TMEM164

Summary

TMEM164 (transmembrane protein 164, HGNC:26217) is a protein-coding gene on chromosome Xq23, encoding Transmembrane protein 164 (Q5U3C3). Positive regulator of ferroptosis.

Involved in positive regulation of ferroptosis. Predicted to be located in membrane.

Source: NCBI Gene 84187 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 98 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_032227

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26217
Approved symbol	TMEM164
Name	transmembrane protein 164
Location	Xq23
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22679, RP13-360B22.2
Ensembl gene	ENSG00000157600
Ensembl biotype	protein_coding
Entrez	84187

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000288381, ENST00000372068, ENST00000372072, ENST00000372073, ENST00000461715, ENST00000464177, ENST00000471255, ENST00000497754, ENST00000896192, ENST00000896193, ENST00000896194, ENST00000956907

RefSeq mRNA: 6 — MANE Select: NM_032227 NM_001353849, NM_001353850, NM_001353851, NM_001410717, NM_017698, NM_032227

CCDS: CCDS14550, CCDS55475, CCDS94649

Canonical transcript exons

ENST00000372068 — 7 exons

Exon	Start	End
ENSE00001456845	110003114	110003178
ENSE00003651240	110144798	110144876
ENSE00003683407	110171420	110171520
ENSE00003895608	110173245	110177788
ENSE00004282430	110067347	110067396
ENSE00004282432	110109080	110109146
ENSE00004282433	110003501	110004164

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 94.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.0100 / max 254.4708, expressed in 1733 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197257	11.0949	1497
197255	2.2322	1188
197258	0.3851	192
197256	0.2978	143

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	94.81	gold quality
lower lobe of lung	UBERON:0008949	93.35	gold quality
monocyte	CL:0000576	93.32	gold quality
mononuclear cell	CL:0000842	93.26	gold quality
upper arm skin	UBERON:0004263	93.05	gold quality
leukocyte	CL:0000738	92.95	gold quality
left ventricle myocardium	UBERON:0006566	92.93	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.93	gold quality
nipple	UBERON:0002030	91.07	gold quality
cardiac muscle of right atrium	UBERON:0003379	90.65	gold quality
upper leg skin	UBERON:0004262	90.46	gold quality
pancreatic ductal cell	CL:0002079	90.30	silver quality
duodenum	UBERON:0002114	89.87	gold quality
blood	UBERON:0000178	89.75	gold quality
islet of Langerhans	UBERON:0000006	89.71	gold quality
tibialis anterior	UBERON:0001385	89.59	silver quality
gastrocnemius	UBERON:0001388	89.57	gold quality
heart left ventricle	UBERON:0002084	89.50	gold quality
mucosa of transverse colon	UBERON:0004991	89.45	gold quality
mammalian vulva	UBERON:0000997	89.44	gold quality
cardiac ventricle	UBERON:0002082	89.43	gold quality
colonic mucosa	UBERON:0000317	89.22	gold quality
muscle of leg	UBERON:0001383	89.18	gold quality
myocardium	UBERON:0002349	89.11	gold quality
apex of heart	UBERON:0002098	89.09	gold quality
muscle organ	UBERON:0001630	88.65	gold quality
skeletal muscle organ	UBERON:0014892	88.65	gold quality
rectum	UBERON:0001052	88.63	gold quality
choroid plexus epithelium	UBERON:0003911	88.52	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.36	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	20.96
E-MTAB-9801	yes	5.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

225 targeting TMEM164, 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-3646	100.00	73.56	5283
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580

Literature-anchored findings (GeneRIF, showing 2)

• Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes are associated with Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis. (PMID:30737907)
• TMEM164 promotes ferroptosis by selectively mediating ATG5-dependent autophagosome formation to inhibit the progression of LUAD. (PMID:39392409)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	TMEM164	ENSDARG00000113609
mus_musculus	Tmem164	ENSMUSG00000047045
rattus_norvegicus	Tmem164	ENSRNOG00000012787
drosophila_melanogaster	CG14591	FBGN0033054
caenorhabditis_elegans		WBGENE00007959

Protein

Protein identifiers

Transmembrane protein 164 — Q5U3C3 (reviewed: Q5U3C3)

Alternative names: Arachidonoyl ether phospholipid synthase

All UniProt accessions (2): Q5U3C3, A1PI58

UniProt curated annotations — full annotation on UniProt →

Function. Positive regulator of ferroptosis. Involved in the acylation of ether lysophospholipids with the arachidonoyl chain (5Z,8Z,11Z,14Z-eicosatetraenoyl; C20:4) of diacylglycerophospholipids, generating C20:4 ether glycerophospholipids (ePEs) such as 1-(1Z-octadecenyl)-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphoethanolamine (PE (P-18:0/20:4)), which promotes ferroptosis. Selectively mediates ATG5-dependent autophagosome formation during ferroptosis, rather than during starvation, and regulates the degradation of ferritin, GPX4 and lipid droplets to increase iron accumulation and lipid peroxidation, thereby promoting ferroptotic cell death.

Subcellular location. Membrane.

Similarity. Belongs to the TMEM164 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5U3C3-1	1	yes
Q5U3C3-2	2

RefSeq proteins (6): NP_001340778, NP_001340779, NP_001340780, NP_001397646, NP_060168, NP_115603* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026508	TMEM164	Family

Pfam: PF14808

Catalyzed reactions (Rhea), 1 shown:

• 1-(1Z-octadecenyl)-sn-glycero-3-phosphoethanolamine + 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine = 1-(1Z-octadecenyl)-2-(5Z,8Z,11Z,14Z- eicosatetraenoyl)-sn-glycero-3-phosphoethanolamine + 1-octadecanoyl-sn-glycero-3-phosphocholine (RHEA:79431)

UniProt features (14 total): transmembrane region 7, sequence variant 2, chain 1, splice variant 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9LW1	ELECTRON MICROSCOPY	2.5
9LW3	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5U3C3-F1	90.02	0.80

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 136 (showing top): ONKEN_UVEAL_MELANOMA_UP, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, HP1SITEFACTOR_Q6, DOUGLAS_BMI1_TARGETS_DN, RYTTCCTG_ETS2_B, GATA4_Q3, XU_GH1_AUTOCRINE_TARGETS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, TGGAAA_NFAT_Q4_01, MARSON_BOUND_BY_FOXP3_STIMULATED, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, GEORGES_TARGETS_OF_MIR192_AND_MIR215, CHEN_METABOLIC_SYNDROM_NETWORK, PR_Q2, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_DN

GO Biological Process (1): positive regulation of ferroptosis (GO:0160020)

GO Molecular Function (0):

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of programmed cell death	1
ferroptosis	1
regulation of ferroptosis	1
cellular anatomical structure	1

Protein interactions and networks

STRING

450 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM164	AMMECR1	Q9Y4X0	625
TMEM164	RTL9	Q8NET4	578
TMEM164	SERTM1	A2A2V5	530
TMEM164	FAM91A1	Q658Y4	527
TMEM164	TMEM14A	Q9Y6G1	506
TMEM164	TMEM62	Q0P6H9	478
TMEM164	FAM156A	Q8NDB6	444
TMEM164	SLITRK2	Q9H156	437
TMEM164	SPAG5	Q96R06	433
TMEM164	CXorf38	Q8TB03	422
TMEM164	ST3GAL3	Q11203	422
TMEM164	TMEM132A	Q24JP5	416
TMEM164	DENND1A	Q8TEH3	413
TMEM164	ZNF607	Q96SK3	407
TMEM164	GUCY2F	P51841	400

IntAct

42 interactions, top by confidence:

A	B	Type	Score
EIF2B2	SLC27A2	psi-mi:“MI:0914”(association)	0.640
GLMN	FKBP5	psi-mi:“MI:0914”(association)	0.640
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC9A6	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
KIF2B	BACH1	psi-mi:“MI:0914”(association)	0.530
LRRC8B	SLC25A17	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
MME	TMEM223	psi-mi:“MI:0914”(association)	0.530
SLC2A12	METTL15	psi-mi:“MI:0914”(association)	0.530
UPK1A	TMEM223	psi-mi:“MI:0914”(association)	0.350
VIPR2	C15orf61	psi-mi:“MI:0914”(association)	0.350
NRG1	HS6ST1	psi-mi:“MI:0914”(association)	0.350
TACR1	GPR89A	psi-mi:“MI:0914”(association)	0.350
P2RY12	GPR89A	psi-mi:“MI:0914”(association)	0.350
SYP	APBB1	psi-mi:“MI:0914”(association)	0.350
SLC22A16	AGPAT2	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
BSCL2	TMEM223	psi-mi:“MI:0914”(association)	0.350
GPR17	TMEM120B	psi-mi:“MI:0914”(association)	0.350
C5AR1	TCAF2	psi-mi:“MI:0914”(association)	0.350

BioGRID (50): TMEM164 (Affinity Capture-RNA), TMEM164 (Affinity Capture-RNA), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GVZ9, A4IFN5, A5PK40, A6NH52, A6NI61, B2LYG4, B2RZC9, B6ID01, D2HKB0, D3ZG27, P86229, Q0VDI3, Q15012, Q15546, Q17QJ2, Q1RLT2, Q2TA01, Q4R4I5, Q4R6E8, Q5H8A4, Q5R7Q1, Q5RAH0, Q5RL79, Q5U3C3, Q5VTY9, Q5ZML7, Q64232, Q6PHN7, Q6QRN8, Q719N3, Q71SV0, Q8BWB6, Q8IY49, Q8N6M3, Q8NFT2, Q8R189, Q8VD53, Q8VDI9, Q8VDR5, Q9CQC4

Diamond homologs: Q5EA91, Q5U3C3, Q6PHN7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	5	22.8×	1e-03
monoatomic ion transport	5	16.2×	3e-03
phospholipase C-activating G protein-coupled receptor signaling pathway	5	13.7×	4e-03
adenylate cyclase-activating G protein-coupled receptor signaling pathway	5	11.8×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	21
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
816379	GRCh37/hg19 Xq23(chrX:109418639-110180983)x1	Pathogenic

SpliceAI

2007 predictions. Top by Δscore:

Variant	Effect	Δscore
X:110004161:GCAT:G	donor_gain	1.0000
X:110004165:G:GG	donor_gain	1.0000
X:110067339:A:AG	acceptor_gain	1.0000
X:110067340:A:G	acceptor_gain	1.0000
X:110067397:G:GG	donor_gain	1.0000
X:110109075:TCTA:T	acceptor_loss	1.0000
X:110109077:TAGG:T	acceptor_gain	1.0000
X:110109077:TAGGC:T	acceptor_loss	1.0000
X:110109078:A:AG	acceptor_gain	1.0000
X:110109078:A:AT	acceptor_loss	1.0000
X:110109078:AG:A	acceptor_gain	1.0000
X:110109079:G:GG	acceptor_gain	1.0000
X:110109079:GG:G	acceptor_gain	1.0000
X:110109142:GGCTG:G	donor_gain	1.0000
X:110109143:GCTG:G	donor_gain	1.0000
X:110109143:GCTGG:G	donor_gain	1.0000
X:110109144:CTGG:C	donor_loss	1.0000
X:110109146:GGT:G	donor_loss	1.0000
X:110109147:G:GC	donor_loss	1.0000
X:110109147:G:GG	donor_gain	1.0000
X:110109148:T:A	donor_loss	1.0000
X:110171415:TCCA:T	acceptor_loss	1.0000
X:110171416:CCA:C	acceptor_loss	1.0000
X:110171417:CAGG:C	acceptor_loss	1.0000
X:110171418:A:AT	acceptor_loss	1.0000
X:110171419:G:GT	acceptor_loss	1.0000
X:110171516:GCCTG:G	donor_gain	1.0000
X:110171518:CTGGT:C	donor_loss	1.0000
X:110171519:TGGT:T	donor_loss	1.0000
X:110171520:GGT:G	donor_loss	1.0000

AlphaMissense

1919 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:110004142:G:A	C123Y	1.000
X:110004144:C:G	H124D	1.000
X:110173259:T:A	N234K	1.000
X:110173259:T:G	N234K	1.000
X:110003860:G:A	C29Y	0.999
X:110003861:T:G	C29W	0.999
X:110003868:T:C	F32L	0.999
X:110003870:C:A	F32L	0.999
X:110003870:C:G	F32L	0.999
X:110003898:A:C	S42R	0.999
X:110003900:T:A	S42R	0.999
X:110003900:T:G	S42R	0.999
X:110004072:T:C	C100R	0.999
X:110004085:G:A	G104E	0.999
X:110004102:A:G	K110E	0.999
X:110004104:G:C	K110N	0.999
X:110004104:G:T	K110N	0.999
X:110004130:T:C	L119P	0.999
X:110004137:C:A	N121K	0.999
X:110004137:C:G	N121K	0.999
X:110004141:T:C	C123R	0.999
X:110004142:G:T	C123F	0.999
X:110004143:T:G	C123W	0.999
X:110004146:C:A	H124Q	0.999
X:110004146:C:G	H124Q	0.999
X:110109102:G:A	G155R	0.999
X:110109102:G:C	G155R	0.999
X:110109103:G:A	G155E	0.999
X:110144831:C:A	H181N	0.999
X:110144831:C:G	H181D	0.999

dbSNP variants (sampled 300 via entrez): RS1000000065 (X:110098264 G>C,T), RS1000029946 (X:110155853 C>T), RS1000048254 (X:110088266 T>A), RS1000080222 (X:110156443 G>A), RS1000127287 (X:110138968 T>C), RS1000136842 (X:110078287 G>C,T), RS1000149379 (X:110088682 T>C), RS1000199791 (X:110123656 A>C,G), RS1000203182 (X:110040278 T>C), RS1000213816 (X:110120096 A>G), RS1000239654 (X:110059754 C>T), RS1000272221 (X:110107420 A>G), RS1000285864 (X:110079007 A>G), RS1000310448 (X:110145123 C>G,T), RS1000325771 (X:110070037 C>T)

Disease associations

OMIM: gene `` | disease phenotypes: MIM:300990

GenCC curated gene-disease

Mondo (1): midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MONDO:0010516)

Orphanet (1): Midface hypoplasia-hearing impairment-elliptocytosis-nephrocalcinosis syndrome (Orphanet:688581)

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: yes

ChEMBL targets (1): CHEMBL6067184 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.59	Kd	2561	nM	CHEMBL5653589
5.52	ED50	3041	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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	2149610: Binding affinity to human TMEM164 incubated for 45 mins by Kinobead based pull down assay	kd	2.5608	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione	increases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	increases methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
abrine	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Coumestrol	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Progesterone	increases expression	1
Dihydrotestosterone	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Isotretinoin	decreases expression	1
Cyclosporine	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
CHEMBL5652652	Binding	Binding affinity to human TMEM164 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

Clinical trials (associated diseases)

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