PLAGL1

Chr 6

PLAG1 like zinc finger 1

Also known as: LOT1, ZAC, ZAC1

NCBI Gene: 5325ENSG00000118495UniProt: Q9UM63

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]

Primary Disease Associations & Inheritance

UniProtDiabetes mellitus, transient neonatal, 1
94
ClinVar variants
17
Pathogenic / LP
0.98
pLI score· haploinsufficient
0
Active trials
Clinical Summary— PLAGL1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
17 Pathogenic / Likely Pathogenic· 55 VUS of 94 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.26LOEUF
pLI 0.976
Z-score 3.14
OE 0.00 (0.00–0.26)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.30Z-score
OE missense 0.77 (0.69–0.87)
198 obs / 256.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.26)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.69–0.87)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 0 / 11.5Missense obs/exp: 198 / 256.5Syn Z: 0.19

ClinVar Variant Classifications

94 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
VUS55
Likely Benign11
Benign11
17
Pathogenic
55
VUS
11
Likely Benign
11
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
17
0
17
Likely Pathogenic
0
0
0
0
0
VUS
0
54
1
0
55
Likely Benign
0
5
0
6
11
Benign
0
4
1
6
11
Total063191294

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PLAGL1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
📖
GeneReview available — PLAGL1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CNS tumors with PLAGL1-fusion: beyond ZFTA and YAP1 in the genetic spectrum of supratentorial ependymomas.
Tauziède-Espariat A et al.·Acta Neuropathol Commun
2024
Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification.
Keck MK et al.·Acta Neuropathol
2023
Concurrent ependymal and ganglionic differentiation in a subset of supratentorial neuroepithelial tumors with EWSR1-PLAGL1 rearrangement.
Lee JC et al.·Acta Neuropathol Commun
2024
PLAG1 fusions define a third subtype of CNS embryonal tumor with PLAG family gene alteration.
Keck MK et al.·Acta Neuropathol
2025
Comparative Clinical and Imaging-Based Evaluation of Therapeutic Modalities in CNS Embryonal Tumours With PLAGL Amplification.
Keck MK et al.·Neuropathol Appl Neurobiol
2025
Transient neonatal diabetes mellitus type 1.
Mackay DJ et al.·Am J Med Genet C Semin Med Genet
2010Review
[Supratentorial neuroepithelial tumor with PLAGL1 gene fusion - a new type of morphologically variable pediatric brain neoplasm defined by a distinct DNA methylation class. A case report and literature review].
Kopachev DN et al.·Zh Vopr Neirokhir Im N N Burdenko
2024Review
Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity.
Dalgaard K et al.·Cell
2016
PLAGL1 epimutation and bladder exstrophy: Coincidence or concurrent etiology?
Kolarova J et al.·Birth Defects Res A Clin Mol Teratol
2016Case report
A novel variation of PLAGL1 in Chinese patients with isolated ventricular septal defect.
Xuan C et al.·Genet Test Mol Biomarkers
2012Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Plagl1 and Lrrc58 control mammalian body size by triggering target-directed microRNA degradation of miR-322 and miR-503.
LaVigne CA et al.·Genes Dev
2026🔓 Open Access
Single-Cell Dissection of Fibroblast Heterogeneity in Diabetic Ulcers: Platelet-Rich Plasma (PRP) Therapy Activates Core Regenerative Programs via PLAGL1/RUNX2/ZKSCAN7 Networks.
Li X et al.·Front Biosci (Landmark Ed)
2025
PLAGL1 overexpression exacerbates type 1 diabetes by inducing β-cell apoptosis via oxidative stress-dependent dual DNA damage and cGAS/STING pathway activation.
Li C et al.·J Diabetes Investig
2026🔓 Open Access
PLAGL1-IGF2 axis regulates osteogenesis of postnatal condyle development.
Sun J et al.·Int J Oral Sci
2025🔓 Open Access
PLAGL1 overexpression induces cytoplasmic DNA accumulation that triggers cGAS/STING activation.
Li C et al.·J Cell Mol Med
2024🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools