TMEM178A

Summary

TMEM178A (transmembrane protein 178A, HGNC:28517) is a protein-coding gene on chromosome 2p22.1, encoding Transmembrane protein 178A (Q8NBL3). Acts as a negative regulator of osteoclast differentiation in basal and inflammatory conditions by regulating TNFSF11-induced Ca (2+) fluxes, thereby controlling the induction of NFATC1.

Predicted to be involved in negative regulation of osteoclast differentiation and regulation of cytosolic calcium ion concentration. Predicted to be located in endoplasmic reticulum and membrane. Predicted to be active in endoplasmic reticulum membrane.

Source: NCBI Gene 130733 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 36 total
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_152390

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28517
Approved symbol	TMEM178A
Name	transmembrane protein 178A
Location	2p22.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC33926
Ensembl gene	ENSG00000152154
Ensembl biotype	protein_coding
Entrez	130733

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000281961, ENST00000413011, ENST00000437068, ENST00000482239, ENST00000495402, ENST00000897340, ENST00000897341, ENST00000897342, ENST00000937468, ENST00000967037

RefSeq mRNA: 2 — MANE Select: NM_152390 NM_001167959, NM_152390

CCDS: CCDS1804

Canonical transcript exons

ENST00000281961 — 4 exons

Exon	Start	End
ENSE00001003696	39665917	39666374
ENSE00001743502	39717010	39717963
ENSE00003649673	39704081	39704194
ENSE00003673880	39707049	39707186

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 99.67.

FANTOM5 (CAGE): breadth broad, TPM avg 3.7143 / max 731.0601, expressed in 425 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
19873	1.6970	374
19866	0.4135	121
19867	0.3905	119
19871	0.3479	84
19872	0.3079	71
19881	0.0877	15
19862	0.0797	20
19860	0.0689	24
19868	0.0573	18
19865	0.0559	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	99.67	gold quality
cerebellar cortex	UBERON:0002129	99.66	gold quality
cerebellum	UBERON:0002037	99.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.64	gold quality
cerebellar vermis	UBERON:0004720	98.80	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.12	gold quality
right frontal lobe	UBERON:0002810	97.68	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.67	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.48	gold quality
spinal cord	UBERON:0002240	97.40	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.35	gold quality
postcentral gyrus	UBERON:0002581	97.31	gold quality
anterior cingulate cortex	UBERON:0009835	96.97	gold quality
superior frontal gyrus	UBERON:0002661	96.89	gold quality
parietal lobe	UBERON:0001872	96.83	gold quality
frontal cortex	UBERON:0001870	96.81	gold quality
frontal lobe	UBERON:0016525	96.81	gold quality
cerebral cortex	UBERON:0000956	96.54	gold quality
neocortex	UBERON:0001950	96.51	gold quality
prefrontal cortex	UBERON:0000451	96.48	gold quality
Ammon’s horn	UBERON:0001954	96.47	gold quality
cortical plate	UBERON:0005343	96.45	gold quality
entorhinal cortex	UBERON:0002728	95.81	gold quality
primary visual cortex	UBERON:0002436	95.79	gold quality
amygdala	UBERON:0001876	95.64	gold quality
pons	UBERON:0000988	95.62	gold quality
occipital lobe	UBERON:0002021	95.55	gold quality
temporal lobe	UBERON:0001871	95.47	gold quality
endothelial cell	CL:0000115	94.90	gold quality
brain	UBERON:0000955	94.87	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	134.31
E-ANND-3	no	2.99

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

57 targeting TMEM178A, 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-4282	99.99	75.36	6408
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 1)

• Tmem178 localizes to the ER membrane and regulates RANKL-induced Ca(2+) fluxes, thus controlling NFATc1 induction (PMID:26644563)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem178a	ENSDARG00000020758
mus_musculus	Tmem178	ENSMUSG00000024245
rattus_norvegicus	Tmem178a	ENSRNOG00000007907

Paralogs (1): TMEM178B (ENSG00000261115)

Protein

Protein identifiers

Transmembrane protein 178A — Q8NBL3 (reviewed: Q8NBL3)

All UniProt accessions (1): Q8NBL3

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a negative regulator of osteoclast differentiation in basal and inflammatory conditions by regulating TNFSF11-induced Ca (2+) fluxes, thereby controlling the induction of NFATC1.

Subunit / interactions. Interacts with STIM1.

Subcellular location. Endoplasmic reticulum membrane.

Similarity. Belongs to the TMEM178 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NBL3-1	1	yes
Q8NBL3-2	2

RefSeq proteins (2): NP_001161431, NP_689603* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004031	PMP22/EMP/MP20/Claudin	Family
IPR039625	T178A/B	Family

Pfam: PF13903

UniProt features (16 total): topological domain 4, transmembrane region 3, compositionally biased region 2, splice variant 2, signal peptide 1, chain 1, glycosylation site 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NBL3-F1	74.31	0.25

Functional residue map

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

Glycosylation sites (1): 158

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 147 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, YAATNRNNNYNATT_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GGGNRMNNYCAT_UNKNOWN, NKX25_02, GCANCTGNY_MYOD_Q6, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, CHX10_01, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_HEMOPOIESIS, NKX62_Q2, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, FOSTER_TOLERANT_MACROPHAGE_DN

GO Biological Process (2): negative regulation of osteoclast differentiation (GO:0045671), regulation of cytosolic calcium ion concentration (GO:0051480)

GO Molecular Function (0):

GO Cellular Component (3): endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
intracellular calcium ion homeostasis	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

658 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM178A	NICN1	Q9BSH3	613
TMEM178A	TMEM94	Q12767	551
TMEM178A	FTSJ3	Q8IY81	503
TMEM178A	PTCHD4	Q6ZW05	475
TMEM178A	TMEM204	Q9BSN7	469
TMEM178A	TMEM88	Q6PEY1	450
TMEM178A	TMEM47	Q9BQJ4	449
TMEM178A	ZNF304	Q9HCX3	448
TMEM178A	SLC4A11	Q8NBS3	443
TMEM178A	INTS2	Q9H0H0	430
TMEM178A	DHX57	Q6P158	405
TMEM178A	TMEM97	Q5BJF2	394
TMEM178A	SNAPC5	O75971	393
TMEM178A	STIMATE	Q86TL2	377
TMEM178A	TMEM179	Q6ZVK1	373

IntAct

86 interactions, top by confidence:

A	B	Type	Score
DLG1	TMEM178A	psi-mi:“MI:0407”(direct interaction)	0.620
TMEM178A	DLG1	psi-mi:“MI:0407”(direct interaction)	0.620
TMEM178A	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
LIN7C	TMEM178A	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI3	TMEM178A	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
MAST2	TMEM178A	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	TMEM178A	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
TMEM178A	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (4): GSTCD (Affinity Capture-MS), CISD2 (Affinity Capture-MS), TMEM178A (Negative Genetic), TMEM178A (Positive Genetic)

ESM2 similar proteins: A0A1D5NY17, A4IF75, B2RVY9, B3SHH9, F6V1J6, O42281, O70578, P19518, P97707, Q06432, Q08CE6, Q08DE1, Q0D289, Q0V9E0, Q14714, Q2MJQ7, Q4R4Z3, Q4V922, Q5CZV0, Q5PRC1, Q5RDV7, Q5XGU1, Q62147, Q66IV3, Q68FV0, Q6AZD1, Q6P0C6, Q6R5J2, Q6ZP80, Q6ZUX7, Q7ZZL8, Q86WI0, Q8BGA2, Q8NBL3, Q8VHW3, Q8VHW4, Q8VHW7, Q8VHW8, Q91Y55, Q925N4

Diamond homologs: F6V1J6, H3BS89, Q08CE6, Q1L8F4, Q5XGU1, Q68FV0, Q8NBL3, Q9CZ16

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 63 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	64.9×	4e-07
Unblocking of NMDA receptors, glutamate binding and activation	5	61.8×	4e-07
Negative regulation of NMDA receptor-mediated neuronal transmission	5	61.8×	4e-07
Long-term potentiation	5	54.1×	7e-07
Assembly and cell surface presentation of NMDA receptors	9	51.9×	6e-12
Neurexins and neuroligins	10	44.8×	2e-12
Protein-protein interactions at synapses	7	42.2×	1e-08
RHOA GTPase cycle	5	8.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein localization to synapse	6	74.1×	3e-08
establishment or maintenance of epithelial cell apical/basal polarity	7	65.6×	4e-09
receptor clustering	6	60.4×	7e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	6	48.0×	2e-07
regulation of small GTPase mediated signal transduction	5	11.6×	2e-03
cell-cell adhesion	7	11.5×	1e-04
protein-containing complex assembly	5	9.2×	4e-03
chemical synaptic transmission	7	8.7×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

984 predictions. Top by Δscore:

Variant	Effect	Δscore
2:39666372:AAGGT:A	donor_loss	1.0000
2:39666373:AGGT:A	donor_loss	1.0000
2:39666375:G:C	donor_loss	1.0000
2:39674805:GTCTT:G	donor_gain	1.0000
2:39704190:GCTTC:G	donor_gain	1.0000
2:39704195:G:GG	donor_gain	1.0000
2:39707040:T:TA	acceptor_gain	1.0000
2:39716238:GAAT:G	donor_gain	1.0000
2:39716241:T:G	donor_gain	1.0000
2:39716241:T:TG	donor_gain	1.0000
2:39666370:GAAAG:G	donor_gain	0.9900
2:39666375:G:GG	donor_gain	0.9900
2:39666376:T:A	donor_loss	0.9900
2:39674794:G:GT	donor_gain	0.9900
2:39704079:A:AC	acceptor_loss	0.9900
2:39704079:A:G	acceptor_gain	0.9900
2:39704177:A:G	donor_gain	0.9900
2:39704191:CTTC:C	donor_gain	0.9900
2:39704192:TTC:T	donor_gain	0.9900
2:39704193:TC:T	donor_gain	0.9900
2:39707044:ATTAG:A	acceptor_loss	0.9900
2:39707045:TTA:T	acceptor_loss	0.9900
2:39707046:TAGA:T	acceptor_loss	0.9900
2:39707047:A:AT	acceptor_loss	0.9900
2:39707048:G:GC	acceptor_loss	0.9900
2:39707183:ACAG:A	donor_loss	0.9900
2:39707184:CAG:C	donor_loss	0.9900
2:39707186:GGTA:G	donor_loss	0.9900
2:39707187:G:C	donor_loss	0.9900
2:39707188:T:G	donor_loss	0.9900

AlphaMissense

1911 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:39704184:G:C	W168C	1.000
2:39704184:G:T	W168C	1.000
2:39707072:T:C	F180L	1.000
2:39707074:C:A	F180L	1.000
2:39707074:C:G	F180L	1.000
2:39666317:T:A	W115R	0.999
2:39666317:T:C	W115R	0.999
2:39666319:G:C	W115C	0.999
2:39666319:G:T	W115C	0.999
2:39666326:T:A	C118S	0.999
2:39666327:G:C	C118S	0.999
2:39666328:C:G	C118W	0.999
2:39666357:A:T	D128V	0.999
2:39704095:T:A	C139S	0.999
2:39704095:T:C	C139R	0.999
2:39704096:G:C	C139S	0.999
2:39704097:C:G	C139W	0.999
2:39704110:T:C	Y144H	0.999
2:39704111:A:G	Y144C	0.999
2:39704168:T:A	I163K	0.999
2:39704176:G:C	D166H	0.999
2:39704177:A:C	D166A	0.999
2:39704177:A:T	D166V	0.999
2:39704182:T:A	W168R	0.999
2:39704182:T:C	W168R	0.999
2:39707052:T:C	L173S	0.999
2:39707058:G:C	R175T	0.999
2:39707058:G:T	R175I	0.999
2:39707059:A:C	R175S	0.999
2:39707059:A:T	R175S	0.999

dbSNP variants (sampled 300 via entrez): RS1000021123 (2:39680811 G>C), RS1000027330 (2:39679492 C>G,T), RS1000033617 (2:39697878 C>A,T), RS1000117719 (2:39669067 G>C), RS1000269107 (2:39735704 T>C), RS1000276779 (2:39702736 TA>T,TAA), RS1000335360 (2:39691115 A>C), RS1000382023 (2:39724994 T>C), RS1000414218 (2:39685830 G>A), RS1000439352 (2:39696919 A>G), RS1000469719 (2:39735519 C>T), RS1000474213 (2:39714282 C>CGCTCA), RS1000522347 (2:39719606 A>G), RS1000658168 (2:39719484 A>C,T), RS1000659940 (2:39665783 C>G)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000824_3	Erectile dysfunction and prostate cancer treatment	2.000000e-06
GCST001762_395	Obesity-related traits	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004730	hormone measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, decreases methylation, affects cotreatment	5
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
trichostatin A	affects cotreatment, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Vorinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	decreases expression	2
Nickel	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	decreases methylation, affects cotreatment	1
sodium arsenite	decreases expression	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
NSC 689534	increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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