PLAG1

Summary

PLAG1 (PLAG1 zinc finger, HGNC:9045) is a protein-coding gene on chromosome 8q12.1, encoding Zinc finger protein PLAG1 (Q6DJT9). Transcription factor whose activation results in up-regulation of target genes, such as IGFII, leading to uncontrolled cell proliferation: when overexpressed in cultured cells, higher proliferation rate and transformation are observed.

Pleomorphic adenoma gene 1 encodes a zinc finger protein with 2 putative nuclear localization signals. PLAG1, which is developmentally regulated, has been shown to be consistently rearranged in pleomorphic adenomas of the salivary glands. PLAG1 is activated by the reciprocal chromosomal translocations involving 8q12 in a subset of salivary gland pleomorphic adenomas. Three transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 5324 — RefSeq curated summary.

At a glance

• Gene–disease (curated): silver-russell syndrome 4 (Strong, GenCC)
• GWAS associations: 21
• Clinical variants (ClinVar): 39 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 41
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Transcription factor: yes — 10 downstream targets (CollecTRI)
• MANE Select transcript: NM_002655

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9045
Approved symbol	PLAG1
Name	PLAG1 zinc finger
Location	8q12.1
Locus type	gene with protein product
Status	Approved
Aliases	ZNF912
Ensembl gene	ENSG00000181690
Ensembl biotype	protein_coding
OMIM	603026
Entrez	5324

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000316981, ENST00000423799, ENST00000429357, ENST00000519027, ENST00000522009, ENST00000878031, ENST00000939997, ENST00000939998, ENST00000962220

RefSeq mRNA: 3 — MANE Select: NM_002655 NM_001114634, NM_001114635, NM_002655

CCDS: CCDS47860, CCDS6165

Canonical transcript exons

ENST00000316981 — 5 exons

Exon	Start	End
ENSE00001256348	56171091	56171189
ENSE00001256355	56179409	56179513
ENSE00002089948	56160909	56167503
ENSE00002135562	56211121	56211273
ENSE00003656014	56168028	56168386

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 88.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.4532 / max 84.5843, expressed in 1163 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93135	3.9565	1119
93136	0.4967	304

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	88.50	gold quality
amniotic fluid	UBERON:0000173	83.93	gold quality
oocyte	CL:0000023	82.24	gold quality
adrenal tissue	UBERON:0018303	80.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.33	gold quality
stromal cell of endometrium	CL:0002255	79.31	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.43	gold quality
epithelium of nasopharynx	UBERON:0001951	77.65	gold quality
right uterine tube	UBERON:0001302	77.13	gold quality
pigmented layer of retina	UBERON:0001782	76.95	gold quality
ventricular zone	UBERON:0003053	76.83	gold quality
palpebral conjunctiva	UBERON:0001812	75.69	gold quality
calcaneal tendon	UBERON:0003701	75.34	gold quality
embryo	UBERON:0000922	74.62	gold quality
ganglionic eminence	UBERON:0004023	74.62	gold quality
tibial nerve	UBERON:0001323	73.89	gold quality
mucosa of paranasal sinus	UBERON:0005030	73.28	silver quality
epithelium of bronchus	UBERON:0002031	71.82	gold quality
bronchial epithelial cell	CL:0002328	71.62	gold quality
bronchus	UBERON:0002185	71.28	gold quality
apex of heart	UBERON:0002098	71.23	gold quality
vagina	UBERON:0000996	70.54	gold quality
right atrium auricular region	UBERON:0006631	70.13	gold quality
pituitary gland	UBERON:0000007	70.10	gold quality
right lung	UBERON:0002167	69.89	gold quality
adenohypophysis	UBERON:0002196	69.88	gold quality
endocervix	UBERON:0000458	69.63	gold quality
heart left ventricle	UBERON:0002084	69.26	gold quality
islet of Langerhans	UBERON:0000006	69.18	gold quality
ectocervix	UBERON:0012249	69.04	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.39

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

Target	Regulation
ABCC6	Activation
CD44
CRLF1	Activation
CTNNB1	Activation
EGR1	Activation
GNAS
H19
IGF2	Activation
PLAG1
XRCC1	Unknown

JASPAR motifs

Motif	Name	Family
MA0163.1	PLAG1	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:16041365

Upstream regulators (CollecTRI, top): PLAG1

miRNA regulators (miRDB)

276 targeting PLAG1, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997

Literature-anchored findings (GeneRIF, showing 40)

• Identification of a karyopherin alpha 2 recognition site in PLAG1, which functions as a nuclear localization signal (PMID:11882654)
• overexpression of PLAG1 does not depend on chromosomal rearrangements in radiation associated pleomorphic adenomas (PMID:11894114)
• PLAG1 regulates promoter P3-dependent transcription of IGF2 in hepatoblastomas. (PMID:14695992)
• a direct repression of the transactivating capacity of the oncoprotein PLAG1 by SUMOylation (PMID:15208321)
• PLAG1 amplification is associated with malignant mixed tumor of salivary gland (PMID:15262430)
• Plag1 and Plagl2 are novel leukemia oncogenes that act by expanding hematopoietic progenitors expressing CbF beta-SMMHC. (PMID:15585652)
• fusion with HAS2 in lipoblastoma (PMID:15642402)
• Finding reinforces the role of PLAG1 on the tumorigenesis of benign and malignant pleomorphic adenoma. (PMID:15920557)
• Results establish the in vivo tumorigenic capacity of PLAG1 and indicate that the transgenic mice constitute a valuable model for pleomorphic salivary gland tumorigenesis and potentially for other glands as well. (PMID:15930271)
• Overexpression of PLAG1 is associated with pleomorphic adenomas in transgenic mice (PMID:16108035)
• PLAG1 protein is overexpressed in epithelial, myoepithelial, and mesenchymal-like tumor cells in tumors with fusions to CHCHD7 and TCEA1. (PMID:16736500)
• The importance and versatility of the PLAG1 oncogene in tumourigenesis is discussed. (PMID:17332914)
• PLAG1 gene rearrangements is associated with pleomorphic adenoma (PMID:17693184)
• Molecular analyses in salivary gland tumors revealed that ring formation consistently generated novel FGFR1-PLAG1 gene fusions in which the 5’-part of FGFR1 is linked to the coding sequence of PLAG1 (PMID:18059337)
• Fluorescence in situ hybridization (FISH) demonstrated rearrangements of the PLAG1 region in lipoblastoma in adolescencts and young adults. (PMID:18269579)
• overexpression of PLAG1 is associated with pleomorphic adenomas of the salivary gland. (PMID:19347935)
• a significant regulation of PLAG1 by miR-181a, miR-181b, miR-107, and miR-424. (PMID:19692702)
• Overexpression in transgenic mice causes hypereinsulinemic normoglycemia and insulin resistance. (PMID:20522588)
• Overexpression of the oncogene PLAG1 is associated with the pathogenesis of chronic lymphocytic leukemia. (PMID:20687796)
• present results also suggest that overexpression of PLAG1 is essential for the tumorigenesis of pleomorphic adenomas, although the mechanisms mediating PLAG1 overexpression seem to be variable. (PMID:21394649)
• close relationship between cutaneous mixed tumors and pleomorphic adenomas of the salivary gland. However, the mechanism of PLAG1 expression in cutaneous mixed tumors appears to be possibly different from that of pleomorphic adenomas. (PMID:21927843)
• myoepithelial tumors with PLAG1 alteration share a common morphologic phenotype with salivary gland-like morphology and are genetically related to their salivary gland counterpart (PMID:22038920)
• PLAG1 immunohistochemistry is useful for distinguishing lipoblastoma from other lipomatous tumors including liposarcoma. (PMID:22192798)
• We conclude that most Carcinoma ex pleomorphic adenoma, regardless of morphologic subtype,carry altered PLAG1 genes (PMID:22485045)
• PLAG1 is evidently not involved in the development of myoepithelial tumours. The proportion of 8q12-alterations in myoepithelial tumours was very low. (PMID:22593475)
• PLAG1 binding to the IGF2 P3 promoter and IGF2 expression is cell type-specific, and that the PLAG1 transcription factor acts as a transcriptional facilitator that partially overrides the insulation by the H19 ICR. (PMID:23023303)
• These results suggest that PLAG1 and CYLD do not play a role in ACC tumorigenesis. (PMID:23404581)
• miR-141 contributes to fetal growth restriction by regulating PLAG1 expression. (PMID:23554918)
• A subset of cutaneous and soft tissue ME tumors appears genetically linked to their salivary gland counterparts, displaying frequent PLAG1 gene rearrangements and occasionally LIFR-PLAG1 fusion. (PMID:23630011)
• PLAG1 not only activates genes that promote cell proliferation and tumor formation but also genes that inhibit these cellular processes. (PMID:23690029)
• Ten cases of salivary duct carcinoma had PLAG1 rearrangement/amplification (22.7%) and eight had HMGA2 (18.2%) rearrangement/amplification. (PMID:23738717)
• a marker with good specificity for salivary gland pleomorphic adenomas (PMID:23958548)
• Extraskeletal myxoid chondrosarcoma of the vulva with PLAG1 gene activation: molecular genetic characterization of 2 cases (PMID:24185117)
• Report illustrates two different tumorigenic pathways implicating PLAG1 in lipoblastoma: amplification through multiple copies of a small marker chromosome derived from chromosome 8, and a paracentric inversion of the long arm of chromosome 8. Review. (PMID:24433523)
• Lacrimal and salivary gland PAs and Ca-ex-PAs have similar genomic profiles and frequently overexpress the PLAG1 oncoprotein. Copy number gains involving 9p23-p22.3 (NFIB) and 22q12-qter (PDGFB) may be of importance for disease progression. (PMID:24468654)
• Altogether, these data suggest that HMGA2 is an upstream activator of PLAG1. (PMID:24516594)
• lipoblastoma is a group of lipomatous tumors with PLAG1 rearrangement and overexpression. (PMID:24700772)
• The nuclear import of PLAG1 by KPNA2 is essential for the role of KPNA2 in HCC cells. (PMID:25060425)
• Fluorescence in situ hybridization for PLAG1 or HMGA2 can be used to distinguish between pleomorphic adenoma and carcinoma ex-pleomorphic adenoma and their morphologic mimics. (PMID:25439740)
• Data indicate that SLIT2, miR-218-1, RET/PLAG1 and SLIT2/ROBO1 pathway involved in Hirschsprung’s disease. (PMID:25786906)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	plag1	ENSDARG00000051926
mus_musculus	Plag1	ENSMUSG00000003282
rattus_norvegicus	Plag1	ENSRNOG00000008846
drosophila_melanogaster	hb	FBGN0001180
drosophila_melanogaster	CG12391	FBGN0033581
caenorhabditis_elegans		WBGENE00001824
caenorhabditis_elegans		WBGENE00012385

Paralogs (29): ZNF446 (ENSG00000083838), REST (ENSG00000084093), ZNF174 (ENSG00000103343), OVOL3 (ENSG00000105261), PLAGL1 (ENSG00000118495), 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), ZSCAN5B (ENSG00000197213), ZNF770 (ENSG00000198146), PEG3 (ENSG00000198300), ZSCAN5C (ENSG00000204532)

Protein

Protein identifiers

Zinc finger protein PLAG1 — Q6DJT9 (reviewed: Q6DJT9)

Alternative names: Pleiomorphic adenoma gene 1 protein

All UniProt accessions (1): Q6DJT9

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor whose activation results in up-regulation of target genes, such as IGFII, leading to uncontrolled cell proliferation: when overexpressed in cultured cells, higher proliferation rate and transformation are observed. Other target genes such as CRLF1, CRABP2, CRIP2, PIGF are strongly induced in cells with PLAG1 induction. Proto-oncogene whose ectopic expression can trigger the development of pleomorphic adenomas of the salivary gland and lipoblastomas. Overexpression is associated with up-regulation of IGFII, is frequently observed in hepatoblastoma, common primary liver tumor in childhood. Cooperates with CBFB-MYH11, a fusion gene important for myeloid leukemia.

Subunit / interactions. Interacts with KPNA2, which escorts protein to the nucleus via interaction with nuclear localization signal. Interacts with E3 SUMO-protein ligase PIAS1, PIAS2 and PIAS4.

Subcellular location. Nucleus.

Tissue specificity. Expressed in fetal tissues such as lung, liver and kidney. Not detected or weak detection in normal adult tissues, but highly expressed in salivary gland with benign or malignant pleiomorphic adenomas with or without 8q12 aberrations, with preferential occurrence in benign tumors.

Post-translational modifications. Sumoylated with SUMO1; which inhibits transcriptional activity, but does not affect nuclear localization. Blockers of sumoylation pathway such as SENP3 and inactive UBE2I increases transcriptional capacity. Sumoylation is increased in the presence of PIAS1. Acetylated by lysine acetyltransferase EP300; which activates transcriptional capacity. Lysine residues that are sumoylated also seem to be target for acetylation.

Disease relevance. Silver-Russell syndrome 4 (SRS4) [MIM:618907] A form of Silver-Russell syndrome, a clinically heterogeneous condition characterized by severe intrauterine growth retardation, poor postnatal growth, craniofacial features such as a triangular shaped face and a broad forehead, body asymmetry, and a variety of minor malformations. The phenotypic expression changes during childhood and adolescence, with the facial features and asymmetry usually becoming more subtle with age. SRS4 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving PLAG1 is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with constitutively expressed beta-catenin/CTNNB1. Fusion occurs in the 5’-regulatory regions, leading to promoter swapping between the 2 genes and activation of PLAG1 expression in adenomas. The chimeric transcript is formed by fusion of CTNNB1 exon 1 to PLAG1 exon 3. Reciprocal fusion transcript consisting of PLAG1 exon 1 and CTNNB1 exon 2-16 is also revealed in some adenomas. Translocation t(3;8)(p21;q12) with transcription elongation factor SII/TCEA1. The fusion transcript is composed of 5’-non-coding sequences as well as 63 nucleotides of the coding region of TCEA1 fused to the acceptor splice site of PLAG1 exon 3. The fusion transcript encodes a truncated TCEA1-PLAG1 protein of 90 AA as well as an apparently normal PLAG1 protein. Reciprocal fusion transcript PLAG1-TCEA1 is also present in one adenoma. Translocation t(5;8)(p13;q12) with leukemia inhibitory factor receptor LIFR. This fusion occured in the 5’-non-coding sequences of both genes, exchanging regulatory control element while preserving the coding sequences. Translocation t(6;8)(p21.3-22;q13) with Coiled-coil-helix-coiled-coil-helix domain-containing protein 7/CHCHD7. Fusion occurs in the 5’ regulatory regions, leading to promoter swapping and up-regulation of PLAG1 expression. Ectopic expression of PLAG1 under the control of promoters of distinct translocation partner genes is a general pathogenetic mechanism for pleiomorphic adenomas with 8q aberrations. These fusion genes are likely to be found in adenomas with normal karyotype as this subgroup of tumors also exhibit PLAG1 activation. A chromosomal aberration involving PLAG1 may be a cause of lipoblastomas, which are benign tumors resulting from transformation of adipocytes, usually diagnosed in children. 8q12.1 to 8q24.1 intrachromosomal rearrangement with hyaluronic acid synthase 2/HAS2 results in promoter swapping and activation of PLAG1 expression. The breakpoint of HAS2 gene is in PLAG1 intron 1, whereas its coding sequence starts at exon 2 or exon 3. Translocation t(7;8)(p22;q13) with collagen 1A2/COL1A2. Fusion transcript COL1A2-PLAG1 as well as HAS2-PLAG1 encode a full-length PLAG1 protein.

Domain organisation. C2H2-type zinc fingers 3 interacts with DNA-binding site G-clusterinc fingers. C2H2-type zinc fingers 6 and 7 interact with DNA-binding site core sequence.

Miscellaneous. Residual nuclear import after mutation of the nuclear localization signal is assigned to zinc finger domains of PLAG1. When cultured cells transformed by PLAG1 overexpression are injected in nude mouse, rapidly growing tumors (fibrosarcomaS) are observed at the site of inoculation.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q6DJT9-1	1	yes
Q6DJT9-2	2

RefSeq proteins (3): NP_001108106, NP_001108107, NP_002646* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096, PF13912

UniProt features (31 total): mutagenesis site 9, zinc finger region 7, region of interest 7, cross-link 2, chain 1, short sequence motif 1, compositionally biased region 1, splice variant 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6DJT9-F1	56.91	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 244, 263

Mutagenesis-validated functional residues (9):

Position	Phenotype
23–24	inhibition of kpna2 interaction when mutation occurs in the nls; decreased nuclear import with localization in the nucle
31–32	no inhibition of kpna2 interaction and no change in nuclear import.
92	prevents formation of functional zinc-finger 3; induces drastic decrease of dna affinity and complete modification of dn
227	prevents formation of functional zinc-finger 7 and inhibits dna binding; no proliferation and transformation of cultured
244	abolishes single and double sumoylation; nuclear localization conserved. increases transcriptional activity and inhibits
263	decreases sumoylation; abolishes double sumoylation only; nuclear localization conserved. increases transcriptional acti
339	no effect on transcription activation capacity.
340	no effect on transcription activation capacity.
353	no effect on sumoylation. increases transcriptional activity and inhibits repression domain activity; when associated wi

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 488 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, FREAC2_01, TAATAAT_MIR126, GOBP_GLAND_MORPHOGENESIS, HNF3ALPHA_Q6, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, NKX25_02, SP3_Q3, GOBP_GROWTH, TATTATA_MIR374, AREB6_01, GOBP_NEUROGENESIS, HNF1_Q6

GO Biological Process (9): regulation of DNA-templated transcription (GO:0006355), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), gland morphogenesis (GO:0022612), multicellular organism growth (GO:0035264), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of glial cell proliferation (GO:0060252), prostate gland growth (GO:0060736), organ growth (GO:0035265)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleoplasm (GO:0005654), centrosome (GO:0005813), cytosol (GO:0005829), nuclear speck (GO:0016607), nucleus (GO:0005634), cytoplasm (GO:0005737), nuclear body (GO:0016604)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of gene expression	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
gene expression	2
multicellular organismal process	2
developmental growth	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
animal organ morphogenesis	1
gland development	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
positive regulation of cell population proliferation	1
glial cell proliferation	1
positive regulation of gliogenesis	1
regulation of glial cell proliferation	1
developmental process involved in reproduction	1
prostate gland development	1
organ growth	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
regulation of DNA-templated transcription	1
transcription regulator activity	1
transition metal ion binding	1
nucleic acid binding	1
cation binding	1
nuclear lumen	1
centriole	1
microtubule organizing center	1
cytoplasm	1
nuclear ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1458 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLAG1	CHCHD7	Q9BUK0	946
PLAG1	TCEA1	P23193	889
PLAG1	F5H6H0	F5H6H0	818
PLAG1	CTNNB1	P35222	778
PLAG1	TCEA2	Q15560	765
PLAG1	TCEA3	O75764	763
PLAG1	IGF2	P01344	740
PLAG1	CYP4F8	P98187	729
PLAG1	LCORL	Q8N3X6	706
PLAG1	XKR4	Q5GH76	608
PLAG1	LYN	P07948	595
PLAG1	TMEM68	Q96MH6	593
PLAG1	ABCC6	P78420	571
PLAG1	NCAPG	Q9BPX3	568
PLAG1	SDR16C5	Q8N3Y7	556

IntAct

11 interactions, top by confidence:

A	B	Type	Score
	PLAG1	psi-mi:“MI:0915”(physical association)	0.370
CXCL5	PLAG1	psi-mi:“MI:0915”(physical association)	0.370
IL31	PLAG1	psi-mi:“MI:0915”(physical association)	0.370
SMAD3	PLAG1	psi-mi:“MI:0915”(physical association)	0.370
ALB	CDC45	psi-mi:“MI:0914”(association)	0.350
UGT2B7	ACTN4	psi-mi:“MI:0914”(association)	0.350
EPHA4	PLAG1	psi-mi:“MI:0915”(physical association)	0.000
APOE	PLAG1	psi-mi:“MI:0915”(physical association)	0.000
	PLAG1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (13): PLAG1 (Two-hybrid), PLAG1 (Reconstituted Complex), PLAG1 (Affinity Capture-RNA), PLAG1 (Affinity Capture-RNA), PLAG1 (Proximity Label-MS), PLAG1 (Proximity Label-MS), PLAG1 (Proximity Label-MS), PLAG1 (Affinity Capture-RNA), PLAG1 (Reconstituted Complex), PLAG1 (Reconstituted Complex), PLAG1 (Reconstituted Complex), PLAG1 (Affinity Capture-MS), PLAG1 (Two-hybrid)

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: B0XS89, B1WBU4, B2RRE4, B2RRF6, J9VE33, P54785, P80944, Q0VCJ6, Q29419, Q2I689, Q499R0, Q58NQ5, Q5SVQ8, Q5U2T6, Q65XX7, Q6AHZ1, Q6DJT9, Q6P882, Q811F1, Q96BR9, Q9C0D4, Q9CWH1, Q9QYE0, Q9UM63, Q9UPG8, B0YDH7, P39943, Q6IQX8, Q8WUU4, Q9P2Y4, Q9Y7G2, A0A1V6NWD3, O77459, P28166, P39956, P60319, Q02027, Q03833, Q10938, Q14119

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
PLAG1	up-regulates	Apoptosis
PLAG1	“up-regulates quantity by expression”	IGF2	“transcriptional regulation”
UBE2I	down-regulates	PLAG1	sumoylation
EP300	up-regulates	PLAG1	acetylation
HDAC7	down-regulates	PLAG1	deacetylation
PLAG1	“up-regulates quantity by expression”	ABCC6	“transcriptional regulation”
PLAG1	up-regulates	Cell_death
Ub:E2	“up-regulates activity”	PLAG1	ubiquitination

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — BRCA, SKCM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	28
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
253033	NM_002655.3(PLAG1):c.1363del (p.Gln455fs)	Pathogenic
1172638	NM_002655.3(PLAG1):c.1190_1197del (p.Asp397fs)	Likely pathogenic
3775171	NM_002655.3(PLAG1):c.199C>T (p.Gln67Ter)	Likely pathogenic

SpliceAI

1248 predictions. Top by Δscore:

Variant	Effect	Δscore
8:56168387:C:CC	acceptor_gain	1.0000
8:56179510:CAAC:C	acceptor_gain	1.0000
8:56179511:AAC:A	acceptor_gain	1.0000
8:56179512:ACC:A	acceptor_loss	1.0000
8:56179514:C:CC	acceptor_gain	1.0000
8:56179515:T:A	acceptor_loss	1.0000
8:56164936:TAAA:T	donor_gain	0.9900
8:56164937:AAAA:A	donor_gain	0.9900
8:56167504:C:CC	acceptor_gain	0.9900
8:56168044:TAGAA:T	donor_gain	0.9900
8:56168045:A:AC	donor_gain	0.9900
8:56168045:AGAAA:A	donor_gain	0.9900
8:56168235:A:AC	donor_gain	0.9900
8:56168236:C:CC	donor_gain	0.9900
8:56168236:CTT:C	donor_gain	0.9900
8:56168383:GGGA:G	acceptor_gain	0.9900
8:56169230:TGCA:T	donor_gain	0.9900
8:56171086:CATA:C	donor_loss	0.9900
8:56171087:ATACC:A	donor_loss	0.9900
8:56171088:TA:T	donor_loss	0.9900
8:56171089:A:T	donor_loss	0.9900
8:56171185:CCAAT:C	acceptor_gain	0.9900
8:56171186:CAAT:C	acceptor_gain	0.9900
8:56171186:CAATC:C	acceptor_gain	0.9900
8:56171188:ATCTA:A	acceptor_loss	0.9900
8:56171189:TC:T	acceptor_loss	0.9900
8:56171190:C:CA	acceptor_loss	0.9900
8:56171190:C:CC	acceptor_gain	0.9900
8:56171191:T:A	acceptor_loss	0.9900
8:56179404:CCTA:C	donor_loss	0.9900

AlphaMissense

3303 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:56167053:A:C	H231Q	1.000
8:56167053:A:T	H231Q	1.000
8:56167055:G:C	H231D	1.000
8:56167055:G:T	H231N	1.000
8:56167063:A:G	L228P	1.000
8:56167080:A:C	F222L	1.000
8:56167080:A:T	F222L	1.000
8:56167081:A:G	F222S	1.000
8:56167082:A:G	F222L	1.000
8:56167092:A:C	C218W	1.000
8:56167093:C:G	C218S	1.000
8:56167093:C:T	C218Y	1.000
8:56167094:A:G	C218R	1.000
8:56167094:A:T	C218S	1.000
8:56167101:A:C	C215W	1.000
8:56167102:C:G	C215S	1.000
8:56167102:C:T	C215Y	1.000
8:56167103:A:G	C215R	1.000
8:56167103:A:T	C215S	1.000
8:56167107:G:C	F213L	1.000
8:56167107:G:T	F213L	1.000
8:56167109:A:G	F213L	1.000
8:56167125:G:C	H207Q	1.000
8:56167125:G:T	H207Q	1.000
8:56167137:G:C	H203Q	1.000
8:56167137:G:T	H203Q	1.000
8:56167164:G:C	F194L	1.000
8:56167164:G:T	F194L	1.000
8:56167165:A:G	F194S	1.000
8:56167166:A:G	F194L	1.000

dbSNP variants (sampled 300 via entrez): RS1000068162 (8:56201041 G>C), RS1000141594 (8:56173370 C>T), RS1000170602 (8:56180166 G>C), RS1000322893 (8:56179283 T>A,C), RS1000371259 (8:56207981 C>G,T), RS1000455362 (8:56192064 G>A), RS1000571321 (8:56191848 C>T), RS1000581439 (8:56178215 T>A), RS1000655117 (8:56177926 G>A,T), RS1000763454 (8:56203553 G>A), RS1000794451 (8:56203171 G>A), RS1000796578 (8:56161111 T>A), RS1000797807 (8:56160807 A>G), RS1000834293 (8:56185309 T>C), RS1000876584 (8:56211873 G>T)

Disease associations

OMIM: gene MIM:603026 | disease phenotypes: MIM:180860, MIM:618907

GenCC curated gene-disease

Disease	Classification	Inheritance
silver-russell syndrome 4	Strong	Autosomal dominant

Mondo (3): intellectual disability (MONDO:0001071), Silver-Russell syndrome 1 (MONDO:0020796), silver-russell syndrome 4 (MONDO:0030118)

Orphanet (2): Silver-Russell syndrome (Orphanet:813), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000045	Abnormal scrotum morphology
HP:0000047	Hypospadias
HP:0000048	Bifid scrotum
HP:0000175	Cleft palate
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000750	Delayed speech and language development
HP:0000821	Hypothyroidism
HP:0000957	Cafe-au-lait spot
HP:0001159	Syndactyly
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001442	Typified by somatic mosaicism
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001562	Oligohydramnios
HP:0001626	Abnormality of the cardiovascular system
HP:0001804	Hypoplastic fingernail
HP:0001943	Hypoglycemia
HP:0002007	Frontal bossing
HP:0002099	Asthma
HP:0003561	Birth length less than 3rd percentile
HP:0004209	Clinodactyly of the 5th finger
HP:0004325	Decreased body weight
HP:0004482	Relative macrocephaly
HP:0006266	Small placenta

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000175_46	Height	7.000000e-08
GCST000372_17	Height	5.000000e-06
GCST000380_3	Height	1.000000e-09
GCST000522_15	Height	3.000000e-06
GCST000611_18	Height	8.000000e-10
GCST002647_142	Height	2.000000e-40
GCST002702_60	Height	3.000000e-29
GCST004067_11	Hip circumference adjusted for BMI	9.000000e-10
GCST004067_124	Hip circumference adjusted for BMI	2.000000e-07
GCST006979_457	Heel bone mineral density	9.000000e-14
GCST008163_506	Height	3.000000e-16
GCST008163_528	Height	9.000000e-11
GCST008362_179	Birth weight	1.000000e-13
GCST008839_49	Height	3.000000e-31
GCST010002_300	Refractive error	1.000000e-19
GCST90000025_360	Appendicular lean mass	7.000000e-126
GCST90002393_573	Monocyte count	4.000000e-10
GCST90002400_444	Plateletcrit	3.000000e-15
GCST90020028_300	Hip circumference adjusted for BMI	3.000000e-13
GCST90020028_301	Hip circumference adjusted for BMI	1.000000e-11
GCST90020028_303	Hip circumference adjusted for BMI	5.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0009270	heel bone mineral density
EFO:0004344	birth weight
EFO:0004980	appendicular lean mass
EFO:0005091	monocyte count
EFO:0007985	platelet crit

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression, decreases methylation	7
bisphenol A	increases expression, increases methylation	2
sodium arsenite	affects expression, increases expression	2
Benzo(a)pyrene	decreases expression, affects methylation	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
pentanal	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
incobotulinumtoxinA	increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Aldehydes	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders