POLR2C

Summary

POLR2C (RNA polymerase II subunit C, HGNC:9189) is a protein-coding gene on chromosome 16q21, encoding DNA-directed RNA polymerase II subunit RPB3 (P19387). 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. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

This gene encodes the third largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene contains a cysteine rich region and exists as a heterodimer with another polymerase subunit, POLR2J. These two subunits form a core subassembly unit of the polymerase. A pseudogene has been identified on chromosome 21.

Source: NCBI Gene 5432 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary ovarian failure (Moderate, GenCC)
• Clinical variants (ClinVar): 29 total — 1 likely-pathogenic
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_032940

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9189
Approved symbol	POLR2C
Name	RNA polymerase II subunit C
Location	16q21
Locus type	gene with protein product
Status	Approved
Aliases	RPB3
Ensembl gene	ENSG00000102978
Ensembl biotype	protein_coding
OMIM	180663
Entrez	5432

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 retained_intron, 2 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000219252, ENST00000562599, ENST00000562953, ENST00000563115, ENST00000563589, ENST00000564626, ENST00000564651, ENST00000567982, ENST00000880578

RefSeq mRNA: 1 — MANE Select: NM_032940 NM_032940

CCDS: CCDS10782

Canonical transcript exons

ENST00000219252 — 9 exons

Exon	Start	End
ENSE00000852925	57462679	57462810
ENSE00000852932	57470280	57470354
ENSE00001415827	57470975	57472009
ENSE00003549839	57469710	57469761
ENSE00003592362	57466175	57466227
ENSE00003606693	57463029	57463078
ENSE00003626213	57469165	57469293
ENSE00003629654	57465953	57466021
ENSE00003660566	57469961	57470129

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 96.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 58.5827 / max 180.7340, expressed in 1825 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154378	58.5827	1825

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	96.79	gold quality
secondary oocyte	CL:0000655	96.32	gold quality
adenohypophysis	UBERON:0002196	95.90	gold quality
ventricular zone	UBERON:0003053	95.85	gold quality
gastrocnemius	UBERON:0001388	95.80	gold quality
pituitary gland	UBERON:0000007	95.78	gold quality
left ovary	UBERON:0002119	95.69	gold quality
muscle of leg	UBERON:0001383	95.67	gold quality
popliteal artery	UBERON:0002250	95.61	gold quality
tibial artery	UBERON:0007610	95.61	gold quality
right ovary	UBERON:0002118	95.50	gold quality
aorta	UBERON:0000947	95.43	gold quality
descending thoracic aorta	UBERON:0002345	95.42	gold quality
right coronary artery	UBERON:0001625	95.34	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.28	gold quality
thoracic aorta	UBERON:0001515	95.27	gold quality
cerebellar hemisphere	UBERON:0002245	95.26	gold quality
right adrenal gland cortex	UBERON:0035827	95.25	gold quality
ascending aorta	UBERON:0001496	95.24	gold quality
cerebellar cortex	UBERON:0002129	95.21	gold quality
left uterine tube	UBERON:0001303	95.16	gold quality
right adrenal gland	UBERON:0001233	95.15	gold quality
left coronary artery	UBERON:0001626	95.14	gold quality
ganglionic eminence	UBERON:0004023	95.12	gold quality
left adrenal gland	UBERON:0001234	95.10	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.09	gold quality
endocervix	UBERON:0000458	94.96	gold quality
gall bladder	UBERON:0002110	94.96	gold quality
left adrenal gland cortex	UBERON:0035825	94.95	gold quality
mucosa of stomach	UBERON:0001199	94.94	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	18.84
E-GEOD-100618	no	621.80
E-MTAB-6108	no	252.50

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4

miRNA regulators (miRDB)

45 targeting POLR2C, 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-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-4520-2-3P	99.14	69.28	1009
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-11399	98.71	65.69	869
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-6764-3P	98.44	67.64	1153
HSA-MIR-6824-3P	98.44	67.62	1154
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-6882-3P	98.23	67.01	1119

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 5)

• interaction between RPB3 and ATF4 (PMID:12860379)
• Rpb3 is a potential nuclear target of insulin-like growth factor binding protein-3 (PMID:16455777)
• eEF1gamma, in addition to its role in translation elongation complex, is involved in regulating Vimentin gene by contacting both pol II and the Vimentin promoter region and shuttling/nursing the Vimentin mRNA (PMID:21217813)
• These findings suggest that N-terminus of Rpb3 selectively inhibits Rpb3-high-expression hepatocellular carcinoma cells proliferation. N-terminus of Rpb3 may be useful in treating patients diagnosed with Rpb3-high-expression hepatocellular carcinoma. (PMID:25211001)
• FUS low-complexicity phase separates to recruit RNA polymerase II C-terminal domain in vitro. (PMID:26455390)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	polr2c	ENSDARG00000033596
mus_musculus	Polr2c	ENSMUSG00000031783
rattus_norvegicus	Polr2c	ENSRNOG00000015720
drosophila_melanogaster	Polr2C	FBGN0026373
caenorhabditis_elegans	rpb-3	WBGENE00007971

Paralogs (2): CRIPT (ENSG00000119878), POLR1C (ENSG00000171453)

Protein

Protein identifiers

DNA-directed RNA polymerase II subunit RPB3 — P19387 (reviewed: P19387)

Alternative names: DNA-directed RNA polymerase II 33 kDa polypeptide, DNA-directed RNA polymerase II subunit C, RPB31

All UniProt accessions (3): P19387, H3BRR2, Q6FGR6

UniProt curated annotations — full annotation on UniProt →

Function. 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.

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. Interacts with PTPN6; this interaction promotes the recruitment of RNA pol II to the PCK1 promoter.

Subcellular location. Nucleus.

Similarity. Belongs to the archaeal Rpo3/eukaryotic RPB3 RNA polymerase subunit family.

RefSeq proteins (1): NP_116558* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001514	DNA-dir_RNA_pol_30-40kDasu_CS	Conserved_site
IPR011262	DNA-dir_RNA_pol_insert	Domain
IPR011263	DNA-dir_RNA_pol_RpoA/D/Rpb3	Domain
IPR022842	RNAP_Rpo3/Rpb3/RPAC1	Family
IPR036603	RBP11-like	Homologous_superfamily
IPR036643	RNApol_insert_sf	Homologous_superfamily
IPR050518	Rpo3/RPB3_RNA_Pol_subunit	Family

Pfam: PF01000, PF01193

UniProt features (34 total): strand 14, helix 7, binding site 4, turn 3, modified residue 2, initiator methionine 1, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
9EHZ	ELECTRON MICROSCOPY	2.6
8XSO	ELECTRON MICROSCOPY	2.7
8XRM	ELECTRON MICROSCOPY	3.13
9EI1	ELECTRON MICROSCOPY	3.2
9EI3	ELECTRON MICROSCOPY	3.2
8XRJ	ELECTRON MICROSCOPY	3.6
9EI4	ELECTRON MICROSCOPY	3.7
5IYB	ELECTRON MICROSCOPY	3.9
5IYC	ELECTRON MICROSCOPY	3.9
5IYD	ELECTRON MICROSCOPY	3.9
6DRD	ELECTRON MICROSCOPY	3.9
8XVS	ELECTRON MICROSCOPY	4.1
6XRE	ELECTRON MICROSCOPY	4.6
9VD9	ELECTRON MICROSCOPY	4.6
7LBM	ELECTRON MICROSCOPY	4.8
5IYA	ELECTRON MICROSCOPY	5.4
5IY9	ELECTRON MICROSCOPY	6.3
5IY6	ELECTRON MICROSCOPY	7.2
6O9L	ELECTRON MICROSCOPY	7.2
5IY8	ELECTRON MICROSCOPY	7.9
5IY7	ELECTRON MICROSCOPY	8.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19387-F1	91.97	0.85

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 (4): 88; 90; 94; 97

Post-translational modifications (2): 124, 257

Function

Pathways and Gene Ontology

Reactome pathways

76 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: 207 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, REACTOME_VIRAL_MESSENGER_RNA_SYNTHESIS, REACTOME_SIGNALING_BY_FGFR, MORF_CDK2, MORF_HDAC2, BROWNE_HCMV_INFECTION_12HR_UP, SHIPP_DLBCL_CURED_VS_FATAL_DN, MORF_TERF1, MODULE_120, MORF_RAF1, NKX62_Q2, REACTOME_HIV_INFECTION, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, KEGG_HUNTINGTONS_DISEASE

GO Biological Process (2): transcription by RNA polymerase II (GO:0006366), DNA-templated transcription (GO:0006351)

GO Molecular Function (4): DNA binding (GO:0003677), DNA-directed RNA polymerase activity (GO:0003899), protein dimerization activity (GO:0046983), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), RNA polymerase II, core complex (GO:0005665), cytosol (GO:0005829), DNA-directed RNA polymerase complex (GO:0000428)

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
RNA biosynthetic process	2
cellular anatomical structure	2
DNA-templated transcription	1
gene expression	1
nucleic acid binding	1
5’-3’ RNA polymerase activity	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
RNA polymerase II, holoenzyme	1
nuclear DNA-directed RNA polymerase complex	1
cytoplasm	1
RNA polymerase complex	1

Protein interactions and networks

STRING

5599 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLR2C	POLR2J	P52435	999
POLR2C	POLR2B	P30876	998
POLR2C	POLR2A	P24928	996
POLR2C	POLR2L	P52436	993
POLR2C	POLR2F	P41584	986
POLR2C	POLR2G	P52433	985
POLR2C	POLR2E	P19388	983
POLR2C	POLR2D	O15514	982
POLR2C	POLR2K	P53803	927
POLR2C	POLR2H	P52434	880
POLR2C	POLR2I	P36954	865
POLR2C	MED17	Q9NVC6	861
POLR2C	SUPT16H	Q9Y5B9	800
POLR2C	POLR2J2	Q9GZM3	794
POLR2C	MED20	Q9H944	781

IntAct

184 interactions, top by confidence:

A	B	Type	Score
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
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
MED11	MED19	psi-mi:“MI:0914”(association)	0.840
POLR2G	POLR2D	psi-mi:“MI:0914”(association)	0.840
POLR2J	POLR1C	psi-mi:“MI:0914”(association)	0.830
POLR2E	POLR2D	psi-mi:“MI:0915”(physical association)	0.790
MED30	MED19	psi-mi:“MI:0914”(association)	0.790
MED9	MED19	psi-mi:“MI:0914”(association)	0.790
MED14	MED19	psi-mi:“MI:0914”(association)	0.790
TET3	OGT	psi-mi:“MI:0914”(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
RPRD1B	POLR2D	psi-mi:“MI:0914”(association)	0.730
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
MED26	MED19	psi-mi:“MI:0914”(association)	0.730
MED18	MED7	psi-mi:“MI:0914”(association)	0.730
MED21	POLR2D	psi-mi:“MI:0914”(association)	0.730
MED28	MED7	psi-mi:“MI:0914”(association)	0.730
POLR2A	POLR2D	psi-mi:“MI:0914”(association)	0.730
POLR2C	POLR2D	psi-mi:“MI:0914”(association)	0.730
POLR2D	POLR2C	psi-mi:“MI:0914”(association)	0.730

BioGRID (542): POLR2C (Co-localization), POLR2C (Co-localization), POLR2C (Co-localization), ESR1 (Co-localization), SRC (Co-localization), PSMB9 (Co-localization), POLR2C (Co-localization), TCEB3 (Co-localization), POLR2C (Affinity Capture-MS), POLR2C (Affinity Capture-MS), POLR2C (Affinity Capture-MS), POLR2C (Affinity Capture-MS), POLR1C (Co-fractionation), POLR1D (Co-fractionation), POLR2A (Co-fractionation)

ESM2 similar proteins: A1ALW7, A1BJ07, A4SCT6, A5CCI9, A5DWY7, A5IHP1, A7A1H2, A8F2C3, A8GPC6, A8GT45, A8GVD7, B0BUN6, B3CT29, B3EP34, B3QYF0, B3RHG9, B4S5A1, B4SBX4, B6K286, B8DNK9, B9W9T4, C3PP83, C4K2F5, C8ZDQ3, O94316, O94616, P07703, P16925, P19387, P46943, P97760, Q1MPP1, Q1RHP5, Q39211, Q39212, Q3APK0, Q3B6D6, Q3T0Q3, Q4UMQ5, Q54DH7

Diamond homologs: A1RSE3, A3MXZ5, A4WNA4, A5UN55, B0R4Y2, B1YC30, B8YB56, C3MJP7, C3MZ05, C3N054, C3N8R8, C3NMQ0, C4KJ93, O15160, O26144, O28002, O59303, O94616, P07703, P0CG28, P16370, P19387, P37382, P39471, P52432, P95989, P97760, Q00813, Q2NFZ6, Q39211, Q39212, Q3IQT6, Q3T0Q3, Q54DH7, Q57648, Q5JJF4, Q6KZP5, Q8PV16, Q8TVB8, Q8U0E4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
POLR2C	“form complex”	“RNA Polymerase II”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 162 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	10	63.4×	7e-16
Signaling by FGFR2 IIIa TM	11	55.1×	2e-16
Abortive elongation of HIV-1 transcript in the absence of Tat	13	53.8×	4e-19
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	15	51.0×	2e-21
RNA Pol II CTD phosphorylation and interaction with CE	15	51.0×	2e-21
mRNA Capping	15	47.6×	8e-21
Pausing and recovery of Tat-mediated HIV elongation	14	43.0×	7e-19
Tat-mediated HIV elongation arrest and recovery	14	43.0×	7e-19

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	20	40.9×	9e-25
RNA polymerase II preinitiation complex assembly	19	35.1×	2e-22
positive regulation of transcription initiation by RNA polymerase II	19	35.1×	2e-22
transcription initiation at RNA polymerase II promoter	8	20.4×	7e-07
mRNA 3’-end processing	5	19.1×	5e-04
somatic stem cell population maintenance	10	16.9×	8e-08
transcription elongation by RNA polymerase II	5	15.1×	1e-03
transcription by RNA polymerase II	15	7.2×	5e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	18
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1256007	NM_032940.3(POLR2C):c.544G>T (p.Val182Leu)	Likely pathogenic

SpliceAI

841 predictions. Top by Δscore:

Variant	Effect	Δscore
16:57462809:GC:G	donor_gain	1.0000
16:57462811:G:GG	donor_gain	1.0000
16:57462826:G:GT	donor_gain	1.0000
16:57462826:G:T	donor_gain	1.0000
16:57463078:GGT:G	donor_loss	1.0000
16:57463079:G:GA	donor_loss	1.0000
16:57463080:T:A	donor_loss	1.0000
16:57465944:A:AG	acceptor_gain	1.0000
16:57465945:T:G	acceptor_gain	1.0000
16:57465948:TTTA:T	acceptor_loss	1.0000
16:57465951:A:AG	acceptor_gain	1.0000
16:57465951:AGCC:A	acceptor_loss	1.0000
16:57465952:G:GA	acceptor_gain	1.0000
16:57465952:GC:G	acceptor_gain	1.0000
16:57465952:GCC:G	acceptor_gain	1.0000
16:57465952:GCCAT:G	acceptor_gain	1.0000
16:57466017:GCTTG:G	donor_gain	1.0000
16:57466021:GGTG:G	donor_loss	1.0000
16:57466022:G:GG	donor_gain	1.0000
16:57466023:T:G	donor_loss	1.0000
16:57466173:A:AG	acceptor_gain	1.0000
16:57466173:AG:A	acceptor_gain	1.0000
16:57466174:G:GA	acceptor_loss	1.0000
16:57466174:G:GG	acceptor_gain	1.0000
16:57466174:GG:G	acceptor_gain	1.0000
16:57466226:GG:G	donor_gain	1.0000
16:57466227:GG:G	donor_gain	1.0000
16:57469157:T:TA	acceptor_gain	1.0000
16:57469159:CCTTA:C	acceptor_loss	1.0000
16:57469160:CTTAG:C	acceptor_loss	1.0000

AlphaMissense

1805 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:57463034:C:A	A31D	1.000
16:57463038:T:A	N32K	1.000
16:57463038:T:G	N32K	1.000
16:57463049:G:C	R36T	1.000
16:57463049:G:T	R36M	1.000
16:57463050:G:C	R36S	1.000
16:57463050:G:T	R36S	1.000
16:57465965:T:A	V50D	1.000
16:57465981:T:A	N55K	1.000
16:57465981:T:G	N55K	1.000
16:57465992:T:C	L59P	1.000
16:57465998:A:T	D61V	1.000
16:57466009:G:C	A65P	1.000
16:57466010:C:A	A65D	1.000
16:57466015:A:G	R67G	1.000
16:57466016:G:C	R67T	1.000
16:57466016:G:T	R67M	1.000
16:57466017:G:C	R67S	1.000
16:57466017:G:T	R67S	1.000
16:57466021:G:A	G69R	1.000
16:57466021:G:C	G69R	1.000
16:57466175:G:A	G69E	1.000
16:57469168:T:C	C88R	1.000
16:57469195:T:C	C97R	1.000
16:57469250:T:A	V115D	1.000
16:57469265:T:C	L120P	1.000
16:57469973:T:A	V151D	1.000
16:57469979:T:C	L153S	1.000
16:57469979:T:G	L153W	1.000
16:57469997:T:C	L159P	1.000

dbSNP variants (sampled 300 via entrez): RS1000507306 (16:57468832 T>C), RS1001784747 (16:57470769 T>C), RS1001954180 (16:57464227 C>T), RS1001985322 (16:57464565 C>G,T), RS1002236868 (16:57470945 C>A), RS1002815766 (16:57461708 C>T), RS1003197466 (16:57461442 A>G), RS1003609007 (16:57465517 G>A,T), RS1003684258 (16:57465774 G>A,T), RS1004284635 (16:57468173 A>C), RS1004358302 (16:57468687 A>G), RS1004899015 (16:57462952 G>A), RS1005967608 (16:57470361 G>A,T), RS1006019957 (16:57470645 C>T), RS1006688241 (16:57466344 C>T)

Disease associations

OMIM: gene MIM:180663 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
primary ovarian failure	Moderate	Autosomal dominant

Mondo (2): infertility disorder (MONDO:0005047), primary ovarian failure (MONDO:0005387)

Orphanet (1): Rare genetic premature ovarian failure (Orphanet:485382)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007246	Infertility	C12.100.750
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
1,12-benzoperylene	increases expression	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
cobaltous chloride	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
nickel acetate	affects expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
bisphenol S	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Temozolomide	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Copper	affects binding, decreases expression	1
Disulfiram	affects binding, decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Selenium	increases expression	1
Smoke	decreases expression	1
Dronabinol	decreases expression	1
Thiram	increases expression	1
Tunicamycin	decreases expression	1
Valproic Acid	affects expression	1
Vitamin E	increases expression	1
Zearalenone	increases expression	1
Lactic Acid	decreases expression	1
Genistein	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT01388907	PHASE4	COMPLETED	Efficacity Assessment of PREVADH® in Adhesion Prevention in Gynaecologic Surgery
NCT01430650	PHASE4	COMPLETED	Endometrial Priming for Embryo Transfer
NCT02607319	PHASE4	COMPLETED	Low Molecular Weight Heparin to Improve Pregnancy Outcome in Patients With Recurrent Implantation Failure
NCT03169166	PHASE4	COMPLETED	The Use of GnRH Agonist Trigger for Final Follicle Maturation in Women Undergoing Assisted Reproductive Technologies
NCT03177122	PHASE4	UNKNOWN	Myo-Inositol- Based Co-treatment in Women With PCOS Undergoing Assisted Reproductive Technology
NCT03477929	PHASE4	UNKNOWN	Cetrorelix and Ganirelix Flexible Protocol for (IVF)
NCT03619707	PHASE4	COMPLETED	Oral Versus Vaginal Progesterone in the Luteal Support in Cryo-warmed Embryo Transfer Cycles
NCT03846544	PHASE4	COMPLETED	Double Pick up in Poor Prognosis Women
NCT05725512	PHASE4	RECRUITING	Prednisolone Administration in Patients With Unexplained REcurrent MIscarriages
NCT06195163	PHASE4	NOT_YET_RECRUITING	TRAP Study: Testosterone for Androgen Receptor Polymorphism
NCT06763926	PHASE4	NOT_YET_RECRUITING	Intranasal Nafarelin For Triggering Oocyte Maturation
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00749853	PHASE3	SUSPENDED	Efficacy of Ovarian Stimulation Based on FSHR Genotype Status
NCT03238092	PHASE3	UNKNOWN	Comparison Between Testosterone and Estradiol Over the Homogenization of Follicular Cohort
NCT03803228	PHASE3	COMPLETED	Dual Ovarian Stimulation (DUOSTIM) for Poor Ovarian Responders
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT04701034	PHASE2	COMPLETED	Intravenous Immunoglobulin and Prednisolone for RPL After ART.
NCT04850261	PHASE2	WITHDRAWN	Injection Free IVF
NCT06997900	PHASE2	RECRUITING	Menopur And Rekovelle Combination Study Version 2.0
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure