PCGF2
protein-codingpolycomb group ring finger 2, the group of Ring finger proteins|Polycomb group ring fingers
Gene summary
The protein encoded by this gene contains a RING finger motif and is similar to the polycomb group (PcG) gene products. PcG gene products form complexes via protein-protein interaction and maintain the transcription repression of genes involved in embryogenesis, cell cycles, and tumorigenesis. This protein was shown to act as a negative regulator of transcription and has tumor suppressor activity. The expression of this gene was detected in various tumor cells, but is limited in neural organs in normal tissues. Knockout studies in mice suggested that this protein may negatively regulate the expression of different cytokines, chemokines, and chemokine receptors, and thus plays an important role in lymphocyte differentiation and migration, as well as in immune responses. [provided by RefSeq, Jul 2008]
- ZNF144
- RNF110
MANE transcript
Inheritance
ClinVar variants
Top phenotype
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~15.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0032707
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0032707
Submitter: ClinGen
The *PCGF2* gene (OMIM: 600346) is located on chromosome 17q12 and encodes the Polycomb Group Ring Finger 2 (*PCGF2*, aka MEL18) protein, a component of the dynamic Polycomb Repressive Complex 1 (PRC1). *PCGF2* was first reported in relation to a distinct dysmorphic syndrome through a recurring hotspot variant (NM_007144.3 p.Pro65Leu) identified in two unrelated individuals enrolled in the Deciphering Developmental Disorders Study (DDD 2015, PMID: 25533962). Three years later, a case series was published describing 10 additional families with variants at the same Pro65 residue of *PCGF2* and an neuro-cardio-skeletal disorder coined Turnpenny-Fry syndrome (OMIM: 618371) (Turnpenny et al., 2018, PMID: 30343942) followed by an additional three patients in subsequent reports (PMIDs: 34750959, 36105049, 38283775). The consistent clinical characteristics of Turnpenny-Fry syndrome across 15 described families include developmental delay, impaired intellectual development, impaired growth, and a recognizable facial dysmorphology. Other common findings are feeding problems, constipation, and a range of brain, cardiac, vascular, and skeletal malformations. All Pro65 variants identified arose de novo in the affected individual aside from one, where the variant was found mosaic in an asymptomatic mother (PMID: 30343942). Currently there are no functional studies available which allow determination of the mechanism of disease for Turnpenny-Fry syndrome, or the significance of the Pro65 hotspot mutations, but knockout models in mice and drosophila for *PCGF2* orthologs support a role for this protein in growth and craniofacial/skeletal development (MGI: 2653494; Akasaka et al., 1996, PMID: 8625838). The impact of other variants in PCFG2 is unknown; given the single position involved to date, other variants would need very careful consideration. More evidence is needed to support pathogenicity of variants affecting codons other than Pro65. This gene-disease pair was originally evaluated by the Syndromic Disorders GCEP on August 20, 2021. It was re-evaluated on April 29, 2026. As a result of this reevaluation, the classification increased from Strong to Definitive with the addition of three new reported de novo cases in the literature demonstrating replication of the gene disease relationship over time (PMIDs: 34750959, 36105049, 38283775) (SOP Version 12).
Inheritance Pattern: AD
Disease ID:MONDO:0032707
Submitter: Broad Center for Mendelian Genomics
Inheritance Pattern: AD
Disease ID:MONDO:0032707
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0032707
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0032707
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic
Intervention: Cardiovascular
Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PCGF2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_007144.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 73 | 5 | 80 | ||
| missense | 3 | 133 | 34 | 5 | 175 | |
| nonsense | 3 | 3 | ||||
| start loss | 0 | |||||
| frameshift | 10 | 10 | ||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 0 | 3 | 153 | 107 | 10 | 273 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_009075.1 | 9 | MANE Select | |
| Ensembl | ENSP00000482815.1 | 9 | MANE Select | |
| RefSeq | NP_001356543.1 | 9 | Standard | |
| RefSeq | NP_001356544.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
- Gene expression (Transcription)
- Transcriptional Regulation by E2F6
- Generic Transcription Pathway
- SUMOylation of DNA damage response and repair proteins
Biological Process
- negative regulation of transcription by RNA polymerase II
- in utero embryonic development
- chromatin silencing
- anterior/posterior pattern specification
- histone acetylation
Molecular Function
- DNA binding
- DNA-binding transcription factor activity
- protein binding
- metal ion binding
- promoter-specific chromatin binding
Cellular Component
- nuclear chromatin
- sex chromatin
- nucleus
- nucleoplasm
- nuclear body
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional repressor. Binds specifically to the DNA sequence 5'-GACTNGACT-3'. Has tumor suppressor activity. May play a role in control of cell proliferation and/or neural cell development. Regulates proliferation of early T progenitor cells by maintaining expression of HES1. Also plays a role in antero- posterior specification of the axial skeleton and negative regulation of the self-renewal activity of hematopoietic stem cells (By similarity). Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:26151332). Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity (PubMed:26151332). {ECO:0000250|UniProtKB:P23798, ECO:0000269|PubMed:26151332}.;
Recessive Scores
- pRec
- 0.108
Intolerance Scores
- LoFtool
- 0.332
- RVIS EVS
- -0.43
- RVIS percentile EVS
- 25.15
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.685
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |