GeneBe

YAP1

protein-coding

Yes1 associated transcriptional regulator

Gene summary

This gene encodes a downstream nuclear effector of the Hippo signaling pathway which is involved in development, growth, repair, and homeostasis. This gene is known to play a role in the development and progression of multiple cancers as a transcriptional regulator of this signaling pathway and may function as a potential target for cancer treatment. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2013]

MANE transcript

NM_001130145.3

Inheritance

AD

ClinVar variants

P:7U:85B:30

Top phenotype

Ocular coloboma with or without hearing impairment, cleft lip/palate, and/or impaired intellectual development

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr11:102,110,447-102,233,424

External References & Databases

Ensembl (ENSG00000137693)NCBI Gene (10413)OMIM (606608)HGNC:16262GenCCUniProt (P46937)AlphaFoldClinVar (YAP1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~123.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or impaired intellectual developmentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007355

Submitter: Labcorp Genetics (formerly Invitae)

coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or impaired intellectual developmentSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007355

Submitter: Orphanet

coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or impaired intellectual developmentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007355

Submitter: PanelApp Australia

coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or impaired intellectual developmentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007355

Submitter: G2P

Clinical Genomic Database (CGD)

Ocular coloboma with or without hearing impairment, cleft lip/palate, and/or impaired intellectual developmentAD

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Neurologic; Ophthalmologic; Renal

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 24462371Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to YAP1 variants in ClinVar

7 Conditions Cataloged
not specifiedTotal: 62
not providedTotal: 56
Uveal coloboma-cleft lip and palate-intellectual disabilityTotal: 11
YAP1-related disorderTotal: 9
Multiple myelomaTotal: 1
Structural eye diseaseTotal: 1
Congenital ocular colobomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001130145.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
22
clinvar
2
clinvar
 25
missense
1
clinvar
1
clinvar
72
clinvar
5
clinvar
1
clinvar
 80
nonsense
3
clinvar
1
clinvar
3
clinvar
 7
start loss
1
clinvar
 1
frameshift
1
clinvar
2
clinvar
 3
splice donor/acceptor (+/-2bp)
6
clinvar
 6
Total4385273122
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001130145.3RefSeqNP_001123617.19MANE Select
ENST00000282441.10EnsemblENSP00000282441.59MANE Select
NM_001195044.2RefSeqNP_001181973.18Standard
NM_001195045.2RefSeqNP_001181974.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
yap1Danio rerio

Structure: neuromast hair cell

Quality: decreased functionality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Hippo signaling pathway - Homo sapiens (human)
  • Hippo signaling pathway - multiple species - Homo sapiens (human)
  • Mesodermal Commitment Pathway
  • Rac1-Pak1-p38-MMP-2 pathway
  • TGF-beta Signaling Pathway

Biological Process

  • cell morphogenesis
  • vasculogenesis
  • tissue homeostasis
  • heart process
  • embryonic heart tube morphogenesis

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • chromatin binding
  • transcription coactivator activity
  • transcription corepressor activity
  • protein binding

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • cytosol
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000282441
Coding exons
9
Length
122963
Individuals with no LoFs
124519
Homozygous LoFs
0
Heterozygous LoFs
5
Defined
124524
p
0.0000201
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.781892710.6970.00001343283
Missense (PolyPhen)2056.8180.352729
Synonymous-0.4061071021.050.000004891020
Loss of Function4.44124.90.04010.00000138242

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000470.000044rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcriptional regulator which can act both as a coactivator and a corepressor and is the critical downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:17974916, PubMed:18280240, PubMed:18579750, PubMed:21364637). The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:18158288). Plays a key role in tissue tension and 3D tissue shape by regulating cortical actomyosin network formation. Acts via ARHGAP18, a Rho GTPase activating protein that suppresses F-actin polymerization (PubMed:25778702). Plays a key role to control cell proliferation in response to cell contact. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration (PubMed:18158288). The presence of TEAD transcription factors are required for it to stimulate gene expression, cell growth, anchorage-independent growth, and epithelial mesenchymal transition (EMT) induction (PubMed:18579750). {ECO:0000269|PubMed:17974916, ECO:0000269|PubMed:18158288, ECO:0000269|PubMed:18280240, ECO:0000269|PubMed:18579750, ECO:0000269|PubMed:21364637, ECO:0000269|PubMed:25778702}.;
Disease
DISEASE: Coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or mental retardation (COB1) [MIM:120433]: An autosomal dominant disease characterized by uveal colobomata, microphthalmia, cataract and cleft lip/palate. Considerable variability is observed among patients, uveal colobomata being the most constant feature. Some patients manifest mental retardation of varying degree and/or sensorineural, mid-frequency hearing loss. {ECO:0000269|PubMed:24462371}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.168

Intolerance Scores

LoFtool
0.0213
RVIS EVS
-0.27
RVIS percentile EVS
34.32

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
E
Essential (gene trap)
H
Indispensability pred.
E
Indispensability score
0.620

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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