PLAGL1

Summary

PLAGL1 (PLAG1 like zinc finger 1, HGNC:9046) is a protein-coding gene on chromosome 6q24.2, encoding Zinc finger protein PLAGL1 (Q9UM63). Acts as a transcriptional activator.

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.

Source: NCBI Gene 5325 — RefSeq curated summary.

At a glance

• Gene–disease (curated): transient neonatal diabetes mellitus (Supportive, GenCC)
• GWAS associations: 18
• Clinical variants (ClinVar): 84 total
• Phenotypes (HPO): 51
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 21 downstream targets (CollecTRI)
• MANE Select transcript: NM_001317162

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9046
Approved symbol	PLAGL1
Name	PLAG1 like zinc finger 1
Location	6q24.2
Locus type	gene with protein product
Status	Approved
Aliases	ZAC, LOT1
Ensembl gene	ENSG00000118495
Ensembl biotype	protein_coding
OMIM	603044
Entrez	5325

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 40 protein_coding, 6 protein_coding_CDS_not_defined

ENST00000354765, ENST00000360537, ENST00000367571, ENST00000367572, ENST00000416623, ENST00000417959, ENST00000437412, ENST00000444202, ENST00000493898, ENST00000625622, ENST00000626022, ENST00000626294, ENST00000626373, ENST00000626462, ENST00000627449, ENST00000628069, ENST00000628630, ENST00000628651, ENST00000629195, ENST00000629890, ENST00000631184, ENST00000647880, ENST00000647988, ENST00000649211, ENST00000649307, ENST00000650125, ENST00000674357, ENST00000891656, ENST00000891657, ENST00000891658, ENST00000891659, ENST00000891660, ENST00000891661, ENST00000891662, ENST00000891663, ENST00000891664, ENST00000940615, ENST00000940616, ENST00000940617, ENST00000972058, ENST00000972059, ENST00000972060, ENST00000972061, ENST00000972062, ENST00000972063, ENST00000972064

RefSeq mRNA: 27 — MANE Select: NM_001317162 NM_001080951, NM_001080952, NM_001080953, NM_001080954, NM_001080955, NM_001080956, NM_001289037, NM_001289038, NM_001289039, NM_001289040, NM_001289041, NM_001289042, NM_001289043, NM_001289044, NM_001289045, NM_001289046, NM_001289047, NM_001289048, NM_001289049, NM_001317156, NM_001317157, NM_001317158, NM_001317159, NM_001317160, NM_001317161, NM_001317162, NM_006718

CCDS: CCDS5202, CCDS5203

Canonical transcript exons

ENST00000674357 — 8 exons

Exon	Start	End
ENSE00001188765	143960469	143960542
ENSE00001348114	143968907	143968978
ENSE00001413661	143940300	143942663
ENSE00001429853	143985135	143985174
ENSE00001431687	143964787	143964818
ENSE00001740928	143966158	143966198
ENSE00002238577	143947985	143948460
ENSE00003831971	144008090	144008259

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 98.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.1935 / max 234.7217, expressed in 1497 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76048	14.5727	1536
76052	3.5540	550
76047	2.6304	894
76049	1.6880	850
76050	0.8886	462
76046	0.2593	106
76051	0.1731	87

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.51	gold quality
skin of hip	UBERON:0001554	98.36	gold quality
placenta	UBERON:0001987	97.79	gold quality
right adrenal gland cortex	UBERON:0035827	96.74	gold quality
tibia	UBERON:0000979	96.52	gold quality
cartilage tissue	UBERON:0002418	96.31	gold quality
pituitary gland	UBERON:0000007	96.22	gold quality
right adrenal gland	UBERON:0001233	96.16	gold quality
synovial joint	UBERON:0002217	96.04	gold quality
penis	UBERON:0000989	95.94	gold quality
descending thoracic aorta	UBERON:0002345	95.88	gold quality
adrenal cortex	UBERON:0001235	95.86	gold quality
upper leg skin	UBERON:0004262	95.83	gold quality
ascending aorta	UBERON:0001496	95.47	gold quality
thoracic aorta	UBERON:0001515	95.47	gold quality
left adrenal gland cortex	UBERON:0035825	95.47	gold quality
adenohypophysis	UBERON:0002196	95.41	gold quality
left adrenal gland	UBERON:0001234	95.35	gold quality
adrenal gland	UBERON:0002369	95.25	gold quality
mammary duct	UBERON:0001765	95.23	gold quality
blood vessel layer	UBERON:0004797	95.12	gold quality
cardia of stomach	UBERON:0001162	94.97	gold quality
lower lobe of lung	UBERON:0008949	94.87	gold quality
skin of abdomen	UBERON:0001416	94.59	gold quality
superior surface of tongue	UBERON:0007371	94.37	gold quality
mammalian vulva	UBERON:0000997	94.30	gold quality
parietal pleura	UBERON:0002400	94.18	gold quality
oral cavity	UBERON:0000167	93.95	gold quality
zone of skin	UBERON:0000014	93.85	gold quality
pleura	UBERON:0000977	93.73	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-24	yes	577.32
E-MTAB-6701	yes	69.39
E-ANND-3	yes	21.75
E-MTAB-6911	no	360.36

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

21 targets.

Target	Regulation
ABCC3
ABCC6	Activation
ADCYAP1
APAF1
CDKN1A	Activation
CDKN1C	Unknown
CDKN2A
IGF2
INS
KAT2B
MYH6
NFKB
NPPA
PLAGL1
PPARG
SDHB	Repression
SLC2A4
SOCS3
SORD	Repression
TGFBR2
TP53	Activation

Upstream regulators (CollecTRI, top): FOS, JUN, MEF2A, PLAGL1, SOX11, TP53, ZNF91

miRNA regulators (miRDB)

93 targeting PLAGL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-34B-5P	99.78	67.56	1175

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• PLAGL1 gene is imprinted, with preferential expression from the paternal allele in many tissues. (PMID:10655556)
• genetically imprinted in neonatal diabetes (PMID:11935319)
• This candidate tumor suppressor gene, located at chromosome 6q24-25, is epigenetically regulated in cancer (PMID:12473647)
• Zac contains transactivation activities that are differentially controlled by DNA binding. (PMID:12529403)
• ZAC expression was studied in transgenic mice. (PMID:15286800)
• The altered expression and LOH of the LOT1 locus support the gene’s potential role in the pathogenesis of ovarian cancer and possibly in other types of cancer. (PMID:15581945)
• Mutated in multiple congenital abnormalities including neonatasl diabstes, hypoplastic pasnscreas, intestinal atresia and gallbladdre dysplasia. (PMID:15592663)
• Mutations in ZAC may contribute to Beckwith-Wiedemann syndrome. (PMID:15888726)
• Down-regulation of PLAGL1 is associated with extraskeletal myxoid chondrosarcoma tumors (PMID:16112421)
• Loss of ZAC expression is associated with basal cell carcinomas of skin. (PMID:16179495)
• Using the ZAC1-specific marker located at 6q24-25, LOH or allelic imbalance was observed. (PMID:16733217)
• coordinated binding of Zac zinc fingers and C terminus to p300 regulates HAT function by increasing histone and acetyl coenzyme A affinities and catalytic activity (PMID:16809786)
• a transgene carrying the human HYMAI/PLAGL1 differentially methylated region was methylated in the correct parent-origin-specific manner in mice and this was sufficient to confer imprinted expression from the transgene (PMID:16928428)
• a functional relationship between Zac and PPARgamma that could be relevant to the understanding of tumorigenesis and diabetes as well. (PMID:17178896)
• Tissue-specific imprinting of PLAGL1 gene results from variable use of monoallelic and biallelic promoters. (PMID:17341487)
• Absence of unmethylated ZAC1 sequence was highly concurrent with ZAC1 region LOH or 6q loss and with lack of ZAC1 expression, suggesting preferential loss of nonimprinted, expressed ZAC1 allele in capillary hemangioblastoma. (PMID:17805016)
• Zac1 might be involved in regulating the p21(WAF1/Cip1) gene and protein expression through its protein-protein interaction with p53 and HDAC1 in HeLa cells. (PMID:18644983)
• Here it is shown that Zac1, together with the coactivators p300 and PCAF, recruit to the p21(Cip1) promoter during the differentiation of embryonic stem cells into neurons. (PMID:18663001)
• No evidence was found that polymorphisms in ZAC1 might influence anthropometric, biochemical or clinical parameters in French individuals. (PMID:19155788)
• The zinc-finger protein ZAC1 is up-regulated under hypertonic stress and negatively regulates expression of sorbitol dehydrogenase, allowing for accumulation of sorbitol as a compatible organic osmolyte. (PMID:19423711)
• Our results do not indicate a relevant role of mutations in LOT1(ZAC1/PLAGL1) in the etiology of Silver-Russell Syndrome. (PMID:19694203)
• Data indicates that downregulation of ZAC occurs in diffuse large B-cell lymphoma. As ZAC expression in normal B lymphocytes is derived from promoter P2, in DLBCL we analyzed both promoter P1 and P2 for gene expression, LOH and abnormal methylation. (PMID:20175198)
• ZAC1 is a novel and previously unknown regulator of cardiomyocyte Glut4 expression and glucose uptake; MEF2 is a regulator of ZAC1 expression in response to induction of hypertrophy (PMID:20363751)
• ZAC1 may have a role in tumorigenesis of von Hippel-Lindau associated central nervous system hemangioblastoma. (PMID:20518900)
• The specific expression of ZAC in the human fetal beta-cells supports it as the gene involved in transient neonatal diabetes mellitus (PMID:21305342)
• Our study suggests the involvement of the imprinted ZAC gene in the pathogenesis of pheochromocytoma. (PMID:21872827)
• Zac1 is able to interact directly with the Sp1-responsive element in the p21(WAF1/Cip1) gene promoter. (PMID:22001409)
• This work indicates that Zac1 functions are regulated, at least in part, via non-covalent interactions with SUMO-1 for the induction of p21, which is important for the modulation of apoptosis. (PMID:22227369)
• detected a synonymous variation in the protein-coding exon-2 of PLAGL1 in isolated VSD patients. It is possible that the etiology of isolated VSD might not be directly linked with this mutation (PMID:22784302)
• Based on these findings we conclude that the imprinted gene expression of KCNQ1OT1, CDKN1C, H19, and PLAGL1 are conserved between human and bovine (PMID:23153226)
• The imprinted PLAGL1 domain is flanked by CTCF-binding sites conserved between species in both expressing and non-expressing cells. (PMID:23295672)
• Paternal methylation aberrations at imprinting control regions of DLK1-GTL2, MEST (PEG1), and ZAC (PLAGL1) and global methylation levels are not associated with idiopathic recurrent spontaneous miscarriages. (PMID:23415968)
• ZAC1 and SSTR2 are down-regulated in non-functioning pituitary adenomas but not in somatotropinomas. (PMID:24098585)
• research identified a specific CpG site where determination of the methylation status was associated with both metastasis-free and overall survival in undifferentiated sarcoma. (PMID:24260468)
• There is positive correlations between the ZAC1 DMR methylation index (MI) and estimated fetal weight (EFW) at 32 weeks of gestation, weight at birth and weight at one year of age (respectively, r = 0.15, 0.09, 0.14; P values = 0.01, 0.15, 0.03). (PMID:24316753)
• Fetal growth can be influenced by altered expression of the PLAGL1 gene network in human placenta. (PMID:24993786)
• DNA deletion and promoter hyper-methylation both contribute to the down-regulation of PLAGL1 in gastric adenocarcinoma (PMID:25091631)
• Results suggest that dysregulation of PLAGL1 expression may be involved in the progression of colorectal cancer (CRC) but the patient survival data do not confirm applicability of the PLAGL1 expression level as a prognostic factor in CRC. (PMID:26134521)
• High PLAGL1 mRNA and protein levels were associated with Clear Cell Renal Cell Carcinoma. (PMID:26851016)
• PLAGL1 methylation/expression may be altered after assisted reproductive technologies. (PMID:27178226)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	plagx	ENSDARG00000036855
danio_rerio	plagl2	ENSDARG00000076657
mus_musculus	Plagl1	ENSMUSG00000019817
rattus_norvegicus	Plagl1	ENSRNOG00000025587
drosophila_melanogaster	hb	FBGN0001180
drosophila_melanogaster	CG12391	FBGN0033581
caenorhabditis_elegans		WBGENE00001824
caenorhabditis_elegans		WBGENE00012385

Paralogs (29): ZNF446 (ENSG00000083838), REST (ENSG00000084093), ZNF174 (ENSG00000103343), OVOL3 (ENSG00000105261), ZSCAN18 (ENSG00000121413), ZNF576 (ENSG00000124444), OVOL2 (ENSG00000125850), PLAGL2 (ENSG00000126003), ZSCAN5A (ENSG00000131848), ZSCAN29 (ENSG00000140265), ZSCAN32 (ENSG00000140987), ZSCAN1 (ENSG00000152467), ZNF18 (ENSG00000154957), ZKSCAN2 (ENSG00000155592), ZNF496 (ENSG00000162714), ZNF202 (ENSG00000166261), ZNF641 (ENSG00000167528), ZNF444 (ENSG00000167685), SCAND1 (ENSG00000171222), ZNF274 (ENSG00000171606), ZNF131 (ENSG00000172262), OVOL1 (ENSG00000172818), ZNF518A (ENSG00000177853), ZNF518B (ENSG00000178163), PLAG1 (ENSG00000181690), ZSCAN5B (ENSG00000197213), ZNF770 (ENSG00000198146), PEG3 (ENSG00000198300), ZSCAN5C (ENSG00000204532)

Protein

Protein identifiers

Zinc finger protein PLAGL1 — Q9UM63 (reviewed: Q9UM63)

Alternative names: Lost on transformation 1, Pleiomorphic adenoma-like protein 1, Tumor suppressor ZAC

All UniProt accessions (8): Q9UM63, A0A0D9SEQ4, A0A0D9SFI7, A0A0D9SFM8, A0A0D9SGF7, A0A3B3IRN7, A1YLA1, A1YLA2

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional activator. Involved in the transcriptional regulation of type 1 receptor for pituitary adenylate cyclase-activating polypeptide.

Subunit / interactions. Interacts with THRSP.

Subcellular location. Nucleus.

Disease relevance. Diabetes mellitus, transient neonatal, 1 (TNDM1) [MIM:601410] An autosomal dominant form of diabetes mellitus defined by the onset of mild-to-severe hyperglycemia within the first month 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. The gene represented in this entry is involved in disease pathogenesis. Imprinted expression of PLAGL1 is relaxed in patients with transient neonatal diabetes (TND). 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.

Similarity. Belongs to the krueppel C2H2-type zinc-finger protein family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UM63-1	1	yes
Q9UM63-2	2, ZACdelta2

RefSeq proteins (27): NP_001074420, NP_001074421, NP_001074422, NP_001074423, NP_001074424, NP_001074425, NP_001275966, NP_001275967, NP_001275968, NP_001275969, NP_001275970, NP_001275971, NP_001275972, NP_001275973, NP_001275974, NP_001275975, NP_001275976, NP_001275977, NP_001275978, NP_001304085, NP_001304086, NP_001304087, NP_001304088, NP_001304089, NP_001304090, NP_001304091, NP_006709 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096

UniProt features (13 total): zinc finger region 7, sequence conflict 2, chain 1, sequence variant 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UM63-F1	57.65	0.01

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6804115	TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain

MSigDB gene sets: 394 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, LEE_NEURAL_CREST_STEM_CELL_DN, PAX4_01, PAL_PRMT5_TARGETS_UP, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, E2F1DP1_01, E2F1DP2_01, WOO_LIVER_CANCER_RECURRENCE_UP, FOSTER_TOLERANT_MACROPHAGE_UP, GAZDA_DIAMOND_BLACKFAN_ANEMIA_PROGENITOR_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_CYTOKINE_PRODUCTION

GO Biological Process (7): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of cytokine production (GO:0001817), regulation of immune system process (GO:0002682), apoptotic process (GO:0006915), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of cell cycle (GO:0051726), regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (10): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), zinc ion binding (GO:0008270), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), nuclear body (GO:0016604), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TP53 Regulates Transcription of Cell Cycle Genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
negative regulation of DNA-templated transcription	1
cytokine production	1
regulation of gene expression	1
regulation of multicellular organismal process	1
immune system process	1
regulation of biological process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
positive regulation of DNA-templated transcription	1
cell cycle	1
regulation of cellular process	1
cis-regulatory region sequence-specific DNA binding	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription repressor activity	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transition metal ion binding	1
transcription regulator activity	1
binding	1
DNA binding	1
cation binding	1
nuclear lumen	1
cytoplasm	1
endomembrane system	1
nucleoplasm	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1278 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLAGL1	MEST	Q5EB52	867
PLAGL1	PEG3	P78418	832
PLAGL1	GRB10	Q13322	820
PLAGL1	DLK1	P15803	784
PLAGL1	ADCYAP1	P18509	776
PLAGL1	PEG10	Q86TG7	728
PLAGL1	RFX6	Q8HWS3	727
PLAGL1	CDKN1C	P49918	703
PLAGL1	NNAT	Q16517	697
PLAGL1	SNRPN	P14648	696
PLAGL1	SGCE	O43556	676
PLAGL1	IGF2	P01344	651
PLAGL1	NAP1L5	Q96NT1	625
PLAGL1	PHACTR2	O75167	608
PLAGL1	GNAS	Q5JWF2	600

IntAct

31 interactions, top by confidence:

A	B	Type	Score
PLAGL1	KANK2	psi-mi:“MI:0915”(physical association)	0.560
KANK2	PLAGL1	psi-mi:“MI:0915”(physical association)	0.560
TLE5	PLAGL1	psi-mi:“MI:0915”(physical association)	0.560
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
	PLAGL1	psi-mi:“MI:0915”(physical association)	0.370
CCL22	PLAGL1	psi-mi:“MI:0915”(physical association)	0.370
CCL24	PLAGL1	psi-mi:“MI:0915”(physical association)	0.370
CSF2	PLAGL1	psi-mi:“MI:0915”(physical association)	0.370
CXCL5	PLAGL1	psi-mi:“MI:0915”(physical association)	0.370
IFNK	PLAGL1	psi-mi:“MI:0915”(physical association)	0.370
IL25	PLAGL1	psi-mi:“MI:0915”(physical association)	0.370
IL3	PLAGL1	psi-mi:“MI:0915”(physical association)	0.370
IL31	PLAGL1	psi-mi:“MI:0915”(physical association)	0.370
LTA	PLAGL1	psi-mi:“MI:0915”(physical association)	0.370
SMAD3	PLAGL1	psi-mi:“MI:0915”(physical association)	0.370
DDOST	ATL3	psi-mi:“MI:0914”(association)	0.350
KRTCAP2	PGRMC1	psi-mi:“MI:0914”(association)	0.350
OST4	ATL3	psi-mi:“MI:0914”(association)	0.350
RPN2	APBB1	psi-mi:“MI:0914”(association)	0.350
PLAGL1	TLE5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (37): PLAGL1 (Affinity Capture-Western), PLAGL1 (Reconstituted Complex), TP73 (Reconstituted Complex), KAT2B (Reconstituted Complex), PLAGL1 (Reconstituted Complex), PLAGL1 (Co-localization), TP73 (Co-localization), PLAGL1 (Affinity Capture-RNA), PLAGL1 (Affinity Capture-Western), SUMO1 (Biochemical Activity), PLAGL1 (Affinity Capture-RNA), PLAGL1 (Two-hybrid), TP53 (Reconstituted Complex), PLAGL1 (Phenotypic Enhancement), PLAGL1 (Affinity Capture-MS)

ESM2 similar proteins: A1L2U9, A2APF3, A2BID7, A2VDT4, B1WAZ8, B1WBU4, G5E869, O08961, O14753, O43298, Q05516, Q0IH98, Q0VCJ6, Q13422, Q2I689, Q2M1K9, Q3U288, Q58NQ5, Q5NBY9, Q5TC79, Q5U2T6, Q6DJT9, Q6NS86, Q6ZPY5, Q80TS5, Q86UZ6, Q8BHZ4, Q8C208, Q8CCH7, Q8CIV7, Q8K0L9, Q8N1W2, Q8N895, Q8NCN2, Q8WW38, Q90W33, Q92610, Q96BR9, Q9BRP0, Q9BYN7

Diamond homologs: A0A1V6NWD3, A1L2U9, B0X9H6, B0XS89, B1WAZ8, B1WBU4, C8VJW0, G5EBU4, J9VX63, O60315, P10925, P15822, P20662, P31629, P36197, P52739, P53243, P56270, P56670, P56671, P78871, P80944, Q00453, Q00900, Q01611, Q03172, Q0IH98, Q0VCJ6, Q12132, Q29419, Q2I689, Q3UHF7, Q4WXK4, Q5JPB2, Q5RAU9, Q60542, Q62947, Q64318, Q6IQX8, Q6P882

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PLAGL1	“up-regulates quantity by expression”	ABCC6	“transcriptional regulation”
Ub:E2	“up-regulates activity”	PLAGL1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
protein N-linked glycosylation	5	65.8×	2e-06
cell-cell signaling	5	17.4×	4e-04
immune response	6	14.1×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

84 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	11
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

1476 predictions. Top by Δscore:

Variant	Effect	Δscore
6:143942659:TATGC:T	acceptor_gain	1.0000
6:143942661:TGC:T	acceptor_gain	1.0000
6:143942664:C:CC	acceptor_gain	1.0000
6:143960471:A:AC	donor_gain	1.0000
6:143960472:C:CC	donor_gain	1.0000
6:143942665:T:G	acceptor_loss	0.9900
6:143942671:C:CT	acceptor_gain	0.9900
6:143942672:A:T	acceptor_gain	0.9900
6:143964785:A:AC	donor_gain	0.9900
6:143964786:C:CC	donor_gain	0.9900
6:143984475:T:TA	donor_gain	0.9900
6:144008088:AC:A	donor_gain	0.9900
6:144008089:CC:C	donor_gain	0.9900
6:144008089:CCCTG:C	donor_gain	0.9900
6:143942660:ATGC:A	acceptor_gain	0.9800
6:143968977:TC:T	acceptor_gain	0.9800
6:143968978:CC:C	acceptor_gain	0.9800
6:144008086:CTACC:C	donor_loss	0.9800
6:144008087:TACC:T	donor_loss	0.9800
6:143942662:GC:G	acceptor_gain	0.9700
6:143942663:CC:C	acceptor_gain	0.9700
6:143984417:G:C	donor_gain	0.9700
6:144008083:CACCT:C	donor_loss	0.9700
6:144008084:ACCTA:A	donor_loss	0.9700
6:144008085:CCTAC:C	donor_loss	0.9700
6:144008088:A:AC	donor_gain	0.9700
6:144008089:C:CC	donor_gain	0.9700
6:143966199:C:CC	acceptor_gain	0.9600
6:143968974:CAATC:C	acceptor_gain	0.9600
6:143968975:AATCC:A	acceptor_loss	0.9600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000069 (6:144007285 G>A), RS1000050174 (6:144013311 C>G), RS1000094904 (6:144014976 C>T), RS1000136351 (6:143960497 G>A), RS1000136884 (6:144057768 G>A), RS1000167464 (6:144027795 C>T), RS1000201614 (6:144025046 AG>A,AGG), RS1000204252 (6:144059124 A>C), RS1000212672 (6:143977261 T>A), RS1000269703 (6:143967520 A>G), RS1000291628 (6:143992246 T>C), RS1000315767 (6:144025190 T>G), RS1000319802 (6:144021113 T>C), RS1000325418 (6:144009387 T>C), RS1000432463 (6:143984882 T>C)

Disease associations

OMIM: gene MIM:603044 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
transient neonatal diabetes mellitus	Supportive	Autosomal dominant

Mondo (2): myoepithelial tumor (MONDO:0002380), transient neonatal diabetes mellitus (MONDO:0020525)

Orphanet (0):

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000065	Labial hypertrophy
HP:0000077	Abnormality of the kidney
HP:0000079	Abnormality of the urinary system
HP:0000158	Macroglossia
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000237	Small anterior fontanelle
HP:0000269	Prominent occiput
HP:0000271	Abnormality of the face
HP:0000278	Retrognathia
HP:0000347	Micrognathia
HP:0000363	Abnormal earlobe morphology
HP:0000365	Hearing impairment
HP:0000448	Prominent nose
HP:0000586	Shallow orbits
HP:0000707	Abnormality of the nervous system
HP:0000821	Hypothyroidism
HP:0000826	Precocious puberty
HP:0000857	Neonatal insulin-dependent diabetes mellitus
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001382	Joint hypermobility
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001525	Severe failure to thrive
HP:0001537	Umbilical hernia
HP:0001562	Oligohydramnios

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST003264_1004	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_880	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST003264_972	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST004608_34	Granulocyte percentage of myeloid white cells	5.000000e-30
GCST004609_27	Monocyte percentage of white cells	2.000000e-29
GCST004617_1	Eosinophil percentage of granulocytes	2.000000e-09
GCST004623_101	Neutrophil percentage of granulocytes	2.000000e-09
GCST004625_91	Monocyte count	3.000000e-16
GCST004633_65	Neutrophil percentage of white cells	5.000000e-17
GCST005025_1	Anti-saccade response	9.000000e-06
GCST005723_4	Peanut allergy (maternal genetic effects)	9.000000e-06
GCST012489_9	Heel bone mineral density x serum urate levels interaction	4.000000e-11
GCST90002389_139	Lymphocyte percentage of white cells	4.000000e-13
GCST90002393_100	Monocyte count	4.000000e-10
GCST90002393_51	Monocyte count	2.000000e-39
GCST90002394_178	Monocyte percentage of white cells	1.000000e-12
GCST90002394_179	Monocyte percentage of white cells	5.000000e-66
GCST90002399_161	Neutrophil percentage of white cells	4.000000e-34

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005091	monocyte count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0006874	antisaccade response measurement
EFO:0005939	parental genotype effect measurement
EFO:0007017	peanut allergy measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0007993	lymphocyte percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2247408	PLAGL1		0.00	0
rs3819811	PLAGL1		0.00	0

CTD chemical–gene interactions

60 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
Valproic Acid	decreases methylation, increases expression	3
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	increases sumoylation	1
urushiol	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
geraniol	increases expression	1
testosterone undecanoate	affects cotreatment, decreases expression	1
kojic acid	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
nickel sulfate	decreases expression	1
coumarin	increases phosphorylation	1
cupric oxide	decreases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	increases reaction, affects binding	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
perfluorobutanesulfonic acid	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A5K1	SEES3-1V human PLAGL1, clone1	Embryonic stem cell	Male
CVCL_A5K2	SEES3-1V human PLAGL1, clone2	Embryonic stem cell	Male
CVCL_A5K3	SEES3-1V human PLAGL1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

7 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05945576	Not specified	RECRUITING	IDMet (RaDiCo Cohort) (RaDiCo-IDMet)
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	PHASE1/PHASE2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis