VGLL3

Summary

VGLL3 (vestigial like family member 3, HGNC:24327) is a protein-coding gene on chromosome 3p12.1, encoding Transcription cofactor vestigial-like protein 3 (A8MV65). May act as a specific coactivator for the mammalian TEFs.

Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus.

Source: NCBI Gene 389136 — RefSeq curated summary.

At a glance

• GWAS associations: 26
• Clinical variants (ClinVar): 53 total
• MANE Select transcript: NM_016206

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24327
Approved symbol	VGLL3
Name	vestigial like family member 3
Location	3p12.1
Locus type	gene with protein product
Status	Approved
Aliases	VGL-3
Ensembl gene	ENSG00000206538
Ensembl biotype	protein_coding
OMIM	609980
Entrez	389136

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000383698, ENST00000398399, ENST00000494229, ENST00000637106, ENST00000852930

RefSeq mRNA: 3 — MANE Select: NM_016206 NM_001320493, NM_001320494, NM_016206

CCDS: CCDS43110, CCDS82807

Canonical transcript exons

ENST00000398399 — 4 exons

Exon	Start	End
ENSE00001498175	86968590	86969123
ENSE00001498176	86978526	86978802
ENSE00001498177	86990618	86991149
ENSE00001533052	86937973	86947067

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 97.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.1565 / max 892.0580, expressed in 1146 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43279	7.4539	850
43280	4.8952	794
43278	4.1642	847
43276	3.2989	688
43275	2.9131	776
43274	0.7136	303
43282	0.4785	335
43283	0.4280	267
43281	0.3905	250
43277	0.3572	215

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower lobe of lung	UBERON:0008949	97.01	gold quality
saphenous vein	UBERON:0007318	96.28	gold quality
placenta	UBERON:0001987	95.65	gold quality
parietal pleura	UBERON:0002400	94.94	gold quality
superficial temporal artery	UBERON:0001614	93.26	gold quality
calcaneal tendon	UBERON:0003701	92.73	gold quality
pleura	UBERON:0000977	92.57	gold quality
pericardium	UBERON:0002407	91.98	gold quality
germinal epithelium of ovary	UBERON:0001304	91.94	gold quality
stromal cell of endometrium	CL:0002255	90.31	gold quality
visceral pleura	UBERON:0002401	89.64	gold quality
synovial joint	UBERON:0002217	89.58	gold quality
sural nerve	UBERON:0015488	89.21	gold quality
vena cava	UBERON:0004087	88.95	gold quality
skin of hip	UBERON:0001554	87.91	gold quality
right lung	UBERON:0002167	87.72	gold quality
amniotic fluid	UBERON:0000173	87.43	gold quality
decidua	UBERON:0002450	87.34	gold quality
adipose tissue	UBERON:0001013	86.79	gold quality
penis	UBERON:0000989	86.70	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.17	gold quality
connective tissue	UBERON:0002384	86.10	gold quality
tibial nerve	UBERON:0001323	86.02	gold quality
lung	UBERON:0002048	85.67	gold quality
mammary duct	UBERON:0001765	85.46	gold quality
colonic epithelium	UBERON:0000397	85.01	gold quality
upper lobe of lung	UBERON:0008948	85.00	gold quality
popliteal artery	UBERON:0002250	84.68	gold quality
tibial artery	UBERON:0007610	84.66	gold quality
upper lobe of left lung	UBERON:0008952	84.27	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	75.01
E-ANND-3	yes	17.90
E-MTAB-6678	yes	16.09
E-CURD-112	yes	10.42
E-CURD-97	no	76.49
E-GEOD-99795	no	5.45

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYF5

miRNA regulators (miRDB)

447 targeting VGLL3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882

Literature-anchored findings (GeneRIF, showing 18)

• This protein was named Vestigial-like 3, because it is related to the Drosophila protein Vestigial. Like other members of this family, it contains a consensus TEF-1 and MEF2(TDU)interaction domain. (PMID:12376544)
• data suggest that the amplification and overexpression of YAP1 and VGLL3 could be involved in oncogenesis and progression of soft tissue sarcomas (PMID:20842732)
• vestigial-like 3 (Vgll3) is an inhibitor of adipogenesis (PMID:23152581)
• VGLL3 is involved in tumor suppressor pathways, a feature that is characterized by the absence of VGLL3 expression in high-grade serous ovarian carcinomas samples. (PMID:23415753)
• this study identified a VGLL3-regulated network as a previously unknown inflammatory pathway that promotes female-biased autoimmunity (PMID:27992404)
• Interaction proteomics revealed that VGLL3 bound TEAD1, TEAD3 and TEAD4 in myoblasts and/or myotubes. (PMID:31138678)
• VGLL3 is a novel prognostic biomarker of both the clinical outcome and immune infiltration in STAD, and may therefore be a promising therapeutic target. (PMID:31992826)
• Vestigial-like family member 3 (VGLL3), a cofactor for TEAD transcription factors, promotes cancer cell proliferation by activating the Hippo pathway. (PMID:32385107)
• Immunometabolic function of the transcription cofactor VGLL3 provides an evolutionary rationale for sexual dimorphism in autoimmunity. (PMID:32803756)
• A new perspective on the interaction between the Vg/VGLL1-3 proteins and the TEAD transcription factors. (PMID:33060790)
• Hybrid schwannoma-perineurioma frequently harbors VGLL3 rearrangement. (PMID:33649458)
• VGLL3 activates inflammatory responses by inducing interleukin-1alpha secretion. (PMID:34679187)
• Clinicopathologic and Molecular Study of Hybrid Nerve Sheath Tumors Reveals Their Common Association With Fusions Involving VGLL3. (PMID:35256555)
• VGLL3 increases the dependency of cancer cells on de novo nucleotide synthesis through GART expression. (PMID:35434822)
• Recurrent VGLL3 fusions define a distinctive subset of spindle cell rhabdomyosarcoma with an indolent clinical course and striking predilection for the head and neck. (PMID:35766997)
• Regulation of type I interferon signature by VGLL3 in the fibroblast-like synoviocytes of rheumatoid arthritis patients via targeting the Hippo pathway. (PMID:35941675)
• VGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid-liquid phase separation. (PMID:36754961)
• Exploring the potential of VGLL3 methylation as a prognostic indicator for intracranial aneurysm with gender-specific considerations. (PMID:38348744)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	vgll3	ENSDARG00000038305
mus_musculus	Vgll3	ENSMUSG00000091243
rattus_norvegicus	Vgll3	ENSRNOG00000028774
drosophila_melanogaster	vg	FBGN0003975

Paralogs (2): VGLL1 (ENSG00000102243), VGLL2 (ENSG00000170162)

Protein

Protein identifiers

Transcription cofactor vestigial-like protein 3 — A8MV65 (reviewed: A8MV65)

All UniProt accessions (3): A8MV65, A0A1B0GTF5, H7C571

UniProt curated annotations — full annotation on UniProt →

Function. May act as a specific coactivator for the mammalian TEFs.

Subcellular location. Nucleus.

Tissue specificity. Enriched in placenta.

Similarity. Belongs to the vestigial family.

Isoforms (2)

UniProt ID	Names	Canonical?
A8MV65-1	1	yes
A8MV65-2	2

RefSeq proteins (3): NP_001307422, NP_001307423, NP_057290* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006627	TDU_repeat	Repeat
IPR011520	Vg_fam	Family

Pfam: PF07545

UniProt features (9 total): region of interest 3, compositionally biased region 2, cross-link 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A8MV65-F1	55.55	0.10

Functional residue map

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

Post-translational modifications (2): 62, 126

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 231 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, HNF3ALPHA_Q6, TGCACTT_MIR519C_MIR519B_MIR519A, CAGCTG_AP4_Q5, WONG_ENDMETRIUM_CANCER_DN, HFH4_01, HFH3_01, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, TAATGTG_MIR323, CUI_TCF21_TARGETS_2_DN, OCT1_B, PIT1_Q6, CTTTGTA_MIR524

GO Biological Process (2): regulation of transcription by RNA polymerase II (GO:0006357), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

666 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VGLL3	TEAD1	P28347	898
VGLL3	WWTR1	Q9GZV5	816
VGLL3	YAP1	P46937	782
VGLL3	TEAD4	Q15561	660
VGLL3	VGLL4	Q14135	631
VGLL3	AKAP11	Q9UKA4	556
VGLL3	GREB1L	Q9C091	503
VGLL3	CHMP2B	Q9UQN3	498
VGLL3	SIX6	O95475	498
VGLL3	ATOH8	Q96SQ7	474
VGLL3	TEAD3	Q99594	457
VGLL3	ETS1	P14921	449
VGLL3	POU1F1	P28069	432
VGLL3	TCN2	P20062	428
VGLL3	VGLL1	Q99990	427

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
TEAD4	VGLL3	psi-mi:“MI:0914”(association)	0.350

BioGRID (73): VGLL3 (Affinity Capture-MS), VGLL3 (Affinity Capture-MS), VGLL3 (Affinity Capture-MS), VGLL3 (Two-hybrid), VGLL3 (Two-hybrid), VGLL3 (Two-hybrid), VGLL3 (Two-hybrid), VGLL3 (Two-hybrid), VGLL3 (Two-hybrid), VGLL3 (Two-hybrid), VGLL3 (Two-hybrid), VGLL3 (Two-hybrid), VGLL3 (Two-hybrid), VGLL3 (Two-hybrid), VGLL3 (Two-hybrid)

ESM2 similar proteins: A0JNC2, A1KXE4, A8E639, A8MV65, D4AEP3, E3X5D6, P05411, P12981, P18870, P54864, P60486, Q08BY2, Q0IHC4, Q0VFP2, Q14157, Q15032, Q15038, Q157S1, Q16656, Q3LRZ1, Q3T0A9, Q3T0K9, Q3U182, Q4R5H7, Q53ET0, Q58D45, Q5BJ83, Q5R526, Q5RDV6, Q5U2U6, Q5XIH2, Q5ZIS9, Q68ED7, Q6PEH8, Q7PXU6, Q80TM6, Q80X50, Q80XQ8, Q8AVW3, Q8BGZ2

Diamond homologs: A8MV65, P85442, Q26366, Q8BGW8, Q8N8G2, Q99990, Q99NC0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

716 predictions. Top by Δscore:

Variant	Effect	Δscore
3:86978685:C:CA	donor_gain	1.0000
3:86990613:CTCA:C	donor_loss	1.0000
3:86990614:TCAC:T	donor_loss	1.0000
3:86990615:CAC:C	donor_loss	1.0000
3:86947004:A:C	donor_gain	0.9900
3:86969120:CTGT:C	acceptor_gain	0.9900
3:86969124:C:CC	acceptor_gain	0.9900
3:86978520:TCTTA:T	donor_loss	0.9900
3:86978521:CTTAC:C	donor_loss	0.9900
3:86978522:TTACC:T	donor_loss	0.9900
3:86978523:TACCT:T	donor_loss	0.9900
3:86978524:A:AG	donor_loss	0.9900
3:86978525:C:CT	donor_loss	0.9900
3:86978803:C:CC	acceptor_gain	0.9900
3:86978808:A:AC	acceptor_gain	0.9900
3:86978808:A:C	acceptor_gain	0.9900
3:86990616:A:AC	donor_gain	0.9900
3:86990617:C:CC	donor_gain	0.9900
3:86990617:CCTG:C	donor_gain	0.9900
3:86947008:A:AC	donor_gain	0.9800
3:86947009:C:CC	donor_gain	0.9800
3:86947045:A:AC	donor_gain	0.9800
3:86947046:C:CC	donor_gain	0.9800
3:86968584:GCTTA:G	donor_loss	0.9800
3:86968585:CTTAC:C	donor_loss	0.9800
3:86968586:TTA:T	donor_loss	0.9800
3:86968587:TACCT:T	donor_loss	0.9800
3:86968588:ACCTG:A	donor_loss	0.9800
3:86969121:TGT:T	acceptor_gain	0.9800
3:86978682:A:AC	donor_gain	0.9800

AlphaMissense

2139 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:86978611:G:C	F106L	1.000
3:86978611:G:T	F106L	1.000
3:86978612:A:G	F106S	1.000
3:86978613:A:G	F106L	1.000
3:86978612:A:C	F106C	0.999
3:86978615:T:G	H105P	0.999
3:86978616:G:C	H105D	0.999
3:86978621:T:A	D103V	0.999
3:86978660:A:G	L90P	0.999
3:86978663:A:T	V89D	0.999
3:86978665:A:C	C88W	0.999
3:86978667:A:G	C88R	0.999
3:86978603:G:T	A109D	0.998
3:86978604:C:G	A109P	0.998
3:86978614:G:C	H105Q	0.998
3:86978614:G:T	H105Q	0.998
3:86978615:T:C	H105R	0.998
3:86978647:G:C	F94L	0.998
3:86978647:G:T	F94L	0.998
3:86978649:A:G	F94L	0.998
3:86978652:A:C	Y93D	0.998
3:86978657:A:G	F91S	0.998
3:86978666:C:G	C88S	0.998
3:86978666:C:T	C88Y	0.998
3:86978667:A:T	C88S	0.998
3:86978605:T:A	R108S	0.997
3:86978605:T:G	R108S	0.997
3:86978610:A:G	S107P	0.997
3:86978613:A:C	F106V	0.997
3:86978613:A:T	F106I	0.997

dbSNP variants (sampled 300 via entrez): RS1000008977 (3:86973642 G>A,C,T), RS1000042388 (3:86954586 G>A), RS1000061522 (3:86973903 C>T), RS1000098494 (3:86957969 C>T), RS1000119196 (3:86986526 T>A), RS1000126823 (3:86980406 G>A), RS1000135459 (3:86942531 G>A), RS1000269139 (3:86957032 A>C), RS1000277791 (3:86951329 A>T), RS1000309016 (3:86980071 C>A,T), RS1000317150 (3:86945303 G>A), RS1000395071 (3:86990946 C>A,T), RS1000425863 (3:86950651 T>A), RS1000426139 (3:86975913 ACCAG>A), RS1000455303 (3:86969688 T>TTTA)

Disease associations

OMIM: gene MIM:609980 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST000880_23	Menarche (age at onset)	4.000000e-10
GCST001762_21	Obesity-related traits	2.000000e-06
GCST001876_4	Pubertal anthropometrics	3.000000e-09
GCST002937_17	Molybdenum levels	9.000000e-06
GCST003148_6	Prostate cancer	6.000000e-06
GCST003993_5	Menarche (age at onset)	1.000000e-08
GCST004988_664	Breast cancer	1.000000e-09
GCST006606_4	Response to TNF inhibitor in rheumatoid arthritis (change in swollen 28-joint count)	5.000000e-08
GCST007323_34	Risk-taking tendency (4-domain principal component model)	2.000000e-08
GCST007323_72	Risk-taking tendency (4-domain principal component model)	4.000000e-11
GCST007324_139	Adventurousness	2.000000e-10
GCST007324_155	Adventurousness	1.000000e-12
GCST007324_64	Adventurousness	3.000000e-15
GCST007325_10	General risk tolerance (MTAG)	7.000000e-09
GCST007325_292	General risk tolerance (MTAG)	1.000000e-16
GCST007326_47	Number of sexual partners	1.000000e-09
GCST007326_59	Number of sexual partners	4.000000e-09
GCST007327_109	Smoking status (ever vs never smokers)	2.000000e-09
GCST008860_19	Prostate cancer	1.000000e-09
GCST009391_2126	Metabolite levels	6.000000e-07
GCST009391_582	Metabolite levels	2.000000e-06
GCST009391_583	Metabolite levels	3.000000e-06
GCST009391_584	Metabolite levels	3.000000e-06
GCST010242_444	HDL cholesterol levels	3.000000e-11
GCST010244_379	Triglyceride levels	1.000000e-10
GCST90020026_454	Hip index	3.000000e-12

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004810	interleukin-6 measurement
EFO:0001382	puberty
EFO:0004653	response to TNF antagonist
EFO:0005413	joint damage measurement
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0010383	phosphatidylcholine 36:5 measurement
EFO:0010501	indole-3-propionate measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, affects cotreatment, increases expression	7
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression	3
Particulate Matter	decreases expression, increases abundance	3
methylmercuric chloride	increases expression	2
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Dexamethasone	decreases expression, increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
bisphenol F	decreases expression, affects cotreatment	1
urushiol	increases expression	1
sulforaphane	decreases expression	1
butyraldehyde	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
enniatins	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dimethylarsinous acid	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	increases expression	1
Cadmium	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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