POLR2A

Summary

POLR2A (RNA polymerase II subunit A, HGNC:9187) is a protein-coding gene on chromosome 17p13.1, encoding DNA-directed RNA polymerase II subunit RPB1 (P24928). Catalytic core component of RNA polymerase II (Pol II), a DNA-dependent RNA polymerase which synthesizes mRNA precursors and many functional non-coding RNAs using the four ribonucleoside triphosphates as substrates.

This gene encodes the largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene contains a carboxy terminal domain composed of heptapeptide repeats that are essential for polymerase activity. These repeats contain serine and threonine residues that are phosphorylated in actively transcribing RNA polymerase. In addition, this subunit, in combination with several other polymerase subunits, forms the DNA binding domain of the polymerase, a groove in which the DNA template is transcribed into RNA.

Source: NCBI Gene 5430 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (Definitive, ClinGen)
• GWAS associations: 13
• Clinical variants (ClinVar): 496 total — 7 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 35
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000937

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9187
Approved symbol	POLR2A
Name	RNA polymerase II subunit A
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	POLRA, RPB1
Ensembl gene	ENSG00000181222
Ensembl biotype	protein_coding
OMIM	180660
Entrez	5430

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 retained_intron, 1 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000572844, ENST00000573603, ENST00000574158, ENST00000575547, ENST00000576114, ENST00000576553, ENST00000576718, ENST00000576952, ENST00000617998, ENST00000674977

RefSeq mRNA: 1 — MANE Select: NM_000937 NM_000937

Canonical transcript exons

ENST00000643490 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 208.1750 / max 10837.8976, expressed in 1827 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159206	201.9162	1827
159209	3.5024	1223
159211	0.7085	413
159213	0.5943	327
159208	0.4505	219
159215	0.4347	221
159207	0.2229	100
159212	0.2024	70
159205	0.1295	35
159214	0.0136	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	98.10	gold quality
left testis	UBERON:0004533	98.06	gold quality
testis	UBERON:0000473	97.55	gold quality
stromal cell of endometrium	CL:0002255	97.31	gold quality
esophagus mucosa	UBERON:0002469	96.91	gold quality
skin of leg	UBERON:0001511	96.86	gold quality
right adrenal gland cortex	UBERON:0035827	96.83	gold quality
metanephros cortex	UBERON:0010533	96.77	gold quality
zone of skin	UBERON:0000014	96.74	gold quality
right adrenal gland	UBERON:0001233	96.64	gold quality
right uterine tube	UBERON:0001302	96.59	gold quality
pituitary gland	UBERON:0000007	96.58	gold quality
left adrenal gland	UBERON:0001234	96.57	gold quality
skin of abdomen	UBERON:0001416	96.55	gold quality
adenohypophysis	UBERON:0002196	96.51	gold quality
left adrenal gland cortex	UBERON:0035825	96.49	gold quality
vagina	UBERON:0000996	96.47	gold quality
endocervix	UBERON:0000458	96.42	gold quality
uterine cervix	UBERON:0000002	96.37	gold quality
mucosa of stomach	UBERON:0001199	96.34	gold quality
minor salivary gland	UBERON:0001830	96.25	gold quality
bone marrow	UBERON:0002371	96.20	gold quality
ectocervix	UBERON:0012249	96.17	gold quality
left lobe of thyroid gland	UBERON:0001120	96.14	gold quality
right ovary	UBERON:0002118	96.12	gold quality
thyroid gland	UBERON:0002046	96.03	gold quality
right lobe of thyroid gland	UBERON:0001119	95.98	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.95	gold quality
saliva-secreting gland	UBERON:0001044	95.94	gold quality
left uterine tube	UBERON:0001303	95.92	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7606	no	706.96
E-GEOD-106540	no	657.95
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
ANKRD37
HNRNPH1
MAGI1
SGK1
STC2
TNF
UHMK1
VIM

Upstream regulators (CollecTRI, top): ZNF143

miRNA regulators (miRDB)

16 targeting POLR2A, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-22-5P	97.67	68.92	1355
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-6786-3P	93.73	60.70	52
HSA-MIR-5195-5P	90.84	65.09	287

Literature-anchored findings (GeneRIF, showing 40)

• cleavage site in RNAPII-LS for caspases during radiation-induced DNA damage/apoptosis. (PMID:12200141)
• A pause of the elongating RNAP II complex caused by nucleotide starvation induced the ubiquitination of the stalled RNAP II. RNAP II ubiquitination may have a role in the regulation of transcription-coupled DNA repair. (PMID:12579324)
• findings show that expression of a human equivalent to Drosophila’s C4 pol II in human cultured cells affects alternative splicing of the fibronectin EDI exon and adenovirus E1a pre-mRNA (PMID:14536091)
• the C-terminal domain (CTD) of RNA polymerase II is required for efficient U2 snRNA transcription (PMID:14701755)
• These data indicate that RNA polymerase II accumulates most often at exons during transcription. (PMID:16086846)
• Hyperphosphorylated RNA polymerase II associates with HYPB, a histone H3 lysine 36-specific methyltransferase, suggesting that the RNA polymerase II phosphorylation directs the histone H3 lysine 36 methylation on the active genes. (PMID:16118227)
• the rate-limiting step during transcript synthesis by RNA polymerase II in vitro occurs at the point in the reaction at which early ternary complexes transform into elongation complexes (PMID:16210313)
• Myosin VI modulates RNAPII-dependent transcription of active genes, implicating the possibility of an actin-myosin based mechanism of transcription. (PMID:16949370)
• These results suggest that the C-terminal domain of RPB1 promotes exon skipping by recruiting SRp20 and that this contributes independently of elongation to the transcriptional control of alternative splicing. (PMID:17028590)
• analysis of conformational flexibility of human RNA polymerase II (PMID:17098194)
• The CTD of POLR2A and ADAR2 function together to enforce the order of events that allows editing to precede splicing, and they furthermore suggest a new role for the CTD as a coordinator of two interdependent pre-mRNA processing events. (PMID:17525170)
• human CD68 gene expression is associated with changes in Pol II phosphorylation and short-range intrachromosomal gene looping (PMID:17583472)
• By reducing transcriptional fidelity in terms of not only discrimination of incoming nucleotides but also recognition of templates, HDAg may facilitate the unusual RNA-dependent RNA synthesis by Pol II. (PMID:17584298)
• The data generated with a nuclear run-on assay demonstrated that synthesis not only of genomic RNA but also of its complement, the antigenome, could be inhibited by low concentrations of amanitin specific for Pol II transcription. (PMID:18032511)
• findings show that mutation of serine-7 to alanine causes a specific defect in snRNA gene expression; also evidence presented that phosphorylation of serine-7 facilitates interaction with the snRNA gene-specific Integrator complex (PMID:18079403)
• results indicate that restriction of serine-7 epitopes to the Linker-proximal region limits carboxyl-terminal repeat domain phosphorylation patterns and is a requirement for optimal gene expression (PMID:18079404)
• These data suggest that icariin exerts its potent osteogenic effect through induction of Runx2 expression, production of BMP-4 and activation of BMP signaling. (PMID:18294453)
• Results describe transcript and template release in the context of both natural and artificial RNA polymerase II terminator sequences, including the timing and relationship between these events. (PMID:18342606)
• c-Myb cooperates with FLASH in foci associated with active RNA polymerase II, leading to enhancement of Myb-dependent gene activation. (PMID:18408764)
• RecQ5beta has suppressive roles in events associated with RNAP II-dependent transcription (PMID:18419580)
• Hyperphosphorylated Rpb1 is not primarily targeted for proteosomal degradation and instead is subjected to cycles of phosphorylation and dephosphorylation as long as Top1 cleavage complexes are trapped by CPT (PMID:18588899)
• ERK1/2-mediated Ser-177 phosphorylation has a role in modulating HDV antigenomic RNA replication, possibly through RNAPII regulation (PMID:18632853)
• histone tails provide a significant part of the nucleosomal barrier to pol II transcript elongation (PMID:18815126)
• Results show overexpression or depletion of RHA could influence the interaction of Pol II with beta-actin and beta-actin-involved gene transcription regulation. (PMID:19309309)
• These data indicate that RNAPII polyubiquitylation requires cooperation between distinct, sequentially acting ubiquitin ligases. (PMID:19920177)
• TATA-binding protein-associated factor sharply decrease the rate at which Pol II, TFIIB, and TFIIF assemble on promoter-bound TFIID-TFIIA. (PMID:20083121)
• Data indicate that RNA polymerase II is built in the cytoplasm and reveal quality-control mechanisms that link HSP90 and its cochaperone hSpagh (RPAP3) to the nuclear import of fully assembled enzymes. (PMID:20864038)
• The deregulation of cellular NIPP1/PP1 holoenzyme affects RNAPII phosphorylation and pointing to NIPP1 as a potential regulatory factor in RNAPII-mediated transcription. (PMID:20941529)
• Elevated PHD1 concomitant with decreased PHD2 are causatively related to Rpb1 hydroxylation and oncogenesis in human renal clear cell carcinomas with WT VHL gene. (PMID:20978146)
• Data show that MicroRNA promoter identification based upon RPol II binding patterns provides important temporal and spatial measurements regarding the initiation of transcription. (PMID:21072189)
• kinetics of RNA polymerase II elongation during co-transcriptional splicing (PMID:21264352)
• Studies suggest activator-induced structural shifts within Mediator trigger activation of stalled Pol II. (PMID:21326907)
• Parcs/Gpn3 plays a critical role in the nuclear accumulation of RNAP II, and this function explains the relative importance of Parcs/Gpn3 in cell proliferation. (PMID:21782856)
• evidence that phosphorylation of Rpb1 CTD Thr4 residues is required specifically for histone mRNA 3’ end processing, functioning to facilitate recruitment of 3’ processing factors to histone genes (PMID:22053051)
• These results suggest that Mediator structural shifts induced by activator binding help stably orient pol II prior to transcription initiation within the human mediator-RNA polymerase II-TFIIF assembly. (PMID:22343046)
• Here, the authors report phosphorylation of Thr4 by Polo-like kinase 3 in mammalian cells. (PMID:22549466)
• Results indicate roles for both the RNA polymerase II C-terminal domain (CTD) and O-GlcNAc in the regulation of transcription initiation. (PMID:22605332)
• Studies indicate that the super elongation complex (SEC) consisting of ELL, P-TEFb (CDK9) and MLL required for rapid transcriptional induction in the presence or absence of paused RNA polymerase II (Pol II). (PMID:22895430)
• SNAPC1 is a general transcriptional coactivator that functions through elongating RNAPII. (PMID:22966203)
• Cyclin K1 is the primary cyclin partner for CDK12/CrkRS and it is required for activation of CDK12/CrkRS to phosphorylate the C-terminal domain of RNA Pol II. (PMID:22988298)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	polr2a	ENSDARG00000099966
mus_musculus	Polr2a	ENSMUSG00000005198
rattus_norvegicus	Polr2a	ENSRNOG00000028834
drosophila_melanogaster	Polr2A	FBGN0003277
caenorhabditis_elegans		WBGENE00000123

Paralogs (2): POLR1A (ENSG00000068654), POLR3A (ENSG00000148606)

Protein

Protein identifiers

DNA-directed RNA polymerase II subunit RPB1 — P24928 (reviewed: P24928)

Alternative names: 3’-5’ exoribonuclease, DNA-directed RNA polymerase II subunit A, DNA-directed RNA polymerase III largest subunit, RNA-directed RNA polymerase II subunit RPB1

All UniProt accessions (1): A0A6Q8PGB0

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic core component of RNA polymerase II (Pol II), a DNA-dependent RNA polymerase which synthesizes mRNA precursors and many functional non-coding RNAs using the four ribonucleoside triphosphates as substrates. Pol II-mediated transcription cycle proceeds through transcription initiation, transcription elongation and transcription termination stages. During transcription initiation, Pol II pre-initiation complex (PIC) is recruited to DNA promoters, with focused-type promoters containing either the initiator (Inr) element, or the TATA-box found in cell-type specific genes and dispersed-type promoters that often contain hypomethylated CpG islands usually found in housekeeping genes. Once the polymerase has escaped from the promoter it enters the elongation phase during which RNA is actively polymerized, based on complementarity with the template DNA strand. Transcription termination involves the release of the RNA transcript and polymerase from the DNA. Forms Pol II active center together with the second largest subunit POLR2B/RPB2. Appends one nucleotide at a time to the 3’ end of the nascent RNA, with POLR2A/RPB1 most likely contributing a Mg(2+)-coordinating DxDGD motif, and POLR2B/RPB2 participating in the coordination of a second Mg(2+) ion and providing lysine residues believed to facilitate Watson-Crick base pairing between the incoming nucleotide and template base. Typically, Mg(2+) ions direct a 5’ nucleoside triphosphate to form a phosphodiester bond with the 3’ hydroxyl of the preceding nucleotide of the nascent RNA, with the elimination of pyrophosphate. The reversible pyrophosphorolysis can occur at high pyrophosphate concentrations. Can proofread the nascent RNA transcript by means of a 3’ -> 5’ exonuclease activity. If a ribonucleotide is mis-incorporated, backtracks along the template DNA and cleaves the phosphodiester bond releasing the mis-incorporated 5’-ribonucleotide. Through its unique C-terminal domain (CTD, 52 heptapeptide tandem repeats) serves as a platform for assembly of factors that regulate transcription initiation, elongation and termination. CTD phosphorylation on Ser-5 mediates Pol II promoter escape, whereas phosphorylation on Ser-2 is required for Pol II pause release during transcription elongation and further pre-mRNA processing. Additionally, the regulation of gene expression levels depends on the balance between methylation and acetylation levels of the CTD-lysines. Initiation or early elongation steps of transcription of growth-factor-induced immediate early genes are regulated by the acetylation status of the CTD. Methylation and dimethylation have a repressive effect on target genes expression. Cooperates with mRNA splicing machinery in co-transcriptional 5’-end capping and co-transcriptional splicing of pre-mRNA. RNA-dependent RNA polymerase that catalyzes the extension of a non-coding RNA (ncRNA) at the 3’-end using the four ribonucleoside triphosphates as substrates. An internal ncRNA sequence near the 3’-end serves as a template in a single-round Pol II-mediated RNA polymerization reaction. May decrease the stability of ncRNAs that repress Pol II-mediated gene transcription. (Microbial infection) Acts as an RNA-dependent RNA polymerase when associated with small delta antigen of Hepatitis delta virus, acting both as a replicase and transcriptase for the viral RNA circular genome.

Subunit / interactions. Component of the RNA polymerase II (Pol II) core complex consisting of 12 subunits: a ten-subunit catalytic core composed of POLR2A/RPB1, POLR2B/RPB2, POLR2C/RPB3, POLR2I/RPB9, POLR2J/RPB11, POLR2E/RPABC1, POLR2F/RPABC2, POLR2H/RPABC3, POLR2K/RPABC4 and POLR2L/RPABC5 and a mobile stalk composed of two subunits POLR2D/RPB4 and POLR2G/RPB7, protruding from the core and functioning primarily in transcription initiation. Part of Pol II(G) complex, in which Pol II core associates with an additional subunit POLR2M; unlike conventional Pol II, Pol II(G) functions as a transcriptional repressor. Part of TBP-based Pol II pre-initiation complex (PIC), in which Pol II core assembles with general transcription factors and other specific initiation factors including GTF2E1, GTF2E2, GTF2F1, GTF2F2, TCEA1, ERCC2, ERCC3, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2A1, GTF2A2, GTF2B and TBP; this large multi-subunit PIC complex mediates DNA unwinding and targets Pol II core to the transcription start site where the first phosphodiester bond forms. Component of a complex which is at least composed of HTATSF1/Tat-SF1, the P-TEFb complex components CDK9 and CCNT1, Pol II, SUPT5H, and NCL/nucleolin. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (active). Interacts (via the C-terminal domain (CTD)) with U2AF2; recruits PRPF19 and the Prp19 complex to the pre-mRNA and may couple transcription to pre-mRNA splicing. Interacts (via the C-terminal domain (CTD)) with SMN1/SMN2; recruits SMN1/SMN2 to RNA Pol II elongation complexes. Interacts via the phosphorylated C-terminal domain with WDR82 and with SETD1A and SETD1B only in the presence of WDR82. When phosphorylated at ‘Ser-5’, interacts with MEN1; the unphosphorylated form, or phosphorylated at ‘Ser-2’ does not interact. When phosphorylated at ‘Ser-5’, interacts with ZMYND8; the form phosphorylated at ‘Ser-2’ does not interact. When phosphorylated at ‘Ser-2’, interacts with SUPT6H (via SH2 domain). Interacts with RECQL5 and TCEA1; binding of RECQL5 prevents TCEA1 binding. The phosphorylated C-terminal domain interacts with FNBP3. The phosphorylated C-terminal domain interacts with SYNCRIP. Interacts with ATF7IP. Interacts with DDX5. Interacts with WWP2. Interacts with SETX. Interacts (phosphorylated) with PIH1D1. Interacts (via the C-terminal domain (CTD)) with TDRD3. Interacts with PRMT5. Interacts with XRN2. Interacts with SAFB/SAFB1. Interacts with CCNL1. Interacts with CCNL2. Interacts with MYO1C. Interacts with PAF1. Interacts with SFRS19. Interacts (via C-terminus) with CMTR1. Interacts (via C-terminus) with CTDSP1. Interacts (via C-terminus) with SCAF8. Interacts (via the C-terminal domain (CTD)) with CCNT2. Interacts with FUS. Interacts with MCM3AP isoform GANP. Interacts with kinase SRPK2; the interaction occurs during the co-transcriptional formation of inappropriate R-loops. Interacts with SETD2. Interacts with UVSSA. Interacts with ERCC6. Interacts with the TFIIH complex. Interacts (via the C-terminal domain) with IVNS1ABP (via Kelch repeats). (Microbial infection) Interacts with herpes simplex virus 1 protein ICP22; this interaction causes loss of CTD ‘Ser-2’ phosphorylation from Pol II engaged in transcription.

Subcellular location. Nucleus. Cytoplasm. Chromosome.

Post-translational modifications. The tandem heptapeptide repeats in the C-terminal domain (CTD) can be highly phosphorylated. The phosphorylation activates Pol II. Phosphorylation occurs mainly at residues ‘Ser-2’ and ‘Ser-5’ of the heptapeptide repeat and is mediated, at least, by CDK7 and CDK9. POLR2A associated with DNA is specifically phosphorylated at ‘Ser-5’ of the CTD by CDK7, promoting transcription initiation by triggering dissociation from DNA. Phosphorylated at ‘Ser-2’ of the CTD by CDK11 (CDK11A or CDK11B), regulating promoter-proximal pause-release. Phosphorylated at ‘Ser-2’, Ser-5’ and ‘Ser-7’ of the CTD by CDK9 (P-TEFb complex), promoting transcription elongation. Phosphorylation also takes place at ‘Ser-7’ of the heptapeptide repeat, which is required for efficient transcription of snRNA genes and processing of the transcripts. The phosphorylation state is believed to result from the balanced action of site-specific CTD kinases and phosphatases, and a ‘CTD code’ that specifies the position of Pol II within the transcription cycle has been proposed. Dephosphorylated by the INTAC complex when transcripts are unfavorably configured for transcriptional elongation, leading to premature transcription termination: dephosphorylation is mediated by the PPP2CA component of the INTAC complex. In response to replication stress, dephosphorylated at ‘Ser-5’ of the CTD by the PNUTS-PP1 complex, promoting RNA polymerase II degradation. Dephosphorylated by the protein phosphatase CTDSP1. Dephosphorylated at ‘Ser-2’ following UV irradiation. Among tandem heptapeptide repeats of the C-terminal domain (CTD) some do not match the Y-S-P-T-S-P-S consensus, the seventh serine residue ‘Ser-7’ being replaced by a lysine. ‘Lys-7’ in these non-consensus heptapeptide repeats can be alternatively acetylated, methylated and dimethylated. EP300 is one of the enzyme able to acetylate ‘Lys-7’. Acetylation at ‘Lys-7’ of non-consensus heptapeptide repeats is associated with ‘Ser-2’ phosphorylation and active transcription. Regulates initiation or early elongation steps of transcription specially for inducible genes. Methylated at Arg-1810 prior to transcription initiation when the CTD is hypophosphorylated, phosphorylation at Ser-1805 and Ser-1808 preventing this methylation. Symmetrically or asymmetrically dimethylated at Arg-1810 by PRMT5 and CARM1 respectively. Symmetric or asymmetric dimethylation modulates interactions with CTD-binding proteins like SMN1/SMN2 and TDRD3. SMN1/SMN2 interacts preferentially with the symmetrically dimethylated form while TDRD3 interacts with the asymmetric form. Through the recruitment of SMN1/SMN2, symmetric dimethylation is required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination. CTD dimethylation may also facilitate the expression of select RNAs. Among tandem heptapeptide repeats of the C-terminal domain (CTD) some do not match the Y-S-P-T-S-P-S consensus, the seventh serine residue ‘Ser-7’ being replaced by a lysine. ‘Lys-7’ in these non-consensus heptapeptide repeats can be alternatively acetylated, methylated, dimethylated and trimethylated. Methylation occurs in the earliest transcription stages and precedes or is concomitant to ‘Ser-5’ and ‘Ser-7’ phosphorylation. Dimethylation and trimethylation at ‘Lys-7’ of non-consensus heptapeptide repeats are exclusively associated with phosphorylated CTD. Following transcription stress, the elongating form of RNA polymerase II (RNA pol IIo) is ubiquitinated by the DCX(ERCC8) complex (also named CSA complex) on Lys-1268 at DNA damage sites without leading to degradation: ubiquitination promotes RNA pol IIo backtracking to allow access by the transcription-coupled nucleotide excision repair (TC-NER) machinery. At stalled RNA pol II where TC-NER has failed, RBX1-mediated polybiquitination at Lys-1268 may lead to proteasome-mediated degradation in a UBAP2- and UBAP2L-dependent manner; presumably to halt global transcription and enable ’last resort’ DNA repair pathways. Ubiquitinated by the BCR(ARMC5) complex when transcripts are unfavorably configured for transcriptional elongation: the BCR(ARMC5) complex specifically catalyzes ubiquitination of POLR2A phosphorylated at ‘Ser-5’ of the C-terminal domain (CTD), leading to POLR2A degradation. Ubiquitination by the BCR(ARMC5) complex takes place at residues distinct from Lys-1268. Ubiquitinated by WWP2 leading to proteasomal degradation.

Disease relevance. Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (NEDHIB) [MIM:618603] An autosomal dominant neurodevelopmental disorder characterized by profound infantile-onset hypotonia, developmental delay with poor speech, delayed walking, and impaired intellectual development. Additional variable features include feeding difficulties, dysmorphic features, and visual defects. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Pol II enzymatic activities are inhibited by alpha-amanitin. 3’->5’ exonuclease activity is stimulated by TCEA1/TFIIS, whereas pyrophosphorolysis is enhanced by TFIIF.

Cofactor. Two Mg(2+) ions are coordinated by both the catalytic residues and the nucleic acid substrate to enhance substrate recognition and catalytic efficiency.

Domain organisation. The C-terminal domain (CTD) serves as a platform for assembly of factors that regulate transcription initiation, elongation, termination and mRNA processing. The trigger loop allows entry of NTPs into the active site, switching between an open and closed state with each NTP addition cycle. The bridging helix crosses the cleft near the catalytic site and is thought to promote polymerase translocation by acting as a ratchet that moves the DNA-RNA hybrid through the active site.

Similarity. Belongs to the RNA polymerase beta’ chain family.

Isoforms (2)

UniProt ID	Names	Canonical?
P24928-1	1	yes
P24928-2	2

RefSeq proteins (1): NP_000928* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000684	RNA_pol_II_repeat_euk	Repeat
IPR000722	RNA_pol_asu	Domain
IPR006592	RNA_pol_N	Domain
IPR007066	RNA_pol_Rpb1_3	Domain
IPR007073	RNA_pol_Rpb1_7	Domain
IPR007075	RNA_pol_Rpb1_6	Domain
IPR007080	RNA_pol_Rpb1_1	Domain
IPR007081	RNA_pol_Rpb1_5	Domain
IPR007083	RNA_pol_Rpb1_4	Domain
IPR038120	Rpb1_funnel_sf	Homologous_superfamily
IPR038593	RNA_pol_Rpb1_7_sf	Homologous_superfamily
IPR042102	RNA_pol_Rpb1_3_sf	Homologous_superfamily
IPR044893	RNA_pol_Rpb1_clamp_domain	Homologous_superfamily
IPR045867	DNA-dir_RpoC_beta_prime	Family

Pfam: PF00623, PF04983, PF04990, PF04992, PF04997, PF04998, PF05000, PF05001

Catalyzed reactions (Rhea), 2 shown:

• RNA(n) + a ribonucleoside 5’-triphosphate = RNA(n+1) + diphosphate (RHEA:21248)
• a 3’-end ribonucleotidyl-ribonucleotide-RNA + H2O = a 3’-end ribonucleotide-RNA + a ribonucleoside 5’-phosphate + H(+) (RHEA:77763)

UniProt features (329 total): modified residue 69, helix 65, strand 59, repeat 52, turn 22, binding site 21, sequence variant 16, mutagenesis site 11, region of interest 4, sequence conflict 3, compositionally biased region 3, splice variant 2, chain 1, cross-link 1

Structure

Experimental structures (PDB)

56 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6G0R	X-RAY DIFFRACTION	1.25
7Z1K	X-RAY DIFFRACTION	1.55
3D9N	X-RAY DIFFRACTION	1.6
6XKB	X-RAY DIFFRACTION	1.6
6IC9	X-RAY DIFFRACTION	1.75
3D9M	X-RAY DIFFRACTION	1.75
2GHT	X-RAY DIFFRACTION	1.8
4JXT	X-RAY DIFFRACTION	1.9
6IC8	X-RAY DIFFRACTION	1.93
3D9O	X-RAY DIFFRACTION	2
2GHQ	X-RAY DIFFRACTION	2.05
3D9P	X-RAY DIFFRACTION	2.1
3D9K	X-RAY DIFFRACTION	2.2
3D9L	X-RAY DIFFRACTION	2.2
7Z42	X-RAY DIFFRACTION	2.42
8PNP	ELECTRON MICROSCOPY	2.49
5M3H	X-RAY DIFFRACTION	2.5
9B9L	X-RAY DIFFRACTION	2.5
9EHZ	ELECTRON MICROSCOPY	2.6
8XSO	ELECTRON MICROSCOPY	2.7
9EI2	ELECTRON MICROSCOPY	2.8
6Q5Y	X-RAY DIFFRACTION	2.85
8PNQ	ELECTRON MICROSCOPY	2.88
8PM0	ELECTRON MICROSCOPY	2.9
9QPX	X-RAY DIFFRACTION	3
8XRM	ELECTRON MICROSCOPY	3.13
9EI1	ELECTRON MICROSCOPY	3.2
9EI3	ELECTRON MICROSCOPY	3.2
8R60	ELECTRON MICROSCOPY	3.23
8R3L	ELECTRON MICROSCOPY	3.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P24928-F1	76.95	0.50

Functional residue map

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

Ligand- & substrate-binding residues (21): 67; 71; 74; 81; 84; 111; 114; 154; 184; 346; 358; 460 …

Post-translational modifications (70): 1861, 1863, 1864, 1866, 1866, 1866, 1866, 1867, 1868, 1870, 1873, 1873, 1873, 1874, 1875, 1877, 1878, 1881, 1882, 1885 …

Mutagenesis-validated functional residues (11):

Position	Phenotype
812–1970	decreases cell viability.
1268	impairs ubiquitination, interaction with the tfiih complex, and its degradation during transcription stress. does not af
1810	misexpression of a variety of small nuclear rnas and small nucleolar rnas. loss of interaction with tdrd3 and smn1/smn2.
1838	loss of acetylation and loss of regulation of growth-factor-induced gene expression; when associated with r-1859; r-1866
1859	loss of acetylation and loss of regulation of growth-factor-induced gene expression; when associated with r-1838; r-1866
1866	loss of acetylation and loss of regulation of growth-factor-induced gene expression; when associated with r-1859; r-1859
1873	loss of acetylation and loss of regulation of growth-factor-induced gene expression; when associated with r-1838; r-1859
1887	loss of acetylation and loss of regulation of growth-factor-induced gene expression; when associated with r-1838; r-1859
1908	loss of acetylation and loss of regulation of growth-factor-induced gene expression; when associated with r.1838; r-1859
1922	loss of acetylation and loss of regulation of growth-factor-induced gene expression; when associated with r-1838; r-1859
1936	loss of acetylation and loss of regulation of growth-factor-induced gene expression; when associated with r-1838; r-1859

Function

Pathways and Gene Ontology

Reactome pathways

43 pathways

ID	Pathway
R-HSA-112382	Formation of RNA Pol II elongation complex
R-HSA-113418	Formation of the Early Elongation Complex
R-HSA-167152	Formation of HIV elongation complex in the absence of HIV Tat
R-HSA-167158	Formation of the HIV-1 Early Elongation Complex
R-HSA-167160	RNA Pol II CTD phosphorylation and interaction with CE during HIV infection
R-HSA-167161	HIV Transcription Initiation
R-HSA-167162	RNA Polymerase II HIV Promoter Escape
R-HSA-167172	Transcription of the HIV genome
R-HSA-167200	Formation of HIV-1 elongation complex containing HIV-1 Tat
R-HSA-167238	Pausing and recovery of Tat-mediated HIV elongation
R-HSA-167242	Abortive elongation of HIV-1 transcript in the absence of Tat
R-HSA-167243	Tat-mediated HIV elongation arrest and recovery
R-HSA-167246	Tat-mediated elongation of the HIV-1 transcript
R-HSA-167287	HIV elongation arrest and recovery
R-HSA-167290	Pausing and recovery of HIV elongation
R-HSA-168325	Viral Messenger RNA Synthesis
R-HSA-203927	MicroRNA (miRNA) biogenesis
R-HSA-5578749	Transcriptional regulation by small RNAs
R-HSA-5601884	PIWI-interacting RNA (piRNA) biogenesis
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-674695	RNA Polymerase II Pre-transcription Events
R-HSA-6781823	Formation of TC-NER Pre-Incision Complex
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-6803529	FGFR2 alternative splicing
R-HSA-6807505	RNA polymerase II transcribes snRNA genes
R-HSA-72086	mRNA Capping
R-HSA-72163	mRNA Splicing - Major Pathway

MSigDB gene sets: 389 (showing top): RNGTGGGC_UNKNOWN, E2F_Q4, TGCGCANK_UNKNOWN, E2F4DP1_01, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, GOBP_POSITIVE_REGULATION_OF_RNA_SPLICING, ENK_UV_RESPONSE_KERATINOCYTE_UP, SP3_Q3, REACTOME_VIRAL_MESSENGER_RNA_SYNTHESIS, REACTOME_SIGNALING_BY_FGFR, MORF_UBE2I, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, MORF_CDK2, MORF_HDAC2

GO Biological Process (9): DNA-templated transcription termination (GO:0006353), regulation of DNA-templated transcription (GO:0006355), transcription by RNA polymerase II (GO:0006366), transcription elongation by RNA polymerase II (GO:0006368), positive regulation of RNA splicing (GO:0033120), mRNA transcription by RNA polymerase II (GO:0042789), DNA-templated transcription (GO:0006351), positive regulation of gene expression (GO:0010628), cellular response to oxygen levels (GO:0071453)

GO Molecular Function (16): magnesium ion binding (GO:0000287), DNA binding (GO:0003677), RNA binding (GO:0003723), DNA-directed RNA polymerase activity (GO:0003899), RNA-directed RNA polymerase activity (GO:0003968), zinc ion binding (GO:0008270), hydrolase activity (GO:0016787), kinase binding (GO:0019900), ubiquitin protein ligase binding (GO:0031625), microfibril binding (GO:0050436), promoter-specific chromatin binding (GO:1990841), core promoter sequence-specific DNA binding (GO:0001046), nucleic acid binding (GO:0003676), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), RNA polymerase II, core complex (GO:0005665), chromosome (GO:0005694), cytoplasm (GO:0005737), DNA-directed RNA polymerase complex (GO:0000428), euchromatin (GO:0000791)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Transcription of the HIV genome	8
HIV Transcription Elongation	3
Gene Silencing by RNA	3
RNA Polymerase II Transcription Elongation	2
Late Phase of HIV Life Cycle	1
Tat-mediated elongation of the HIV-1 transcript	1
Influenza Viral RNA Transcription and Replication	1
Activation of HOX genes during differentiation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	3
RNA biosynthetic process	3
regulation of gene expression	2
transcription by RNA polymerase II	2
gene expression	2
nucleic acid binding	2
5’-3’ RNA polymerase activity	2
catalytic activity	2
cellular anatomical structure	2
regulation of RNA biosynthetic process	1
DNA-templated transcription elongation	1
RNA splicing	1
positive regulation of gene expression	1
regulation of RNA splicing	1
mRNA transcription	1
positive regulation of macromolecule biosynthetic process	1
response to oxygen levels	1
cellular response to chemical stimulus	1
metal ion binding	1
RNA-templated transcription	1
transition metal ion binding	1
enzyme binding	1
ubiquitin-like protein ligase binding	1
extracellular matrix binding	1
chromatin binding	1
transcription cis-regulatory region binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
RNA polymerase II, holoenzyme	1
nuclear DNA-directed RNA polymerase complex	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
RNA polymerase complex	1
chromatin	1

Protein interactions and networks

STRING

4388 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLR2A	POLR2K	P53803	999
POLR2A	POLR2B	P30876	999
POLR2A	POLR2C	P19387	996
POLR2A	SETD2	Q9BYW2	995
POLR2A	POLR2E	P19388	995
POLR2A	POLR2G	P52433	993
POLR2A	POLR2D	O15514	980
POLR2A	POLR2F	P41584	975
POLR2A	POLR2I	P36954	973
POLR2A	POLR2H	P52434	972
POLR2A	TBP	P20226	946
POLR2A	POLR2L	P52436	926
POLR2A	SUPT6H	Q7KZ85	919
POLR2A	GTF2B	Q00403	907
POLR2A	POLR2J	P52435	893

IntAct

412 interactions, top by confidence:

A	B	Type	Score
RPRD1B	POLR2A	psi-mi:“MI:0914”(association)	0.920
RPRD1B	POLR2A	psi-mi:“MI:0915”(physical association)	0.920
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
POLR2E	POLR3A	psi-mi:“MI:0914”(association)	0.870
SUPT5H	POLR2A	psi-mi:“MI:0915”(physical association)	0.840
POLR2A	SUPT5H	psi-mi:“MI:0914”(association)	0.840
MED18	MED19	psi-mi:“MI:0914”(association)	0.840
MED31	MED19	psi-mi:“MI:0914”(association)	0.840
MED7	MED19	psi-mi:“MI:0914”(association)	0.840
POLR2E	POLR2D	psi-mi:“MI:0915”(physical association)	0.790
MED30	MED19	psi-mi:“MI:0914”(association)	0.790
MED23	MED19	psi-mi:“MI:2364”(proximity)	0.770
CCAR2	MYC	psi-mi:“MI:0915”(physical association)	0.750
POLR2A	RECQL5	psi-mi:“MI:0915”(physical association)	0.740
RECQL5	POLR2A	psi-mi:“MI:0914”(association)	0.740
RECQL5	POLR2A	psi-mi:“MI:0407”(direct interaction)	0.740
RECQL5	POLR2A	psi-mi:“MI:0915”(physical association)	0.740
POLR2A	ASB6	psi-mi:“MI:0915”(physical association)	0.740
POLR2G	RECQL5	psi-mi:“MI:0914”(association)	0.730
RPRD1B	RECQL5	psi-mi:“MI:0914”(association)	0.730
POLR2D	MED19	psi-mi:“MI:0914”(association)	0.730
POLR2E	MED19	psi-mi:“MI:0914”(association)	0.730

BioGRID (1246): POLR2A (Reconstituted Complex), POLR2A (Biochemical Activity), POLR2A (Co-localization), POLR2A (Co-localization), ESR1 (Co-localization), SRC (Co-localization), PSMB9 (Co-localization), POLR2A (Co-localization), TCEB3 (Co-localization), POLR2A (Biochemical Activity), POLR2A (Affinity Capture-Western), POLR2A (Affinity Capture-Western), POLR2A (Affinity Capture-Western), POLR2A (Affinity Capture-RNA), POLR2A (Affinity Capture-RNA)

ESM2 similar proteins: A3N326, A4IF62, A5DCV3, A5WH34, A6TGP1, A6VKC4, A9MHE9, A9N0J5, B0BSF6, B0URZ7, B3GYV5, F4JXF9, G3MZY8, O14802, O35134, O54889, O94666, O95602, P04050, P04051, P04052, P08775, P0A2R4, P0A2R5, P10964, P11414, P15398, P16356, P17545, P17546, P24928, P28364, P35074, P35084, P36594, P41556, P91875, Q0I5B8, Q47UW0, Q57H68

Diamond homologs: A0PXT9, A2RML8, A3CKD4, A4FWF5, A4IF62, A4YCR0, A5CUC6, A5DCV3, A6UV49, A6VGV0, A8AZI2, A8F4G1, A9A9U9, A9BCH4, B0R8D3, B0RB26, B4U738, B6YT17, B8YB54, C0ZVQ7, C1AYV8, C3MRK4, C3MYA0, C3MZM9, C3N7Q1, C3NFS2, C4KIV9, C5A207, F4JXF9, G3MZY8, O14802, O27126, O28390, O35134, O54889, O93777, O94666, O95602, P04050, P04051

SIGNOR signaling

200 interactions.

A	Effect	B	Mechanism
MAPK1	down-regulates	POLR2A	phosphorylation
CDK7	down-regulates	POLR2A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 151 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
FGFR2 mutant receptor activation	6	49.1×	1e-08
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	11	48.2×	3e-15
RNA Pol II CTD phosphorylation and interaction with CE	11	48.2×	3e-15
HIV Transcription Elongation	13	47.0×	1e-17
mRNA Capping	11	45.0×	8e-15
HIV elongation arrest and recovery	12	44.6×	4e-16
Pausing and recovery of HIV elongation	12	44.6×	4e-16
Pausing and recovery of Tat-mediated HIV elongation	11	43.6×	1e-14

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	17	41.9×	1e-20
transcription elongation by RNA polymerase II	8	29.1×	4e-08
positive regulation of transcription initiation by RNA polymerase II	12	26.7×	5e-12
transcription initiation at RNA polymerase II promoter	8	24.6×	2e-07
RNA polymerase II preinitiation complex assembly	11	24.5×	1e-10
transcription by RNA polymerase II	20	11.6×	3e-13
positive regulation of apoptotic process	10	4.7×	4e-03
DNA damage response	10	4.4×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	26
Uncertain significance	318
Likely benign	85
Benign	19

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2576553	NM_000937.5(POLR2A):c.2289C>G (p.Tyr763Ter)	Pathogenic
3342858	NM_000937.5(POLR2A):c.3865G>A (p.Glu1289Lys)	Pathogenic
3658562	NM_000937.5(POLR2A):c.1524dup (p.Leu509fs)	Pathogenic
691497	NM_000937.5(POLR2A):c.1370T>C (p.Ile457Thr)	Pathogenic
691498	NM_000937.5(POLR2A):c.2098C>T (p.Gln700Ter)	Pathogenic
691500	NM_000937.5(POLR2A):c.2207C>T (p.Thr736Met)	Pathogenic
691501	NM_000937.5(POLR2A):c.3371T>C (p.Leu1124Pro)	Pathogenic
1064637	NM_000937.5(POLR2A):c.3373_3375del (p.Lys1125del)	Likely pathogenic
1320165	NM_000937.5(POLR2A):c.1357_1360dup (p.Asp454fs)	Likely pathogenic
1331629	NM_000937.5(POLR2A):c.3700A>G (p.Lys1234Glu)	Likely pathogenic
1343251	NM_000937.5(POLR2A):c.1379G>A (p.Arg460Gln)	Likely pathogenic
1800795	NM_000937.5(POLR2A):c.5734A>G (p.Thr1912Ala)	Likely pathogenic
1802041	NM_000937.5(POLR2A):c.706C>G (p.Leu236Val)	Likely pathogenic
2500278	NM_000937.5(POLR2A):c.1112C>T (p.Pro371Leu)	Likely pathogenic
2626901	NM_000937.5(POLR2A):c.742A>T (p.Met248Leu)	Likely pathogenic
3381396	NM_000937.5(POLR2A):c.1228A>T (p.Asn410Tyr)	Likely pathogenic
3572961	NM_000937.5(POLR2A):c.1348_1349del (p.Met450fs)	Likely pathogenic
3764219	NM_000937.5(POLR2A):c.2201G>A (p.Arg734Gln)	Likely pathogenic
3766788	NM_000937.5(POLR2A):c.2173dup (p.Leu725fs)	Likely pathogenic
3777158	NM_000937.5(POLR2A):c.2141T>C (p.Ile714Thr)	Likely pathogenic
3898892	NM_000937.5(POLR2A):c.2200C>T (p.Arg734Trp)	Likely pathogenic
4077439	NM_000937.5(POLR2A):c.21dup (p.Ser8fs)	Likely pathogenic
4277862	NM_000937.5(POLR2A):c.3712G>A (p.Gly1238Ser)	Likely pathogenic
4529678	NM_000937.5(POLR2A):c.439C>T (p.Leu147Phe)	Likely pathogenic
4796773	NM_000937.5(POLR2A):c.1452G>C (p.Leu484Phe)	Likely pathogenic
4845428	NM_000937.5(POLR2A):c.3379C>T (p.Leu1127Phe)	Likely pathogenic
691499	NM_000937.5(POLR2A):c.2203C>T (p.Gln735Ter)	Likely pathogenic
808215	NM_000937.5(POLR2A):c.3368G>T (p.Arg1123Leu)	Likely pathogenic
873135	NM_000937.5(POLR2A):c.1314_1319del (p.His439_Leu440del)	Likely pathogenic
873137	NM_000937.5(POLR2A):c.3407C>T (p.Thr1136Ile)	Likely pathogenic

SpliceAI

3473 predictions. Top by Δscore:

Variant	Effect	Δscore
17:7495936:TGCAG:T	acceptor_loss	1.0000
17:7495937:GCAGA:G	acceptor_loss	1.0000
17:7495938:CA:C	acceptor_loss	1.0000
17:7495939:A:AG	acceptor_gain	1.0000
17:7495939:A:C	acceptor_loss	1.0000
17:7495940:G:GA	acceptor_gain	1.0000
17:7495940:GA:G	acceptor_gain	1.0000
17:7495940:GAA:G	acceptor_gain	1.0000
17:7495940:GAAGC:G	acceptor_gain	1.0000
17:7496069:TGCAG:T	donor_gain	1.0000
17:7496070:GCAG:G	donor_gain	1.0000
17:7496070:GCAGG:G	donor_gain	1.0000
17:7496072:AG:A	donor_gain	1.0000
17:7496073:GG:G	donor_gain	1.0000
17:7496073:GGTA:G	donor_loss	1.0000
17:7496074:G:GG	donor_gain	1.0000
17:7496436:CCA:C	acceptor_loss	1.0000
17:7496437:CAGA:C	acceptor_loss	1.0000
17:7496438:A:AG	acceptor_gain	1.0000
17:7496439:G:GT	acceptor_gain	1.0000
17:7496439:GA:G	acceptor_gain	1.0000
17:7496439:GAAC:G	acceptor_gain	1.0000
17:7496439:GAACA:G	acceptor_gain	1.0000
17:7496758:T:A	acceptor_gain	1.0000
17:7496759:G:A	acceptor_gain	1.0000
17:7496762:AG:A	acceptor_gain	1.0000
17:7496763:G:A	acceptor_gain	1.0000
17:7496763:GGGCC:G	acceptor_gain	1.0000
17:7497043:CAGG:C	donor_loss	1.0000
17:7497348:T:TA	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000137218 (17:7514821 C>A), RS1000219256 (17:7511779 G>A,T), RS1000332341 (17:7507453 T>A,G), RS1000364604 (17:7492880 T>A,C), RS1000460840 (17:7484368 T>C,G), RS1000485110 (17:7511084 A>C), RS1000564858 (17:7510718 G>A,C), RS1000795532 (17:7484407 A>G), RS1000834577 (17:7510870 C>G,T), RS1000918214 (17:7493076 C>G,T), RS1000919990 (17:7483979 A>C), RS1000933432 (17:7502967 C>G,T), RS1000964977 (17:7491801 C>T), RS1001052116 (17:7492859 G>A,C), RS1001093221 (17:7487124 C>G)

Disease associations

OMIM: gene MIM:180660 | disease phenotypes: MIM:618603

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities	Definitive	AD

Mondo (2): neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (MONDO:0032829), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000348	High forehead
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000692	Tooth malposition
HP:0000729	Autistic behavior
HP:0000767	Pectus excavatum
HP:0001250	Seizure
HP:0001274	Agenesis of corpus callosum
HP:0001290	Generalized hypotonia
HP:0001357	Plagiocephaly
HP:0001508	Failure to thrive
HP:0001558	Decreased fetal movement
HP:0002020	Gastroesophageal reflux
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002188	Delayed CNS myelination
HP:0002205	Recurrent respiratory infections
HP:0002280	Enlarged cisterna magna
HP:0002360	Sleep disturbance
HP:0002453	Abnormal globus pallidus morphology
HP:0003202	Skeletal muscle atrophy
HP:0003546	Exercise intolerance
HP:0007281	Developmental stagnation

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST003997_1	Myopia	8.000000e-15
GCST006061_191	Atrial fibrillation	1.000000e-11
GCST006061_202	Atrial fibrillation	5.000000e-12
GCST006291_1	Spherical equivalent or myopia (age of diagnosis)	9.000000e-09
GCST006366_13	Central corneal thickness	2.000000e-08
GCST006979_801	Heel bone mineral density	1.000000e-16
GCST010002_119	Refractive error	3.000000e-22
GCST010703_158	Brain morphology (MOSTest)	3.000000e-09
GCST011823_4	Parkinson’s disease progression (cognitive)	7.000000e-07
GCST90002391_88	Mean corpuscular hemoglobin concentration	2.000000e-10
GCST90002395_270	Mean platelet volume	3.000000e-15
GCST90020025_1296	Waist-to-hip ratio adjusted for BMI	8.000000e-09
GCST90020027_543	Waist-hip index	6.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0005213	central corneal thickness
EFO:0009270	heel bone mineral density
EFO:0004346	neuroimaging measurement
EFO:0008336	disease progression measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1641353 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2228130	Toxicity	3	gemcitabine	Non-Small Cell Lung Carcinoma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2228130	POLR2A	3	0.25	1	gemcitabine

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.82	IC50	150	nM	MOLIBRESIB
6.80	Kd	157	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 16 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178481: Inhibition of POLR2A (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.1500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases reaction, decreases expression, increases expression, affects binding	5
(+)-JQ1 compound	increases expression, affects binding, affects cotreatment, decreases reaction, decreases phosphorylation (+1 more)	5
sodium arsenite	decreases phosphorylation, decreases reaction, decreases expression, increases abundance, increases expression (+2 more)	4
Benzo(a)pyrene	increases expression, increases methylation	3
Estradiol	affects binding, increases reaction, increases expression	3
alvocidib	decreases expression, decreases phosphorylation, increases reaction	2
Dichlororibofuranosylbenzimidazole	decreases reaction, decreases phosphorylation, increases reaction	2
Zinc	increases expression	2
Cadmium Chloride	increases expression, decreases expression, increases abundance, decreases methylation	2
Okadaic Acid	increases expression, increases phosphorylation	2
Particulate Matter	increases expression, increases abundance	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	affects binding, affects cotreatment, decreases reaction, decreases phosphorylation	1
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
1,12-benzoperylene	increases expression	1
decabromobiphenyl ether	decreases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	increases abundance, decreases expression	1
versicolorin A	increases expression	1
nickel sulfate	increases expression	1
coumarin	affects phosphorylation	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide	decreases phosphorylation, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
4-phenylbutyric acid	decreases expression, increases expression	1
2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone	decreases phosphorylation	1
ICG 001	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1639860	Binding	Inhibition of human RNA polymerase 2 assessed as synthesis of RNA products at 500 uM	PSI-7851, a pronucleotide of beta-D-2’-deoxy-2’-fluoro-2’-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication. — Antimicrob Agents Chemother

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B5S2	KICRi002-A-5	Induced pluripotent stem cell	Male
CVCL_B8MS	Abcam HCT 116 POLR2A KO	Cancer cell line	Male
CVCL_B9AG	Abcam MCF-7 POLR2A KO	Cancer cell line	Female
CVCL_B9Q1	Abcam A-549 POLR2A KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice