YY1

protein-coding

YY1 transcription factor, the group of INO80 complex |Zinc fingers C2H2-type

Gene summary

YY1 is a ubiquitously distributed transcription factor belonging to the GLI-Kruppel class of zinc finger proteins. The protein is involved in repressing and activating a diverse number of promoters. YY1 may direct histone deacetylases and histone acetyltransferases to a promoter in order to activate or repress the promoter, thus implicating histone modification in the function of YY1. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003403.5

Inheritance

ClinVar variants

P:53U:84B:38

Top phenotype

Gabriele-de Vries syndrome (GADEVS)

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr14:100,238,298-100,282,788

External References & Databases

Ensembl (ENSG00000100811)

Transcript & Mutation Effects

hg38 • Region Span ~44.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*YY1* was first reported in relation to autosomal dominant complex neurodevelopmental disorder (also called Gabriele de Vries syndrome (GADVS)) in 2017 (Gabriele et al., PMID: 28575647). Phenotypic features reported in affected individuals include variable intellectual disability (ID), various neurological disorders (hypotonia, abnormal movements, behavioral disorders, brain abnormalities), feeding difficulties, ophthalmological abnormalities, significant but not specific facial features, and more rarely cardiac or renal malformations. Twenty-nine variants (missense variants in the *YY1* zinc finger or nonsense and frameshift variants) have been reported in 29 probands in 11 publications (including PMIDs: 28575647, 32627382, 35027293, 39987231, and others documented in the genetic evidence) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function that leads to reduced DNA binding, widespread transcriptional downregulation and abnormal gene methylation (PMID: 28575647). This gene-disease relationship is also supported by experimental evidence of distinct DNA methylation signatures in patients with *YY1* pathogenic mutations (PMID: 350207293) and impaired transcriptional regulation in patient-derived induced pluripotent stem cells (PMID: 39987231). In addition to widespread transcriptional downregulation, brain organoids from patient-derived iPS cells showed impaired formation of ventricle-like structures in early stages of cortical development (PMID: 39987231). In summary, there is definitive evidence to support the gene-disease relationship between *YY1* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 1, 2025 (SOP Version 11).

Gabriele de Vries syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0044738

Submitter: Labcorp Genetics (formerly Invitae)

Gabriele de Vries syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0044738

Submitter: G2P

Gabriele de Vries syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0044738

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Gabriele-de Vries syndrome (GADEVS)AD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 28575647

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to YY1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 93

Gabriele de Vries syndromeTotal: 50

not specifiedTotal: 38

Inborn genetic diseasesTotal: 31

YY1-related disorderTotal: 16

Neurodevelopmental disorderTotal: 2

Intellectual disabilityTotal: 2

Developmental and epileptic encephalopathy, 78Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003403.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	1 clinvar	30 clinvar		32
missense	8 clinvar	23 clinvar	80 clinvar	7 clinvar	1 clinvar	119
nonsense	5 clinvar	1 clinvar				6
start loss			1 clinvar			1
frameshift	8 clinvar	4 clinvar	2 clinvar			14
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar				3
Total	22	31	84	37	1	175

Highest pathogenic variant AF is 6.840441e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003403.5	RefSeq	NP_003394.1	5	MANE Select
ENST00000262238.10	Ensembl	ENSP00000262238.4	5	MANE Select
ENST00000553625.5	Ensembl	ENSP00000452140.1	3	Standard
ENST00000554371.1	Ensembl	ENSP00000451329.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
yy1a	Danio rerio	Structure: trunk Quality: increased branchiness abnormal

Gene / Model

Organism

Observed Phenotype

yy1a

Danio rerio

Structure: trunk

Quality: increased branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Sterol Regulatory Element-Binding Proteins (SREBP) signalling
Notch
DNA Repair
Signal Transduction
Gene expression (Transcription)

Biological Process

negative regulation of transcription by RNA polymerase II
double-strand break repair via homologous recombination
regulation of transcription by RNA polymerase II
RNA localization
cellular response to DNA damage stimulus

Molecular Function

four-way junction DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
proximal promoter sequence-specific DNA binding

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
transcription factor complex
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262238
Coding exons: 5
Length: 44495
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.31	97	242	0.401	0.0000119	2707
Missense (PolyPhen)		6	59.651	0.10059		696
Synonymous	-1.55	121	101	1.20	0.00000548	797
Loss of Function	3.60	0	15.1	0.00	8.24e-7	187

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Multifunctional transcription factor that exhibits positive and negative control on a large number of cellular and viral genes by binding to sites overlapping the transcription start site. Binds to the consensus sequence 5'-CCGCCATNTT-3'; some genes have been shown to contain a longer binding motif allowing enhanced binding; the initial CG dinucleotide can be methylated greatly reducing the binding affinity. The effect on transcription regulation is depending upon the context in which it binds and diverse mechanisms of action include direct activation or repression, indirect activation or repression via cofactor recruitment, or activation or repression by disruption of binding sites or conformational DNA changes. Its activity is regulated by transcription factors and cytoplasmic proteins that have been shown to abrogate or completely inhibit YY1-mediated activation or repression. For example, it acts as a repressor in absence of adenovirus E1A protein but as an activator in its presence. Acts synergistically with the SMAD1 and SMAD4 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression (PubMed:15329343). Binds to SMAD binding elements (SBEs) (5'- GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions. May play an important role in development and differentiation. Proposed to recruit the PRC2/EED-EZH2 complex to target genes that are transcriptional repressed. Involved in DNA repair. In vitro, binds to DNA recombination intermediate structures (Holliday junctions). Plays a role in regulating enhancer activation (PubMed:28575647). {ECO:0000269|PubMed:15329343, ECO:0000269|PubMed:24326773, ECO:0000269|PubMed:25787250, ECO:0000269|PubMed:28575647}.;
Disease: DISEASE: Gabriele-de Vries syndrome (GADEVS) [MIM:617557]: An autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development and intellectual disability. Most patients have behavioral and feeding problems, movement abnormalities, mild distal skeletal anomalies, and dysmorphic facial features. {ECO:0000269|PubMed:21076407, ECO:0000269|PubMed:28575647}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.546

Intolerance Scores

RVIS EVS: 0.15
RVIS percentile EVS: 64.11

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium