMEM165 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3JL	Abcam HEK293T TMEM165 KO	Transformed cell line	Female
CVCL_D4R8	HCT116-TMEM165-KO-c21	Cancer cell line	Male
CVCL_D4R9	HCT116-TMEM165-KO-c36	Cancer cell line	Male
CVCL_E0RA	Ubigene HeLa TMEM165 KO	Cancer cell line	Female
CVCL_E2M2	HAP1 TMEM165 (-) 1	Cancer cell line	Male
CVCL_E2M3	HAP1 TMEM165 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00171977	PHASE4	COMPLETED	Post-Marketing Clinical Study of Postoperative Adjuvant Therapy With Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT00510354	PHASE4	COMPLETED	Treatment of Patients With Everolimus and Imatinib Mesylate Who Have Progressive Gastro Intestinal Stromal Tumors (GIST) and Are Resistant to Imatinib Mesylate
NCT00756509	PHASE4	COMPLETED	Treatment of Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors in First Line With Nilotinib
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT02800330	PHASE4	COMPLETED	The Effects of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib
NCT04825574	PHASE4	COMPLETED	Study for Patients Previously Treated in Avapritinib Clinical Trials
NCT00009906	PHASE3	TERMINATED	Comparison of Two Different Doses of STI571 in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00041197	PHASE3	COMPLETED	Imatinib Mesylate in Treating Patients With Primary Gastrointestinal Stromal Tumor That Has Been Completely Removed By Surgery
NCT00075218	PHASE3	COMPLETED	A Study To Assess The Safety And Efficacy Of SU11248 In Patients With Gastrointestinal Stromal Tumor(GIST)
NCT00103168	PHASE3	COMPLETED	Imatinib Mesylate or Observation Only in Treating Patients Who Have Undergone Surgery for Localized Gastrointestinal Stromal Tumor
NCT00293124	PHASE3	COMPLETED	Open-label Trial of GlivecWith Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumors
NCT00324987	PHASE3	TERMINATED	Imatinib Mesylate With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00372567	PHASE3	TERMINATED	Safety And Effectiveness Of Daily Dosing With Sunitinib Or Imatinib In Patients With Gastrointestinal Stromal Tumors
NCT00471328	PHASE3	COMPLETED	Efficacy and Safety of Nilotinib (AMN107) Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib
NCT00685828	PHASE3	UNKNOWN	Imatinib Mesylate in Treating Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumor
NCT00688766	PHASE3	TERMINATED	Study Evaluating IPI-504 in Patients With Gastrointestinal Stromal Tumors (GIST) Following Failure of at Least Imatinib and Sunitinib
NCT00751036	PHASE3	TERMINATED	Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg
NCT00785785	PHASE3	COMPLETED	A Study of Nilotinib Versus Imatinib in GIST Patients
NCT00812240	PHASE3	TERMINATED	Masitinib in First Line Treatment of Gastro-Intestinal Stromal Tumor (GIST)
NCT00956072	PHASE3	TERMINATED	Imatinib Mesylate With or Without Surgery in Treating Patients With Metastatic Gastrointestinal Stromal Tumor That is Responding to Imatinib Mesylate
NCT01031628	PHASE3	TERMINATED	Study of Dose Escalation Versus no Dose Escalation of Imatinib in Metastatic Gastrointestinal Stromal Tumors (GIST) Patients
NCT01151852	PHASE3	COMPLETED	Rechallenge of Imatinib in GIST Having no Effective Treatment: RIGHT
NCT01265810	PHASE3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01271712	PHASE3	COMPLETED	Study of Regorafenib as a 3rd-line or Beyond Treatment for Gastrointestinal Stromal Tumors (GIST)
NCT01289028	PHASE3	COMPLETED	Efficacy of Nilotinib in Adult Patients With Gastrointestinal Stromal Tumors Resistant to Imatinib and Sunitinib.
NCT01462994	PHASE3	COMPLETED	Detection of CF-DNA in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT01694277	PHASE3	COMPLETED	Masitinib in Patients With Gastrointestinal Stromal Tumour After Progression With Imatinib
NCT02260505	PHASE3	COMPLETED	Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)
NCT02576080	PHASE3	UNKNOWN	Efficacy of Imatinib in Patients With Intermediate-risk Gastrointestinal Stromal Tumor With a High-risk Genomic Grade Index
NCT02866045	PHASE3	UNKNOWN	EUS-FNB vs. Single-incision Needle-knife (SINK) Biopsy for Gastrointestinal SELs
NCT03353753	PHASE3	COMPLETED	Phase 3 Study of DCC-2618 vs Placebo in Advanced GIST Patients Who Have Been Treated With Prior Anticancer Therapies
NCT03426722	PHASE3	COMPLETED	L-carnitine vs Placebo for the Treatment of Muscle Cramps After Imatinib in Gastrointestinal Stromal Tumors
NCT03465722	PHASE3	COMPLETED	(VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST
NCT03673501	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Advanced GIST Patients After Treatment With Imatinib
NCT04409223	PHASE3	TERMINATED	Efficacy and Safety of Famitinib Versus Sunitinib in the Treatment of Advanced Gastrointestinal Stromal Tumour Patients After Failure of Imatinib
NCT05208047	PHASE3	ACTIVE_NOT_RECRUITING	(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors
NCT05734105	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Patients With Advanced GIST With Specific KIT Exon Mutations Who Were Previously Treated With Imatinib
NCT06640361	PHASE3	RECRUITING	A Study of Olverembatinib in SDH-deficient GIST.
NCT07585266	PHASE3	NOT_YET_RECRUITING	A Study to Investigate Velzatinib Compared With Imatinib in Adult Participants With Previously Untreated Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (StrateGIST Frontline)
NCT00003939	PHASE2	COMPLETED	Ecteinascidin 743 in Treating Patients With Advanced Soft Tissue Sarcoma