VGLL2

Summary

VGLL2 (vestigial like family member 2, HGNC:20232) is a protein-coding gene on chromosome 6q22.1, encoding Transcription cofactor vestigial-like protein 2 (Q8N8G2). May act as a specific coactivator for the mammalian TEFs.

This gene encodes a protein with a transcriptional enhancer factor 1 (TEF-1) interaction domain. The encoded protein may act as a co-factor of TEF-1 regulated gene expression during skeletal muscle development. Alternatively spliced transcript variants encoding multiple isoforms have been observed.

Source: NCBI Gene 245806 — RefSeq curated summary.

At a glance

• Gene–disease (curated): isolated congenital syngnathia (Strong, GenCC)
• GWAS associations: 20
• Clinical variants (ClinVar): 66 total
• MANE Select transcript: NM_182645

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20232
Approved symbol	VGLL2
Name	vestigial like family member 2
Location	6q22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170162
Ensembl biotype	protein_coding
OMIM	609979
Entrez	245806

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000326274, ENST00000352536, ENST00000963224, ENST00000963225

RefSeq mRNA: 2 — MANE Select: NM_182645 NM_153453, NM_182645

CCDS: CCDS5114, CCDS5115

Canonical transcript exons

ENST00000326274 — 4 exons

Exon	Start	End
ENSE00001125990	117268182	117268491
ENSE00001229738	117270543	117271064
ENSE00001343964	117265558	117265844
ENSE00001397066	117272454	117273565

Expression profiles

Bgee: expression breadth broad, 86 present calls, max score 97.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9496 / max 160.9558, expressed in 135 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69445	0.9496	135

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.25	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.13	gold quality
tibialis anterior	UBERON:0001385	95.83	gold quality
skeletal muscle tissue	UBERON:0001134	95.74	gold quality
biceps brachii	UBERON:0001507	95.69	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.36	gold quality
quadriceps femoris	UBERON:0001377	95.22	gold quality
vastus lateralis	UBERON:0001379	94.98	gold quality
deltoid	UBERON:0001476	94.62	gold quality
gastrocnemius	UBERON:0001388	94.01	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.96	gold quality
muscle of leg	UBERON:0001383	92.69	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.18	silver quality
muscle tissue	UBERON:0002385	89.21	gold quality
left ventricle myocardium	UBERON:0006566	88.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.54	gold quality
upper arm skin	UBERON:0004263	85.71	gold quality
kidney epithelium	UBERON:0004819	82.01	gold quality
nasal cavity epithelium	UBERON:0005384	73.74	gold quality
pancreatic ductal cell	CL:0002079	73.46	silver quality
body of tongue	UBERON:0011876	72.63	gold quality
epithelial cell of pancreas	CL:0000083	69.27	gold quality
tongue	UBERON:0001723	69.14	gold quality
superficial temporal artery	UBERON:0001614	69.11	gold quality
epithelium of nasopharynx	UBERON:0001951	68.22	gold quality
ileal mucosa	UBERON:0000331	68.18	silver quality
cerebellar vermis	UBERON:0004720	66.18	gold quality
cardiac atrium	UBERON:0002081	65.44	gold quality
lateral nuclear group of thalamus	UBERON:0002736	65.44	silver quality
superior surface of tongue	UBERON:0007371	64.73	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FEZF1, MEF2C, MYF5, MYOD1, MYOG, NR0B1, SATB2

miRNA regulators (miRDB)

60 targeting VGLL2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-20B-3P	99.29	67.05	784
HSA-MIR-6731-5P	99.28	67.42	2375

Literature-anchored findings (GeneRIF, showing 5)

• role in promoting skeletal muscle differention (PMID:12376544)
• VITO-1 is a crucial new cofactor of the muscle regulatory programme (PMID:14762206)
• Identify novel and recurrent VGLL2-related fusions in pediatric spindle and sclerosing rhabdomyosarcomas. (PMID:26501226)
• A new perspective on the interaction between the Vg/VGLL1-3 proteins and the TEAD transcription factors. (PMID:33060790)
• VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis. (PMID:36656711)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	vgll2a	ENSDARG00000041706
mus_musculus	Vgll2	ENSMUSG00000049641
rattus_norvegicus	Vgll2	ENSRNOG00000000405
drosophila_melanogaster	vg	FBGN0003975

Paralogs (2): VGLL1 (ENSG00000102243), VGLL3 (ENSG00000206538)

Protein

Protein identifiers

Transcription cofactor vestigial-like protein 2 — Q8N8G2 (reviewed: Q8N8G2)

Alternative names: Protein VITO1

All UniProt accessions (1): Q8N8G2

UniProt curated annotations — full annotation on UniProt →

Function. May act as a specific coactivator for the mammalian TEFs. May play a role in the development of skeletal muscles.

Subunit / interactions. Interacts with TEFs. Binds to TEAD1/TEF1.

Subcellular location. Nucleus.

Tissue specificity. Skeletal muscle.

Similarity. Belongs to the vestigial family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N8G2-1	1	yes
Q8N8G2-2	2

RefSeq proteins (2): NP_703154, NP_872586* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011520	Vg_fam	Family

Pfam: PF07545

UniProt features (11 total): compositionally biased region 5, region of interest 4, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N8G2-F1	55.14	0.13

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 48 (showing top): GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, AGTCTTA_MIR499, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_SKELETAL_MUSCLE_ORGAN_DEVELOPMENT, YRTCANNRCGC_UNKNOWN, chr6q22, GOMF_TRANSCRIPTION_COACTIVATOR_ACTIVITY, MEISSNER_NPC_HCP_WITH_H3K4ME2_AND_H3K27ME3, MEISSNER_BRAIN_HCP_WITH_H3K4ME2_AND_H3K27ME3, MIKKELSEN_MCV6_HCP_WITH_H3K27ME3, MIKKELSEN_NPC_HCP_WITH_H3K27ME3, GOBP_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, YANG_BCL3_TARGETS_UP, GOMF_TRANSCRIPTION_COREGULATOR_ACTIVITY

GO Biological Process (4): regulation of transcription by RNA polymerase II (GO:0006357), skeletal muscle tissue development (GO:0007519), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (2): transcription coactivator activity (GO:0003713), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	2
positive regulation of DNA-templated transcription	2
regulation of DNA-templated transcription	1
striated muscle tissue development	1
skeletal muscle organ development	1
regulation of transcription by RNA polymerase II	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription coregulator activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

308 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VGLL2	TEAD1	P28347	915
VGLL2	WWTR1	Q9GZV5	758
VGLL2	NCOA2	Q15596	716
VGLL2	YAP1	P46937	678
VGLL2	MYOD1	P15172	670
VGLL2	MYOG	P15173	622
VGLL2	TEAD4	Q15561	593
VGLL2	VGLL4	Q14135	526
VGLL2	MEF2A	Q02078	518
VGLL2	TFCP2	Q12800	498
VGLL2	ACTA1	P02568	495
VGLL2	MYH1	P12882	491
VGLL2	PAX3	P23760	447
VGLL2	CITED2	Q99967	399
VGLL2	TCN2	P20062	387

IntAct

5 interactions, top by confidence:

A	B	Type	Score
TEAD3	VGLL2	psi-mi:“MI:0915”(physical association)	0.560
TEAD4	VGLL3	psi-mi:“MI:0914”(association)	0.350

BioGRID (2): VGLL2 (Two-hybrid), VGLL2 (Affinity Capture-MS)

ESM2 similar proteins: A0A087WPF7, A2AQ25, A8E4V2, A8MV65, B3F209, O14503, O35185, O35780, O77628, O88479, O97930, P01100, P01101, P10158, P12841, P15407, P15408, P15806, P15923, P18625, P47930, P48755, P51145, P85442, Q05AQ8, Q08E26, Q157S1, Q2VPM4, Q3LRZ1, Q3U182, Q53ET0, Q566L4, Q56TN0, Q56TT7, Q5EA15, Q5RAI7, Q68ED7, Q68FF7, Q7ZWN6, Q80TM6

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

647 predictions. Top by Δscore:

Variant	Effect	Δscore
6:117265842:CAGG:C	donor_loss	1.0000
6:117265843:AGG:A	donor_loss	1.0000
6:117265844:GGTA:G	donor_loss	1.0000
6:117265845:G:GA	donor_loss	1.0000
6:117265846:T:A	donor_loss	1.0000
6:117268487:GCGAG:G	donor_gain	1.0000
6:117268489:GAG:G	donor_gain	1.0000
6:117268492:G:GA	donor_loss	1.0000
6:117268492:G:GG	donor_gain	1.0000
6:117268493:T:A	donor_loss	1.0000
6:117265845:G:GG	donor_gain	0.9900
6:117268175:T:A	acceptor_gain	0.9900
6:117268179:CAG:C	acceptor_loss	0.9900
6:117268180:A:AG	acceptor_gain	0.9900
6:117268180:AG:A	acceptor_loss	0.9900
6:117268181:G:GA	acceptor_gain	0.9900
6:117268181:GA:G	acceptor_gain	0.9900
6:117268181:GAA:G	acceptor_gain	0.9900
6:117268181:GAAA:G	acceptor_gain	0.9900
6:117268488:CGAG:C	donor_gain	0.9900
6:117268489:GAGG:G	donor_gain	0.9900
6:117268490:AG:A	donor_gain	0.9900
6:117268491:GG:G	donor_gain	0.9900
6:117270517:A:AG	acceptor_gain	0.9900
6:117265841:CCAG:C	donor_gain	0.9800
6:117270517:ACTCC:A	acceptor_gain	0.9800
6:117272531:T:TA	acceptor_gain	0.9800
6:117265840:ACCAG:A	donor_gain	0.9700
6:117270521:C:A	acceptor_gain	0.9700
6:117270529:C:CA	acceptor_gain	0.9700

AlphaMissense

2064 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:117268357:T:A	V86D	1.000
6:117268360:T:C	L87P	1.000
6:117268407:T:C	F103L	1.000
6:117268408:T:C	F103S	1.000
6:117268408:T:G	F103C	1.000
6:117268409:C:A	F103L	1.000
6:117268409:C:G	F103L	1.000
6:117265770:T:C	C3R	0.999
6:117268338:T:C	Y80H	0.999
6:117268353:T:C	C85R	0.999
6:117268355:C:G	C85W	0.999
6:117268363:T:C	F88S	0.999
6:117268372:T:C	F91S	0.999
6:117268377:G:A	G93R	0.999
6:117268377:G:C	G93R	0.999
6:117268377:G:T	G93W	0.999
6:117268399:A:T	D100V	0.999
6:117268404:C:G	H102D	0.999
6:117268405:A:C	H102P	0.999
6:117268406:T:A	H102Q	0.999
6:117268406:T:G	H102Q	0.999
6:117268407:T:A	F103I	0.999
6:117268407:T:G	F103V	0.999
6:117268417:C:A	A106D	0.999
6:117265772:T:G	C3W	0.998
6:117268338:T:G	Y80D	0.998
6:117268339:A:C	Y80S	0.998
6:117268339:A:G	Y80C	0.998
6:117268354:G:A	C85Y	0.998
6:117268360:T:A	L87H	0.998

dbSNP variants (sampled 300 via entrez): RS1000168985 (6:117264266 G>C), RS1000544443 (6:117263910 G>A), RS1000908212 (6:117265371 T>A), RS1001805968 (6:117263746 A>T), RS1001875462 (6:117269717 G>A,C), RS1002300861 (6:117264019 C>T), RS1002527460 (6:117266101 A>T), RS1003316918 (6:117270894 C>G,T), RS1003938803 (6:117267762 T>G), RS1004702551 (6:117268751 T>A,C), RS1005013111 (6:117268531 C>T), RS1005365312 (6:117271402 C>G), RS1005382838 (6:117264934 G>C), RS1005817326 (6:117271336 A>G), RS1006180516 (6:117273512 G>A)

Disease associations

OMIM: gene MIM:609979 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
isolated congenital syngnathia	Strong	Autosomal recessive

Mondo (1): isolated congenital syngnathia (MONDO:0015409)

Orphanet (0):

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST000817_167	Height	1.000000e-11
GCST003542_92	Night sleep phenotypes	2.000000e-06
GCST004731_1	Facial emotion recognition (fearful faces)	1.000000e-06
GCST004748_50	Lung cancer	5.000000e-06
GCST005989_17	Serum total protein levels	2.000000e-08
GCST006014_12	Creatine kinase levels	6.000000e-15
GCST007094_65	Diastolic blood pressure	4.000000e-09
GCST008155_71	Waist-hip ratio	1.000000e-06
GCST008839_448	Height	8.000000e-11
GCST010796_1266	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_1267	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_1268	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-10
GCST010796_2412	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_2413	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_2414	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-14
GCST010989_111	Body size at age 10	5.000000e-10
GCST012226_683	Waist circumference adjusted for body mass index	6.000000e-10
GCST90011899_47	Aspartate aminotransferase levels	4.000000e-14
GCST90020028_543	Hip circumference adjusted for BMI	1.000000e-13
GCST90020028_544	Hip circumference adjusted for BMI	2.000000e-09

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0008329	facial emotion recognition measurement
EFO:0004534	creatine kinase measurement
EFO:0006336	diastolic blood pressure
EFO:0004343	waist-hip ratio
EFO:0004327	electrocardiography
EFO:0009819	comparative body size at age 10, self-reported
EFO:0007789	BMI-adjusted waist circumference
EFO:0004736	aspartate aminotransferase 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

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	2
Nickel	decreases expression	2
bisphenol A	affects cotreatment, decreases methylation	1
terbufos	increases methylation	1
arsenite	increases methylation	1
ferrous chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
pentanal	increases expression	1
abrine	increases expression	1
incobotulinumtoxinA	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Diethylhexyl Phthalate	increases expression	1
Fonofos	increases methylation	1
Lipopolysaccharides	affects cotreatment, increases expression, affects response to substance	1
Parathion	increases methylation	1
Smoke	increases expression	1
Dronabinol	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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