TMEM64

Summary

TMEM64 (transmembrane protein 64, HGNC:25441) is a protein-coding gene on chromosome 8q21.3, encoding Transmembrane protein 64 (Q6YI46). Positively regulates TNFSF11-induced osteoclast differentiation.

Predicted to be involved in several processes, including negative regulation of canonical Wnt signaling pathway; negative regulation of osteoblast differentiation; and positive regulation of cell differentiation. Predicted to act upstream of or within regulation of ATP-dependent activity. Predicted to be located in membrane. Predicted to be active in endoplasmic reticulum.

Source: NCBI Gene 169200 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 18 total
• MANE Select transcript: NM_001008495

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25441
Approved symbol	TMEM64
Name	transmembrane protein 64
Location	8q21.3
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp762C1112
Ensembl gene	ENSG00000180694
Ensembl biotype	protein_coding
OMIM	620429
Entrez	169200

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000418210, ENST00000422900, ENST00000458549, ENST00000519519, ENST00000521211, ENST00000521852, ENST00000523902, ENST00000883954

RefSeq mRNA: 2 — MANE Select: NM_001008495 NM_001008495, NM_001146273

CCDS: CCDS34920, CCDS55260

Canonical transcript exons

ENST00000458549 — 3 exons

Exon	Start	End
ENSE00001228110	90631552	90631707
ENSE00001646472	90645111	90646083
ENSE00003845732	90622000	90625862

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 99.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.9131 / max 511.0529, expressed in 1781 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93895	21.1440	1717
93893	9.5777	1632
205252	1.0367	208
93890	0.6526	148
93889	0.4732	110
93894	0.4703	150
93892	0.3479	126
93891	0.2109	103

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.65	gold quality
cauda epididymis	UBERON:0004360	97.47	gold quality
adult organism	UBERON:0007023	94.59	gold quality
adrenal tissue	UBERON:0018303	93.83	gold quality
caput epididymis	UBERON:0004358	92.51	gold quality
seminal vesicle	UBERON:0000998	92.11	gold quality
germinal epithelium of ovary	UBERON:0001304	91.58	gold quality
jejunal mucosa	UBERON:0000399	90.60	gold quality
deltoid	UBERON:0001476	90.18	gold quality
tibialis anterior	UBERON:0001385	90.01	gold quality
pigmented layer of retina	UBERON:0001782	89.54	gold quality
buccal mucosa cell	CL:0002336	89.08	gold quality
ileal mucosa	UBERON:0000331	88.90	gold quality
islet of Langerhans	UBERON:0000006	88.51	gold quality
corpus callosum	UBERON:0002336	88.12	gold quality
quadriceps femoris	UBERON:0001377	87.91	gold quality
lower lobe of lung	UBERON:0008949	87.76	gold quality
superficial temporal artery	UBERON:0001614	87.71	gold quality
vastus lateralis	UBERON:0001379	87.66	gold quality
jejunum	UBERON:0002115	87.56	gold quality
biceps brachii	UBERON:0001507	86.88	gold quality
urinary bladder	UBERON:0001255	86.86	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.49	gold quality
mammalian vulva	UBERON:0000997	86.48	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	86.05	gold quality
upper arm skin	UBERON:0004263	86.03	gold quality
smooth muscle tissue	UBERON:0001135	85.94	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	85.05	gold quality
parietal pleura	UBERON:0002400	85.03	gold quality
skeletal muscle tissue	UBERON:0001134	84.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.08
E-HCAD-38	no	433.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

252 targeting TMEM64, 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-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-548C-3P	99.99	74.01	7587
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-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345

Literature-anchored findings (GeneRIF, showing 2)

• Low TMEM64 expression is associated with Osteoporosis. (PMID:31814858)
• [TMEM64 is highly expressed in hepatocellular carcinoma and promotes tumor cell proliferation and invasion]. (PMID:37712271)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem64	ENSDARG00000061723
mus_musculus	Tmem64	ENSMUSG00000043252
rattus_norvegicus	Tmem64	ENSRNOG00000007426
rattus_norvegicus	AABR07002627.1	ENSRNOG00000060587
drosophila_melanogaster	CG11367	FBGN0037185

Paralogs (2): TMEM41A (ENSG00000163900), TMEM41B (ENSG00000166471)

Protein

Protein identifiers

Transmembrane protein 64 — Q6YI46 (reviewed: Q6YI46)

All UniProt accessions (3): Q6YI46, E5RIS8, H0Y6S7

UniProt curated annotations — full annotation on UniProt →

Function. Positively regulates TNFSF11-induced osteoclast differentiation. Acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with SERCA2 which is critical for the TNFSF11-induced CREB1 activation and mitochondrial ROS generation necessary for proper osteoclast generation. Association between TMEM64 and SERCA2 in the ER leads to cytosolic Ca (2+) spiking for activation of NFATC1 and production of mitochondrial ROS, thereby triggering Ca (2+) signaling cascades that promote osteoclast differentiation and activation. Negatively regulates osteoblast differentiation and positively regulates adipocyte differentiation via modulation of the canonical Wnt signaling pathway. Mediates the switch in lineage commitment to osteogenesis rather than to adipogenesis in mesenchymal stem cells by negatively regulating the expression, activity and nuclear localization of CTNNB1.

Subunit / interactions. Interacts with ATP2A2.

Subcellular location. Membrane. Endoplasmic reticulum.

Domain organisation. The VTT domain was previously called the SNARE-assoc domain. As there is no evidence that this domain associates with SNARE proteins, it was renamed as VMP1, TMEM41, and TVP38 (VTT) domain.

Similarity. Belongs to the TVP38/TMEM64 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q6YI46-1	1	yes
Q6YI46-2	2
Q6YI46-3	3
Q6YI46-4	4

RefSeq proteins (2): NP_001008495, NP_001139745 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR032816	VTT_dom	Domain
IPR053069	TVP38/TMEM64	Family

Pfam: PF09335

UniProt features (14 total): transmembrane region 6, splice variant 4, sequence conflict 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6YI46-F1	66.43	0.19

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 263 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, HORIUCHI_WTAP_TARGETS_DN, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOZGIT_ESR1_TARGETS_DN, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_HEMOPOIESIS

GO Biological Process (7): osteoclast differentiation (GO:0030316), positive regulation of fat cell differentiation (GO:0045600), negative regulation of osteoblast differentiation (GO:0045668), positive regulation of osteoclast differentiation (GO:0045672), positive regulation of bone resorption (GO:0045780), regulation of cytosolic calcium ion concentration (GO:0051480), negative regulation of canonical Wnt signaling pathway (GO:0090090)

GO Molecular Function (0):

GO Cellular Component (2): endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
myeloid leukocyte differentiation	1
fat cell differentiation	1
positive regulation of cell differentiation	1
regulation of fat cell differentiation	1
osteoblast differentiation	1
negative regulation of cell differentiation	1
regulation of osteoblast differentiation	1
positive regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
regulation of bone resorption	1
bone resorption	1
positive regulation of multicellular organismal process	1
intracellular calcium ion homeostasis	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

530 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM64	ATP2A2	P16614	698
TMEM64	TMEM41A	Q96HV5	491
TMEM64	C12orf71	A8MTZ7	445
TMEM64	FBXO8	Q9NRD0	433
TMEM64	ITPKC	Q96DU7	431
TMEM64	FUBP3	Q96I24	427
TMEM64	KPNA3	O00505	406
TMEM64	TMEM41B	Q5BJD5	398
TMEM64	LRCH1	Q9Y2L9	394
TMEM64	SMARCD1	Q96GM5	369
TMEM64	IGFL4	Q6B9Z1	365
TMEM64	VMP1	Q96GC9	354
TMEM64	PHYHIP	Q92561	353
TMEM64	XKRX	Q6PP77	352
TMEM64	PURA	Q00577	348

IntAct

0 interactions, top by confidence:

BioGRID (6): TMEM64 (Affinity Capture-MS), TMEM64 (Affinity Capture-MS), TMEM64 (Synthetic Lethality), TMEM64 (Affinity Capture-MS), TMEM64 (Affinity Capture-RNA), TMEM64 (Affinity Capture-RNA)

ESM2 similar proteins: A2XCD4, A2YA15, A2YM35, A7KVC2, B4F8Z1, B4FTR7, B6IDH3, B6SZW0, B8AK78, B9FGV7, D5L1S4, F4I5Q2, F4KGN5, O22780, O80905, Q10CI8, Q10LH0, Q10MN3, Q10PZ4, Q10RX7, Q195N6, Q2N2K2, Q2QNK7, Q3U145, Q42713, Q5AVT9, Q5N800, Q5N941, Q5N9A1, Q5SML4, Q5Z922, Q6ATB4, Q6DG19, Q6EUK7, Q6K9C1, Q6NQL6, Q6YI46, Q6YSY5, Q75IS2, Q75LD5

Diamond homologs: B0W2W6, B3MB79, B3MZY6, B3NEF0, B4GN43, B4GN46, B4IB36, B4J3A3, B4KVI7, B4LF72, B4PIP5, B4QL99, B5DR03, B5DRY3, Q08D62, Q3U145, Q6YI46, Q9VNS0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

338 predictions. Top by Δscore:

Variant	Effect	Δscore
8:90625692:T:TA	donor_gain	1.0000
8:90631548:TCA:T	donor_loss	1.0000
8:90631549:CAC:C	donor_loss	1.0000
8:90631550:A:C	donor_loss	1.0000
8:90631551:C:CA	donor_loss	1.0000
8:90631581:CA:C	donor_gain	1.0000
8:90631581:CACT:C	donor_gain	1.0000
8:90631704:TAAT:T	acceptor_gain	1.0000
8:90631705:AATC:A	acceptor_loss	1.0000
8:90631706:ATC:A	acceptor_loss	1.0000
8:90631707:TC:T	acceptor_loss	1.0000
8:90631708:C:CA	acceptor_loss	1.0000
8:90631708:C:CC	acceptor_gain	1.0000
8:90631709:T:G	acceptor_loss	1.0000
8:90645106:CTTA:C	donor_loss	1.0000
8:90645107:TTA:T	donor_loss	1.0000
8:90645108:TA:T	donor_loss	1.0000
8:90625677:A:AT	donor_gain	0.9900
8:90625705:AGGGT:A	donor_gain	0.9900
8:90631604:T:TA	donor_gain	0.9900
8:90631703:GTAAT:G	acceptor_gain	0.9900
8:90631705:AAT:A	acceptor_gain	0.9900
8:90631706:AT:A	acceptor_gain	0.9900
8:90645105:ACTT:A	donor_loss	0.9900
8:90645109:A:AC	donor_gain	0.9900
8:90645110:C:CC	donor_gain	0.9900
8:90625660:T:C	donor_gain	0.9800
8:90625687:C:CT	donor_gain	0.9800
8:90625688:C:CT	donor_gain	0.9800
8:90625709:T:TA	donor_gain	0.9800

AlphaMissense

2398 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:90625851:A:C	S321R	1.000
8:90625851:A:T	S321R	1.000
8:90625853:T:G	S321R	1.000
8:90645123:A:C	N261K	1.000
8:90645123:A:T	N261K	1.000
8:90625799:C:G	A339P	0.999
8:90625807:A:G	L336S	0.999
8:90625822:C:G	R331P	0.999
8:90625855:A:T	I320K	0.999
8:90631626:C:G	G293R	0.999
8:90631652:G:T	P284H	0.999
8:90631661:C:T	G281E	0.999
8:90631662:C:G	G281R	0.999
8:90631662:C:T	G281R	0.999
8:90645135:A:C	F257L	0.999
8:90645135:A:T	F257L	0.999
8:90645137:A:G	F257L	0.999
8:90645142:A:T	I255K	0.999
8:90645151:A:G	L252P	0.999
8:90625820:C:G	A332P	0.998
8:90625843:A:G	L324P	0.998
8:90625843:A:T	L324H	0.998
8:90631625:C:T	G293D	0.998
8:90631643:A:G	L287P	0.998
8:90631652:G:C	P284R	0.998
8:90631658:A:G	L282P	0.998
8:90631670:G:A	S278F	0.998
8:90645125:T:A	N261Y	0.998
8:90645126:C:A	Q260H	0.998
8:90645126:C:G	Q260H	0.998

dbSNP variants (sampled 300 via entrez): RS1000012190 (8:90633977 T>C), RS1000071107 (8:90646231 G>A,C), RS1000084579 (8:90646532 C>T), RS1000295521 (8:90627383 A>C), RS1000352275 (8:90621494 G>C,T), RS1000536483 (8:90633657 T>C,G), RS1000565807 (8:90629414 C>G,T), RS1000573662 (8:90635426 G>A), RS1000613893 (8:90628657 A>T), RS1000624028 (8:90628876 C>T), RS1000627408 (8:90635776 T>C), RS1001015195 (8:90641898 G>A), RS1001036788 (8:90646565 G>T), RS1001473906 (8:90645778 G>A,T), RS1001477473 (8:90641138 A>T)

Disease associations

OMIM: gene MIM:620429 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003134_6	Cerebrospinal fluid clusterin levels	2.000000e-06
GCST007576_207	Chronotype	3.000000e-08
GCST012353_2	Serum metabolite concentrations in chronic kidney disease	3.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	8
Estradiol	increases expression	4
trichostatin A	increases expression, affects cotreatment	3
Tretinoin	decreases expression, increases expression	3
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
belinostat	affects cotreatment, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Nickel	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1I5	Abcam A-549 TMEM64 KO 1	Cancer cell line	Male
CVCL_B2QP	Abcam A-549 TMEM64 KO 2	Cancer cell line	Male

Clinical trials (associated diseases)

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