POLR2F

Summary

POLR2F (RNA polymerase II, I and III subunit F, HGNC:9193) is a protein-coding gene on chromosome 22q13.1, encoding DNA-directed RNA polymerases I, II, and III subunit RPABC2 (P61218). DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. It is a common-essential gene (DepMap: required in 99.7% of cancer cell lines).

This gene encodes the sixth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. In yeast, this polymerase subunit, in combination with at least two other subunits, forms a structure that stabilizes the transcribing polymerase on the DNA template. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5435 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 596 total — 137 pathogenic, 86 likely-pathogenic
• Phenotypes (HPO): 1
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_021974

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9193
Approved symbol	POLR2F
Name	RNA polymerase II, I and III subunit F
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Aliases	RPB6, HRBP14.4
Ensembl gene	ENSG00000100142
Ensembl biotype	protein_coding
OMIM	604414
Entrez	5435

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 15 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000333418, ENST00000405557, ENST00000407936, ENST00000427034, ENST00000442738, ENST00000443002, ENST00000460648, ENST00000470701, ENST00000483713, ENST00000484894, ENST00000488684, ENST00000492213, ENST00000606538, ENST00000608713, ENST00000927750, ENST00000927752, ENST00000927753, ENST00000927756, ENST00000927757

RefSeq mRNA: 5 — MANE Select: NM_021974 NM_001301129, NM_001301130, NM_001301131, NM_001363825, NM_021974

CCDS: CCDS13963, CCDS77673, CCDS87025

Canonical transcript exons

ENST00000442738 — 5 exons

Exon	Start	End
ENSE00001109302	37967625	37969312
ENSE00003696138	37967099	37967170
ENSE00003697260	37956773	37956842
ENSE00003698914	37959346	37959476
ENSE00003699348	37953699	37953807

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 94.1463 / max 553.9949, expressed in 1826 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192225	86.6036	1825
192226	5.7990	1628
192229	1.7437	161

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	97.95	gold quality
spinal cord	UBERON:0002240	97.24	gold quality
tibial nerve	UBERON:0001323	96.95	gold quality
tendon of biceps brachii	UBERON:0008188	96.91	gold quality
apex of heart	UBERON:0002098	96.70	gold quality
right lobe of liver	UBERON:0001114	96.66	gold quality
right atrium auricular region	UBERON:0006631	96.52	gold quality
amygdala	UBERON:0001876	96.41	gold quality
heart left ventricle	UBERON:0002084	96.28	gold quality
adenohypophysis	UBERON:0002196	96.27	gold quality
ganglionic eminence	UBERON:0004023	96.24	gold quality
prefrontal cortex	UBERON:0000451	96.22	gold quality
putamen	UBERON:0001874	96.19	gold quality
cardiac ventricle	UBERON:0002082	96.18	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.16	gold quality
nucleus accumbens	UBERON:0001882	96.10	gold quality
caudate nucleus	UBERON:0001873	96.09	gold quality
left coronary artery	UBERON:0001626	96.03	gold quality
stromal cell of endometrium	CL:0002255	96.00	gold quality
gastrocnemius	UBERON:0001388	96.00	gold quality
pituitary gland	UBERON:0000007	95.98	gold quality
cingulate cortex	UBERON:0003027	95.86	gold quality
anterior cingulate cortex	UBERON:0009835	95.82	gold quality
left adrenal gland	UBERON:0001234	95.78	gold quality
coronary artery	UBERON:0001621	95.75	gold quality
left ovary	UBERON:0002119	95.73	gold quality
mucosa of transverse colon	UBERON:0004991	95.73	gold quality
right adrenal gland	UBERON:0001233	95.72	gold quality
muscle of leg	UBERON:0001383	95.69	gold quality
left adrenal gland cortex	UBERON:0035825	95.69	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	1039.30
E-MTAB-6819	no	266.11
E-MTAB-8271	no	7.04
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1, ATF2, CTCF, ESR1, FOS, GTF2I, HNF4A, MYC, NCOA1, NCOA2, NCOA3, NFKB, PITX2, RUNX1, STAT3, TAF1, TBP, THRB, ZNF143, ZNF91

miRNA regulators (miRDB)

57 targeting POLR2F, 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-5193	100.00	67.26	1744
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 4)

• Solution structure of the hRPABC14.4 subunit of human RNA polymerases.(RPABC14.4 ?) (PMID:10542096)
• POLR2F and PRNP exhibited elevated levels in carcinomas compared to normal tissue samples suggesting a possible role for these molecules in colorectal cancer. (PMID:18505059)
• These results suggest that RPAP2 controls Pol II activity through a direct interaction with Rpb6 (PMID:25639305)
• Three human RNA polymerases interact with TFIIH via a common RPB6 subunit. (PMID:34268577)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	polr2f	ENSDARG00000036625
mus_musculus	Polr2f	ENSMUSG00000033020
rattus_norvegicus	Polr2f	ENSRNOG00000011214
drosophila_melanogaster	Polr2F	FBGN0003275
caenorhabditis_elegans		WBGENE00007355

Protein

Protein identifiers

DNA-directed RNA polymerases I, II, and III subunit RPABC2 — P61218 (reviewed: P61218)

Alternative names: DNA-directed RNA polymerase II subunit F, DNA-directed RNA polymerases I, II, and III 14.4 kDa polypeptide, RPABC14.4, RPB6 homolog, RPC15

All UniProt accessions (11): P61218, B0QYL8, B0QYL9, F8WC47, H0Y2U7, H0Y439, U3KPV3, U3KPY1, U3KQB0, U3KQQ7, U3KQS8

UniProt curated annotations — full annotation on UniProt →

Function. DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II, and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2F/RPABC2 is part of the clamp element and together with parts of POLR2A/RPB1 and POLR2B/RPB2 forms a pocket to which the POLR2D/RPB4-POLR2G/RPB7 subcomplex binds.

Subunit / interactions. Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively. Pol I complex consists of a ten-subunit catalytic core composed of POLR1A/RPA1, POLR1B/RPA2, POLR1C/RPAC1, POLR1D/RPAC2, POLR1H/RPA12, POLR2E/RPABC1, POLR2F/RPABC2, POLR2H/RPABC3, POLR2K/RPABC4 and POLR2L/RPABC5; a mobile stalk subunit POLR1F/RPA43 protruding from the core and additional subunits homologous to general transcription factors POLR1E/RPA49 and POLR1G/RPA34. Part of Pol I pre-initiation complex (PIC), in which Pol I core assembles with RRN3 and promoter-bound UTBF and SL1/TIF-IB complex. Pol II complex contains 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. 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. Pol III complex consists of a ten-subunit catalytic core composed of POLR3A/RPC1, POLR3B/RPC2, POLR1C/RPAC1, POLR1D/RPAC2, POLR3K/RPC10, POLR2E/RPABC1, POLR2F/RPABC2, POLR2H/RPABC3, POLR2K/RPABC4 and POLR2L/RPABC5; a mobile stalk composed of two subunits POLR3H/RPC8 and CRCP/RPC9, protruding from the core and functioning primarily in transcription initiation; and additional subunits homologous to general transcription factors of the RNA polymerase II machinery, POLR3C/RPC3-POLR3F/RPC6-POLR3G/RPC7 heterotrimer required for transcription initiation and POLR3D/RPC4-POLR3E/RPC5 heterodimer involved in both transcription initiation and termination.

Subcellular location. Nucleus. Nucleolus.

Similarity. Belongs to the archaeal Rpo6/eukaryotic RPB6 RNA polymerase subunit family.

RefSeq proteins (5): NP_001288058, NP_001288059, NP_001288060, NP_001350754, NP_068809* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006110	Pol_omega/Rpo6/RPB6	Family
IPR006111	Rpo6/Rpb6	Family
IPR020708	DNA-dir_RNA_polK_14-18kDa_CS	Conserved_site
IPR028363	RPB6	Family
IPR036161	RPB6/omega-like_sf	Homologous_superfamily

Pfam: PF01192

UniProt features (23 total): strand 11, helix 3, turn 2, modified residue 2, initiator methionine 1, chain 1, region of interest 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

60 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9EHZ	ELECTRON MICROSCOPY	2.6
7OB9	ELECTRON MICROSCOPY	2.7
8XSO	ELECTRON MICROSCOPY	2.7
7AE1	ELECTRON MICROSCOPY	2.8
9K39	ELECTRON MICROSCOPY	2.8
7VBB	ELECTRON MICROSCOPY	2.81
7VBA	ELECTRON MICROSCOPY	2.89
7D58	ELECTRON MICROSCOPY	2.9
9K36	ELECTRON MICROSCOPY	2.9
9K2G	ELECTRON MICROSCOPY	3
9K3U	ELECTRON MICROSCOPY	3
7VBC	ELECTRON MICROSCOPY	3.01
7AE3	ELECTRON MICROSCOPY	3.1
7D59	ELECTRON MICROSCOPY	3.1
7OBA	ELECTRON MICROSCOPY	3.1
9K38	ELECTRON MICROSCOPY	3.1
8XRM	ELECTRON MICROSCOPY	3.13
9EI1	ELECTRON MICROSCOPY	3.2
9EI3	ELECTRON MICROSCOPY	3.2
9FSO	ELECTRON MICROSCOPY	3.28
7A6H	ELECTRON MICROSCOPY	3.3
7OBB	ELECTRON MICROSCOPY	3.3
9LXN	ELECTRON MICROSCOPY	3.3
7DU2	ELECTRON MICROSCOPY	3.35
9FSP	ELECTRON MICROSCOPY	3.39
7AEA	ELECTRON MICROSCOPY	3.4
8IUH	ELECTRON MICROSCOPY	3.4
7DN3	ELECTRON MICROSCOPY	3.5
9K3V	ELECTRON MICROSCOPY	3.5
9LKT	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61218-F1	78.65	0.56

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): 2, 2

Function

Pathways and Gene Ontology

Reactome pathways

97 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-1834949	Cytosolic sensors of pathogen-associated DNA
R-HSA-203927	MicroRNA (miRNA) biogenesis
R-HSA-427413	NoRC negatively regulates rRNA expression
R-HSA-5250924	B-WICH complex positively regulates rRNA expression
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

MSigDB gene sets: 247 (showing top): REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_INITIATION_FROM_TYPE_3_PROMOTER, REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_TERMINATION, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_RNA_POLYMERASE_III_CHAIN_ELONGATION, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, BASSO_B_LYMPHOCYTE_NETWORK, REACTOME_VIRAL_MESSENGER_RNA_SYNTHESIS, REACTOME_SIGNALING_BY_FGFR, REACTOME_RNA_POLYMERASE_I_TRANSCRIPTION_INITIATION, GOBP_TRNA_METABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_TRANSCRIPTION_BY_RNA_POLYMERASE_III, KYNG_DNA_DAMAGE_DN, KYNG_DNA_DAMAGE_BY_4NQO

GO Biological Process (4): transcription by RNA polymerase I (GO:0006360), transcription by RNA polymerase II (GO:0006366), tRNA transcription by RNA polymerase III (GO:0042797), DNA-templated transcription (GO:0006351)

GO Molecular Function (2): DNA binding (GO:0003677), DNA-directed RNA polymerase activity (GO:0003899)

GO Cellular Component (9): fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), RNA polymerase II, core complex (GO:0005665), RNA polymerase III complex (GO:0005666), RNA polymerase I complex (GO:0005736), cytosol (GO:0005829), DNA-directed RNA polymerase complex (GO:0000428), nucleolus (GO:0005730)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Transcription of the HIV genome	8
HIV Transcription Elongation	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
Innate Immune System	1
Gene Silencing by RNA	1
Negative epigenetic regulation of rRNA expression	1
Positive epigenetic regulation of rRNA expression	1

GO top-level categories

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

62 interactions, top by confidence:

A	B	Type	Score
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
POLR2E	POLR3A	psi-mi:“MI:0915”(physical association)	0.870
MED17	MED19	psi-mi:“MI:0914”(association)	0.840
POLR2E	POLR2D	psi-mi:“MI:0915”(physical association)	0.790
MED9	MED19	psi-mi:“MI:0914”(association)	0.790
POLR2D	MED19	psi-mi:“MI:0914”(association)	0.730
POLR2E	MED19	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
POLR3GL	POLR3A	psi-mi:“MI:0914”(association)	0.730
RPRD1B	POLR2D	psi-mi:“MI:0914”(association)	0.730
POLR2J	POLR2D	psi-mi:“MI:0914”(association)	0.730
TCEA1	POLR2A	psi-mi:“MI:0914”(association)	0.710
PAF1	POLR2A	psi-mi:“MI:0914”(association)	0.710
POLR1E	POLR1C	psi-mi:“MI:0914”(association)	0.670
POLR2L	RCCD1	psi-mi:“MI:0914”(association)	0.640
POLR3K	POLR3A	psi-mi:“MI:0914”(association)	0.640
POLR2F	POLR3A	psi-mi:“MI:0914”(association)	0.640
RPAP3	POLR3A	psi-mi:“MI:0914”(association)	0.560
POLR3H	POLR3A	psi-mi:“MI:0914”(association)	0.530
ASB6	POLR2D	psi-mi:“MI:0914”(association)	0.530
POLR2F	BDP1	psi-mi:“MI:0914”(association)	0.350
POLR1A	POLR2H	psi-mi:“MI:0914”(association)	0.350

BioGRID (307): POLR2F (Co-localization), POLR2F (Co-localization), POLR2F (Co-localization), ESR1 (Co-localization), SRC (Co-localization), PSMB9 (Co-localization), POLR2F (Co-localization), TCEB3 (Co-localization), POLR2F (Affinity Capture-MS), POLR2F (Affinity Capture-MS), POLR2F (Affinity Capture-MS), POLR2F (Affinity Capture-MS), POLR2F (Affinity Capture-MS), CRCP (Co-fractionation), POLR1A (Co-fractionation)

ESM2 similar proteins: A1L0Z6, A1SJF7, A9CB91, A9CB92, B6KG46, H9G301, O60071, O74521, O84512, O88828, P03520, P04603, P04880, P0CK49, P0CK50, P0CK62, P11823, P11824, P20435, P36595, P61217, P61218, P61219, Q01656, Q01657, Q11107, Q1E0W9, Q2NL37, Q2UKV7, Q4WXX5, Q54FA8, Q5B3I9, Q5R4R7, Q5R592, Q5TD94, Q6BER5, Q6CN69, Q6IQ63, Q6X1D7, Q7S1X9

Diamond homologs: A0B6E6, A1RWX0, A2SSV2, A8WSV7, B0R4Y7, B6YSQ8, B8YB61, B9LPW5, C3MUV8, C3N5H2, C4KH38, C5A244, O26148, O29134, O88828, P20435, P29200, P36595, P39463, P58232, P61217, P61218, P61219, P62014, P62015, Q17684, Q24320, Q32PE0, Q54FA8, Q57650, Q5JJD0, Q5R592, Q6L1M4, Q8PW42, Q8TT40, Q8U0E8, Q8ZTF9, Q972B1, Q97ZJ9, Q9FJ98

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
POLR2F	“form complex”	“RNA Polymerase III”	binding
POLR2F	“form complex”	“RNA Polymerase II”	binding
POLR2F	“form complex”	“RNA Polymerase I”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 55 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
RNA Polymerase III Chain Elongation	13	179.3×	2e-26
RNA Polymerase III Transcription Termination	13	140.3×	5e-25
RNA Polymerase III Transcription Initiation From Type 2 Promoter	14	128.7×	7e-26
RNA Polymerase III Transcription Initiation From Type 1 Promoter	14	124.1×	7e-26
RNA Polymerase III Transcription Initiation From Type 3 Promoter	14	124.1×	7e-26
FGFR2 mutant receptor activation	7	115.9×	3e-13
Signaling by FGFR2 IIIa TM	8	104.5×	1e-14
RNA Polymerase III Transcription Initiation	14	102.2×	1e-24

GO biological processes:

GO term	Partners	Fold	FDR
transcription by RNA polymerase III	6	90.1×	3e-09
transcription initiation at RNA polymerase II promoter	5	36.7×	5e-06
positive regulation of transcription elongation by RNA polymerase II	6	35.4×	9e-07
RNA polymerase II preinitiation complex assembly	6	32.0×	1e-06
positive regulation of transcription initiation by RNA polymerase II	6	32.0×	1e-06
transcription by RNA polymerase II	9	12.4×	1e-06
defense response to virus	6	8.2×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	137
Likely pathogenic	86
Uncertain significance	174
Likely benign	101
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048554	NM_006941.4(SOX10):c.198_262del (p.Lys67fs)	Pathogenic
1048555	NM_006941.4(SOX10):c.529_556del (p.Arg177fs)	Pathogenic
1065048	NM_006941.4(SOX10):c.570C>A (p.Cys190Ter)	Pathogenic
1065835	NM_006941.4(SOX10):c.366_376del (p.Ala123fs)	Pathogenic
1065836	NM_006941.4(SOX10):c.336G>A (p.Met112Ile)	Pathogenic
1065838	NM_006941.4(SOX10):c.299_300insA (p.Ser100fs)	Pathogenic
1065839	NM_006941.4(SOX10):c.267del (p.Met90fs)	Pathogenic
1185066	NM_006941.4(SOX10):c.378C>A (p.Tyr126Ter)	Pathogenic
1185090	NM_006941.4(SOX10):c.520C>T (p.Gln174Ter)	Pathogenic
1202633	NM_006941.4(SOX10):c.448A>G (p.Lys150Glu)	Pathogenic
1220524	NM_006941.4(SOX10):c.12_13delinsAT (p.Gln5Ter)	Pathogenic
1323634	NM_006941.4(SOX10):c.254G>A (p.Trp85Ter)	Pathogenic
1329463	NM_006941.4(SOX10):c.395C>G (p.Ala132Gly)	Pathogenic
1329464	NM_006941.4(SOX10):c.966dup (p.Ala323fs)	Pathogenic
1386978	NM_006941.4(SOX10):c.1086del (p.Gln364fs)	Pathogenic
1998015	NM_006941.4(SOX10):c.856del (p.Met286fs)	Pathogenic
2000837	NM_006941.4(SOX10):c.616dup (p.His206fs)	Pathogenic
2024383	NM_006941.4(SOX10):c.29_138del (p.Val10fs)	Pathogenic
2029320	NM_006941.4(SOX10):c.355C>G (p.Arg119Gly)	Pathogenic
2127174	NM_006941.4(SOX10):c.903del (p.Pro302fs)	Pathogenic
228398	NM_006941.3(SOX10):c.(?698)(1401_?)del	Pathogenic
2441943	NM_006941.4(SOX10):c.671C>A (p.Ser224Ter)	Pathogenic
2445675	NM_006941.4(SOX10):c.1195_1196del (p.Gln399fs)	Pathogenic
2445676	NM_006941.4(SOX10):c.383dup (p.His128fs)	Pathogenic
265607	NM_006941.4(SOX10):c.425G>A (p.Trp142Ter)	Pathogenic
2700103	NM_006941.4(SOX10):c.1173dup (p.Phe392fs)	Pathogenic
2754706	NM_006941.4(SOX10):c.488del (p.Gln163fs)	Pathogenic
2771372	NM_006941.4(SOX10):c.21_42dup (p.Val15fs)	Pathogenic
2851250	NM_006941.4(SOX10):c.1272del (p.Phe425fs)	Pathogenic
2875340	NM_006941.4(SOX10):c.998G>A (p.Trp333Ter)	Pathogenic

SpliceAI

1888 predictions. Top by Δscore:

Variant	Effect	Δscore
22:37953451:AAGAC:A	donor_gain	1.0000
22:37953471:C:A	donor_gain	1.0000
22:37953808:G:GG	donor_gain	1.0000
22:37956766:T:TA	acceptor_gain	1.0000
22:37956769:A:AG	acceptor_gain	1.0000
22:37956770:C:G	acceptor_gain	1.0000
22:37956770:CA:C	acceptor_loss	1.0000
22:37956771:A:AG	acceptor_gain	1.0000
22:37956772:G:GA	acceptor_gain	1.0000
22:37956772:GT:G	acceptor_gain	1.0000
22:37956772:GTT:G	acceptor_gain	1.0000
22:37956772:GTTT:G	acceptor_gain	1.0000
22:37956772:GTTTT:G	acceptor_gain	1.0000
22:37956838:AAGAG:A	donor_loss	1.0000
22:37956839:AGAGG:A	donor_loss	1.0000
22:37956840:GAG:G	donor_gain	1.0000
22:37956840:GAGGT:G	donor_loss	1.0000
22:37956841:AGGTC:A	donor_loss	1.0000
22:37956842:GGTC:G	donor_loss	1.0000
22:37956843:G:GA	donor_loss	1.0000
22:37956844:T:G	donor_loss	1.0000
22:37956845:CAGTA:C	donor_loss	1.0000
22:37959336:T:A	acceptor_gain	1.0000
22:37959337:G:A	acceptor_gain	1.0000
22:37959339:T:TA	acceptor_gain	1.0000
22:37959343:CA:C	acceptor_loss	1.0000
22:37959344:A:AG	acceptor_gain	1.0000
22:37959345:G:GC	acceptor_loss	1.0000
22:37959345:G:GG	acceptor_gain	1.0000
22:37959345:GGA:G	acceptor_gain	1.0000

AlphaMissense

836 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:37959433:T:C	Y60H	1.000
22:37959434:A:G	Y60C	1.000
22:37959438:G:C	E61D	1.000
22:37959438:G:T	E61D	1.000
22:37959440:G:C	R62P	1.000
22:37959443:C:A	A63D	1.000
22:37959446:G:C	R64P	1.000
22:37959452:T:C	L66P	1.000
22:37959454:G:C	G67R	1.000
22:37959454:G:T	G67C	1.000
22:37959455:G:A	G67D	1.000
22:37959455:G:T	G67V	1.000
22:37959461:G:C	R69P	1.000
22:37959467:T:C	L71P	1.000
22:37959475:G:C	A74P	1.000
22:37967107:C:A	A77D	1.000
22:37967146:T:C	L90P	1.000
22:37967155:C:A	A93D	1.000
22:37967163:G:A	E96K	1.000
22:37967167:T:C	L97P	1.000
22:37967651:G:C	R107P	1.000
22:37967653:C:A	R108S	1.000
22:37967699:T:C	L123P	1.000
22:37959428:C:T	T58I	0.999
22:37959430:A:G	K59E	0.999
22:37959432:G:C	K59N	0.999
22:37959432:G:T	K59N	0.999
22:37959433:T:G	Y60D	0.999
22:37959436:G:A	E61K	0.999
22:37959437:A:T	E61V	0.999

dbSNP variants (sampled 300 via entrez): RS1000036136 (22:38008277 C>T), RS1000038348 (22:37984977 G>A,T), RS1000042176 (22:37962650 T>C), RS1000121289 (22:37966570 C>T), RS1000277272 (22:37960350 C>A,T), RS1000363856 (22:38001601 C>T), RS1000422643 (22:37979931 T>A), RS1000458886 (22:38035142 CCT>C), RS1000462345 (22:37996111 C>T), RS1000474971 (22:37979694 C>T), RS1000491678 (22:38021698 C>T), RS1000597031 (22:38007712 C>A), RS1000604855 (22:38033429 G>A,C), RS1000620867 (22:38039089 C>T), RS1000657802 (22:38020620 T>TATAC)

Disease associations

OMIM: gene MIM:604414 | disease phenotypes: MIM:609136, MIM:611584, MIM:613266, MIM:193500, MIM:147950, MIM:142623, MIM:130650, MIM:193510, MIM:277580, MIM:118220

GenCC curated gene-disease

Mondo (15): PCWH syndrome (MONDO:0012198), Waardenburg syndrome type 2E (MONDO:0012698), Waardenburg syndrome type 4C (MONDO:0013202), Waardenburg syndrome type 1 (MONDO:0008670), hypogonadotropic hypogonadism (MONDO:0018555), Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), Waardenburg syndrome (MONDO:0018094), Kallmann syndrome (MONDO:0018800), Beckwith-Wiedemann syndrome (MONDO:0007534), intellectual disability (MONDO:0001071), Waardenburg syndrome type 2A (MONDO:0008671), Waardenburg syndrome type 4A (MONDO:0010192), Hirschsprung disease (MONDO:0018309), Charcot-Marie-Tooth disease (MONDO:0015626), hearing loss disorder (MONDO:0005365)

Orphanet (11): Peripheral demyelinating neuropathy-central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease (Orphanet:163746), Waardenburg syndrome (Orphanet:3440), Waardenburg-Shah syndrome (Orphanet:897), Waardenburg syndrome type 1 (Orphanet:894), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Hirschsprung disease (Orphanet:388), Rare genetic deafness (Orphanet:96210), Kallmann syndrome (Orphanet:478), Beckwith-Wiedemann syndrome (Orphanet:116), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000044	Hypogonadotropic hypogonadism

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006976_92	Macular thickness	7.000000e-09
GCST010703_11	Brain morphology (MOSTest)	9.000000e-10
GCST010726_76	Periventricular white matter hyperintensities	8.000000e-06
GCST90002397_607	Mean spheric corpuscular volume	4.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0005665	white matter hyperintensity measurement

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D001506	Beckwith-Wiedemann Syndrome	C16.131.077.133; C16.131.260.080; C16.320.180.080; C16.320.447.375
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D017436	Kallmann Syndrome	C12.050.351.875.253.096.750; C12.200.706.316.096.750; C12.800.316.096.750; C16.131.939.316.096.750; C16.320.467; C19.391.119.096.750; C19.391.482.600
D014849	Waardenburg Syndrome	C16.131.077.938
C563789	Peripheral Demyelinating Neuropathy, Central Dysmyelination, Waardenburg Syndrome, and Hirschsprung Disease (supp.)
C567679	Waardenburg Syndrome, Type 4c (supp.)
C536464	Waardenburg syndrome type 2A (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs139887	POLR2F, SOX10	3	3.00	1	carboplatin;docetaxel;paclitaxel

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
chloropicrin	decreases expression	1
K 7174	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	increases expression, decreases reaction	1
Arsenic Trioxide	decreases expression	1
Vehicle Emissions	decreases reaction, increases expression	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Diazinon	increases methylation	1
Diclofenac	affects expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Methapyrilene	increases methylation	1
Smoke	decreases expression	1
Theophylline	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Tunicamycin	decreases expression	1
Valproic Acid	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	increases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT03687606	PHASE4	UNKNOWN	Efficacy and Safety of Long Term Use of hCG or hCG Plus hMG in Males With Isolated Hypogonadotropic Hypogonadism (IHH)
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
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00945009	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor
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
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism