PLAGL1
protein-codingPLAG1 like zinc finger 1, the group of Zinc fingers C2H2-type
Gene summary
This gene encodes a C2H2 zinc finger protein that functions as a suppressor of cell growth. This gene is often deleted or methylated and silenced in cancer cells. In addition, overexpression of this gene during fetal development is thought to be the causal factor for transient neonatal diabetes mellitus (TNDM). Alternative splicing and the use of alternative promoters results in multiple transcript variants encoding two different protein isoforms. The P1 downstream promoter of this gene is imprinted, with preferential expression from the paternal allele in many tissues. [provided by RefSeq, Nov 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~124.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0020525
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
*PLAGL1* was first reported in relation to autosomal dominant congenital heart disease in 2012 (Xuan et al. PMID: 22784302). A synonymous variant and an intronic variant were reported in two individuals with congenital heart disease but were not scored due to a lack of predicted or proven damaging impact for the synonymous variant and high population frequency without proven functional impact for the deep intronic variant (PMID: 22784302, 39402625). This gene-disease relationship is supported by expression studies in the developing murine heart, protein interaction studies between Zac1 and Nkx2-5, and a *Plagl1*-null mouse model with cardiac malformations (PMID: 20167925). In summary, due to the lack of convincing human genetic evidence, the relationship between *PLAGL1* and autosomal dominant congenital heart disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role of *PLAGL1* in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date on August 4, 2026. (SOP Version 12).
Clinical Genomic Database (CGD)
Manifestation: Endocrine
Intervention: Endocrine
Rationale: Individuals present early in life with failure to thrive, hyperglycemia, and dehydration, and prompt recognition and treatment can reduce morbidity
Comments: The pathogenesis may involve loss of methylation
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PLAGL1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001317162.2. 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 | 11 | 6 | 17 | |||
| missense | 55 | 5 | 4 | 64 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 56 | 16 | 10 | 82 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001304091.1 | 2 | MANE Select | |
| Ensembl | ENSP00000501459.1 | 2 | MANE Select | |
| RefSeq | NP_001074420.1 | 2 | Standard | |
| RefSeq | NP_001074421.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Aryl Hydrocarbon Receptor
- TP53 Regulates Transcription of Cell Cycle Genes
- Gene expression (Transcription)
- Generic Transcription Pathway
- RNA Polymerase II Transcription
Biological Process
- apoptotic process
- DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
- cell cycle arrest
- positive regulation of transcription by RNA polymerase II
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA binding
- metal ion binding
Cellular Component
- nucleoplasm
- Golgi apparatus
- nuclear body
- intracellular membrane-bounded organelle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000360537
- Coding exons
- 2
- Length
- 124299
- Individuals with no LoFs
- 125739
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125745
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.30 | 198 | 257 | 0.772 | 0.0000133 | 3021 |
| Missense (PolyPhen) | 47 | 92.806 | 0.50643 | 1070 | ||
| Synonymous | 0.191 | 109 | 112 | 0.977 | 0.00000609 | 960 |
| Loss of Function | 3.14 | 0 | 11.5 | 0.00 | 5.29e-7 | 158 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a transcriptional activator (PubMed:9722527). Involved in the transcriptional regulation of type 1 receptor for pituitary adenylate cyclase-activating polypeptide. {ECO:0000269|PubMed:18299245, ECO:0000269|PubMed:9722527}.;
- Disease
- DISEASE: Transient neonatal diabetes mellitus 1 (TNDM1) [MIM:601410]: Neonatal diabetes is a form of diabetes mellitus defined by the onset of mild-to-severe hyperglycemia within the first months of life. In about half of the neonates, diabetes is transient and resolves at a median age of 3 months, whereas the rest have a permanent form of diabetes. {ECO:0000269|PubMed:11935319}. Note=The gene represented in this entry is involved in disease pathogenesis. Imprinted expression of PLAGL1 is relaxed in patients with transient neonatal diabetes (TND) (PubMed:11935319). Aberrant hypomethylation of the TND differentially methylated region within the PLAGL1 promoter as well as other imprinted loci at chromosome 6q24 is caused by ZFP57 mutations (PubMed:18622393). {ECO:0000269|PubMed:11935319, ECO:0000269|PubMed:18622393}.;
Recessive Scores
- pRec
- 0.195
Intolerance Scores
- LoFtool
- 0.255
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 42.06
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.875
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |