TM4SF19

Summary

TM4SF19 (transmembrane 4 L six family member 19, HGNC:25167) is a protein-coding gene on chromosome 3q29, encoding Transmembrane 4 L6 family member 19 (Q96DZ7). Negatively regulates vacuolar (H+)-ATPase (V-ATPase) activity by interacting with members of V-ATPase V0 complex and hence inhibiting V1-V0 complex assembly.

The protein encoded by this gene is a member of the four-transmembrane L6 superfamily. Members of this family function in various cellular processes including cell proliferation, motility, and adhesion via their interactions with integrins. In human brain tissue, this gene is expressed at high levels in the parietal lobe, occipital lobe, hippocampus, pons, white matter, corpus callosum, and cerebellum. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 116211 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 42 total
• MANE Select transcript: NM_138461

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25167
Approved symbol	TM4SF19
Name	transmembrane 4 L six family member 19
Location	3q29
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000145107
Ensembl biotype	protein_coding
OMIM	620845
Entrez	116211

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000273695, ENST00000440822, ENST00000446879, ENST00000454715

RefSeq mRNA: 3 — MANE Select: NM_138461 NM_001204897, NM_001204898, NM_138461

CCDS: CCDS3316, CCDS56299

Canonical transcript exons

ENST00000273695 — 5 exons

Exon	Start	End
ENSE00001266870	196323547	196323997
ENSE00003705327	196324271	196324440
ENSE00003707284	196327390	196327591
ENSE00003708912	196326955	196327032
ENSE00003900346	196338264	196338388

Expression profiles

Bgee: expression breadth ubiquitous, 122 present calls, max score 77.22.

FANTOM5 (CAGE): breadth broad, TPM avg 23.2354 / max 1588.6217, expressed in 390 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46344	22.3311	294
46350	0.2694	115
46347	0.2424	135
46351	0.1817	68
46348	0.1215	70
46349	0.0893	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.22	gold quality
granulocyte	CL:0000094	71.13	gold quality
right testis	UBERON:0004534	69.79	gold quality
testis	UBERON:0000473	69.65	gold quality
left testis	UBERON:0004533	69.63	gold quality
esophagus mucosa	UBERON:0002469	68.09	gold quality
upper lobe of left lung	UBERON:0008952	64.01	gold quality
subcutaneous adipose tissue	UBERON:0002190	63.53	gold quality
right uterine tube	UBERON:0001302	63.12	gold quality
blood	UBERON:0000178	62.52	gold quality
lower esophagus mucosa	UBERON:0035834	59.76	gold quality
skeletal muscle tissue	UBERON:0001134	59.62	gold quality
gastrocnemius	UBERON:0001388	58.70	gold quality
lung	UBERON:0002048	58.10	gold quality
muscle of leg	UBERON:0001383	57.61	gold quality
corpus callosum	UBERON:0002336	57.43	gold quality
vagina	UBERON:0000996	57.21	gold quality
placenta	UBERON:0001987	56.77	gold quality
adipose tissue	UBERON:0001013	55.63	gold quality
thoracic mammary gland	UBERON:0005200	54.99	gold quality
minor salivary gland	UBERON:0001830	54.35	gold quality
ectocervix	UBERON:0012249	53.50	gold quality
muscle tissue	UBERON:0002385	52.86	gold quality
esophagus	UBERON:0001043	52.32	gold quality
saliva-secreting gland	UBERON:0001044	52.10	gold quality
tonsil	UBERON:0002372	51.88	gold quality
bone marrow cell	CL:0002092	51.33	silver quality
hindlimb stylopod muscle	UBERON:0004252	50.92	gold quality
right lung	UBERON:0002167	50.79	gold quality
islet of Langerhans	UBERON:0000006	49.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-11	no	52.43
E-ANND-3	no	2.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting TM4SF19, 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-8068	99.98	73.85	2376
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-8070	99.07	69.30	1303
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-6755-3P	98.61	66.90	834
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-6765-3P	97.83	64.59	1165
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-4327	97.21	67.71	676
HSA-MIR-3622A-3P	97.06	66.43	1000
HSA-MIR-3622B-3P	96.82	66.36	988

Literature-anchored findings (GeneRIF, showing 3)

• TM4SF19 aggravates LPS-induced attenuation of vascular endothelial cell adherens junctions by suppressing VE-cadherin expression. (PMID:33059922)
• TM4SF19-AS1 facilitates the proliferation of lung squamous cell carcinoma by recruiting WDR5 to mediate TM4SF19. (PMID:35987447)
• TM4SF19 controls GABP-dependent YAP transcription in head and neck cancer under oxidative stress conditions. (PMID:38315837)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:dkey-83h2.3	ENSDARG00000100378
mus_musculus	Tm4sf19	ENSMUSG00000079625
rattus_norvegicus	Tm4sf19	ENSRNOG00000001757

Paralogs (5): TM4SF5 (ENSG00000142484), TM4SF18 (ENSG00000163762), TM4SF20 (ENSG00000168955), TM4SF4 (ENSG00000169903), TM4SF1 (ENSG00000169908)

Protein

Protein identifiers

Transmembrane 4 L6 family member 19 — Q96DZ7 (reviewed: Q96DZ7)

Alternative names: Osteoclast maturation-associated gene 4 protein, Tetraspan membrane protein OCTM4

All UniProt accessions (3): C9JCD5, Q96DZ7, H7C405

UniProt curated annotations — full annotation on UniProt →

Function. Negatively regulates vacuolar (H+)-ATPase (V-ATPase) activity by interacting with members of V-ATPase V0 complex and hence inhibiting V1-V0 complex assembly. Required for multinucleation during osteoclast differentiation.

Subunit / interactions. May form homodimers and homooligomers. Interacts with integrins ITGAV and ITGB3. Interacts with components of members of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), including ATP6V0B and ATP6V0D2; this interaction inhibits V1-V0 complex assembly.

Subcellular location. Lysosome membrane. Cytoplasm. Cytoskeleton. Cell projection. Filopodium.

Tissue specificity. In adipose tissue, expressed by macrophages.

Induction. Up-regulated by bacterial lipopolysaccharide (LPS) in human umbilical vein endothelial cells (HUVECs).

Similarity. Belongs to the L6 tetraspanin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96DZ7-1	1	yes
Q96DZ7-2	2

RefSeq proteins (3): NP_001191826, NP_001191827, NP_612470* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008661	L6_membrane	Family

Pfam: PF05805

UniProt features (15 total): topological domain 5, transmembrane region 4, sequence variant 2, chain 1, region of interest 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96DZ7-F1	82.05	0.36

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): 133

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 58 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOCC_VACUOLAR_MEMBRANE, GTTAAAG_MIR302B, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, TGANTCA_AP1_C, GOBP_POSITIVE_REGULATION_OF_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_POSITIVE_REGULATION_OF_CELL_DEVELOPMENT

GO Biological Process (1): positive regulation of osteoclast differentiation (GO:0045672)

GO Molecular Function (2): protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (8): lysosomal membrane (GO:0005765), actin cytoskeleton (GO:0015629), membrane (GO:0016020), filopodium (GO:0030175), cytoplasm (GO:0005737), lysosome (GO:0005764), cytoskeleton (GO:0005856), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
identical protein binding	1
protein dimerization activity	1
binding	1
lysosome	1
lytic vacuole membrane	1
cytoskeleton	1
actin-based cell projection	1
intracellular anatomical structure	1
lytic vacuole	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1020 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TM4SF19	SMCO1	Q147U7	644
TM4SF19	WDR53	Q7Z5U6	582
TM4SF19	ZDHHC19	Q8WVZ1	538
TM4SF19	TM4SF20	Q53R12	528
TM4SF19	DYNLT2B	Q8WW35	519
TM4SF19	CEP19	Q96LK0	512
TM4SF19	UBXN7	O94888	477
TM4SF19	PIGZ	Q86VD9	474
TM4SF19	LRRN4CL	Q8ND94	472
TM4SF19	LEPROTL1	O95214	468
TM4SF19	NAA30	Q147X3	460
TM4SF19	TRNAU1AP	Q9NX07	459
TM4SF19	TRMT10B	Q6PF06	458
TM4SF19	PCYT1A	P49585	448
TM4SF19	CRACR2A	Q9BSW2	444

IntAct

113 interactions, top by confidence:

A	B	Type	Score
TMEM42	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
ERG28	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
SERP2	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
TM4SF19	TMEM237	psi-mi:“MI:0915”(physical association)	0.560
TM4SF19	CCDC167	psi-mi:“MI:0915”(physical association)	0.560
GPR152	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
PMP22	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
SEC22B	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
TM4SF19	TMEM167B	psi-mi:“MI:0915”(physical association)	0.560
TSNARE1	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
TM4SF19	CYBC1	psi-mi:“MI:0915”(physical association)	0.560
ZFPL1	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
ABHD16A	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
STX7	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
BNIP1	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
VAMP3	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
CYP4F2	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
TM4SF19	GIMAP5	psi-mi:“MI:0915”(physical association)	0.560
GET1	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
SYS1	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
HMOX1	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
CD79A	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
TM4SF19	UBE2J1	psi-mi:“MI:0915”(physical association)	0.560
PLP2	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
TM4SF19	ERG28	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (62): TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid), TM4SF19 (Two-hybrid)

ESM2 similar proteins: A0A1B0GTI8, A6NN92, E9Q9H8, F6RWY9, O18968, O64761, O70610, O75712, O93533, O95377, O95452, P08033, P08034, P08983, P25305, P28230, P28231, P28232, P28233, P36380, P49111, P51916, P70689, P79826, Q02738, Q02739, Q0IIL2, Q13571, Q2KJA5, Q3SZ36, Q3T110, Q3TUD9, Q49LS6, Q4VV71, Q58D78, Q5E9Z5, Q5F410, Q5JW98, Q5REZ0, Q60HF7

Diamond homologs: E9Q9H8, O14894, P30408, P48230, P49111, Q2KIG8, Q5R6Z4, Q5RE43, Q64302, Q91XD3, Q96DZ7, Q9EQL5, Q3T110, Q53R12, Q96CE8, Q9CQY8, Q3T0Z4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1036 predictions. Top by Δscore:

Variant	Effect	Δscore
3:196323746:ACT:A	donor_gain	1.0000
3:196323747:CTC:C	donor_gain	1.0000
3:196326953:A:AC	donor_gain	1.0000
3:196326954:C:CC	donor_gain	1.0000
3:196326954:CG:C	donor_gain	1.0000
3:196326954:CGCTT:C	donor_gain	1.0000
3:196326976:A:AC	donor_gain	1.0000
3:196326977:C:CC	donor_gain	1.0000
3:196323743:CCCA:C	donor_gain	0.9900
3:196323746:A:AC	donor_gain	0.9900
3:196323747:C:CC	donor_gain	0.9900
3:196323822:T:TA	donor_gain	0.9900
3:196324004:C:CT	acceptor_gain	0.9900
3:196324004:C:T	acceptor_gain	0.9900
3:196324005:A:T	acceptor_gain	0.9900
3:196324273:A:AC	donor_gain	0.9900
3:196324274:C:CC	donor_gain	0.9900
3:196327031:ACCT:A	acceptor_loss	0.9900
3:196327034:T:C	acceptor_loss	0.9900
3:196323747:CT:C	donor_gain	0.9800
3:196323995:TTC:T	acceptor_gain	0.9800
3:196323998:C:CC	acceptor_gain	0.9800
3:196323998:CTATC:C	acceptor_loss	0.9800
3:196323999:T:A	acceptor_loss	0.9800
3:196324274:CTATG:C	donor_gain	0.9800
3:196327431:G:A	donor_gain	0.9800
3:196327467:C:A	donor_gain	0.9800
3:196338262:A:C	donor_loss	0.9800
3:196338263:C:CT	donor_loss	0.9800
3:196323873:C:CT	donor_gain	0.9700

AlphaMissense

1329 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:196323895:G:C	S184R	0.980
3:196323895:G:T	S184R	0.980
3:196323897:T:G	S184R	0.980
3:196323970:C:A	W159C	0.975
3:196323970:C:G	W159C	0.975
3:196324289:A:C	F144C	0.971
3:196324288:G:C	F144L	0.970
3:196324288:G:T	F144L	0.970
3:196324290:A:G	F144L	0.970
3:196324339:A:C	F127L	0.965
3:196324339:A:T	F127L	0.965
3:196324341:A:G	F127L	0.965
3:196323916:G:C	F177L	0.953
3:196323916:G:T	F177L	0.953
3:196323918:A:G	F177L	0.953
3:196324346:C:G	C125S	0.953
3:196324347:A:T	C125S	0.953
3:196324356:C:A	G122C	0.949
3:196323959:C:G	C163S	0.945
3:196323960:A:T	C163S	0.945
3:196324355:C:T	G122D	0.944
3:196324346:C:T	C125Y	0.937
3:196327492:G:C	N33K	0.933
3:196327492:G:T	N33K	0.933
3:196324345:G:C	C125W	0.925
3:196324387:G:C	C111W	0.918
3:196323958:G:C	C163W	0.917
3:196324289:A:G	F144S	0.915
3:196323972:A:G	W159R	0.912
3:196323972:A:T	W159R	0.912

dbSNP variants (sampled 300 via entrez): RS1000008545 (3:196331431 T>C), RS1000136578 (3:196338286 G>C), RS1000803125 (3:196324768 T>C), RS1000875130 (3:196338221 G>A), RS1000916973 (3:196330426 T>TA), RS1000928995 (3:196331588 G>A), RS1001113453 (3:196337233 T>C), RS1001153719 (3:196324583 G>A), RS1001557913 (3:196337978 C>A,T), RS1001590126 (3:196333030 T>C), RS1001683551 (3:196332710 T>C), RS1001778228 (3:196340029 G>C), RS1002203473 (3:196332443 G>A), RS1002205341 (3:196324922 G>A), RS1002254701 (3:196325222 A>C,G)

Disease associations

OMIM: gene MIM:620845 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

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: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	3
Particulate Matter	increases abundance, increases expression	3
Air Pollutants	increases abundance, increases expression	2
sotorasib	decreases expression, affects cotreatment	1
bisphenol A	decreases methylation	1
dimethylselenide	decreases expression, increases oxidation	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
nickel sulfate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
jinfukang	affects cotreatment, increases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	decreases expression, affects cotreatment	1
Temozolomide	decreases expression	1
Decitabine	increases expression	1
Arsenic	affects methylation	1
Cholesterol	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Ozone	increases oxidation, decreases expression	1
Phenobarbital	affects expression	1
Rotenone	increases expression	1

Clinical trials (associated diseases)

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