POLR1C

Summary

POLR1C (RNA polymerase I and III subunit C, HGNC:20194) is a protein-coding gene on chromosome 6p21.1, encoding DNA-directed RNA polymerases I and III subunit RPAC1 (O15160). 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 100.0% of cancer cell lines).

The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 9533 — RefSeq curated summary.

At a glance

• Gene–disease (curated): POLR1C-related disorder (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 571 total — 21 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 87
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_203290

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20194
Approved symbol	POLR1C
Name	RNA polymerase I and III subunit C
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	RPA40, RPA39, RPA5, RPAC1, AC40, RPC40
Ensembl gene	ENSG00000171453
Ensembl biotype	protein_coding
OMIM	610060
Entrez	9533

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 21 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000304004, ENST00000372344, ENST00000423780, ENST00000428025, ENST00000455605, ENST00000481352, ENST00000488601, ENST00000512472, ENST00000607635, ENST00000642195, ENST00000643341, ENST00000643799, ENST00000645141, ENST00000646188, ENST00000646433, ENST00000646700, ENST00000908069, ENST00000908070, ENST00000908071, ENST00000930067, ENST00000930068, ENST00000930069, ENST00000930070, ENST00000930071, ENST00000930072, ENST00000930073, ENST00000945270

RefSeq mRNA: 3 — MANE Select: NM_203290 NM_001318876, NM_001363658, NM_203290

CCDS: CCDS4901, CCDS87408

Canonical transcript exons

ENST00000642195 — 9 exons

Exon	Start	End
ENSE00002031107	43520066	43520185
ENSE00002049166	43517089	43517178
ENSE00002169258	43520932	43521048
ENSE00002441316	43519706	43519838
ENSE00003483389	43517306	43517377
ENSE00003598136	43520625	43520774
ENSE00003607392	43520275	43520427
ENSE00003617547	43519333	43519440
ENSE00003818640	43521182	43521513

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 96.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.8723 / max 276.5256, expressed in 1812 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67913	29.8723	1812

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	96.01	gold quality
sperm	CL:0000019	95.58	gold quality
cervix squamous epithelium	UBERON:0006922	93.98	gold quality
male germ cell	CL:0000015	93.88	gold quality
oocyte	CL:0000023	93.09	gold quality
pancreatic ductal cell	CL:0002079	92.27	gold quality
calcaneal tendon	UBERON:0003701	92.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.06	gold quality
islet of Langerhans	UBERON:0000006	91.54	gold quality
right uterine tube	UBERON:0001302	91.01	gold quality
squamous epithelium	UBERON:0006914	90.95	gold quality
stromal cell of endometrium	CL:0002255	90.59	gold quality
right lobe of thyroid gland	UBERON:0001119	90.56	gold quality
epithelium of nasopharynx	UBERON:0001951	90.55	gold quality
nasopharynx	UBERON:0001728	90.54	gold quality
left lobe of thyroid gland	UBERON:0001120	90.42	gold quality
gingival epithelium	UBERON:0001949	90.33	gold quality
esophagus mucosa	UBERON:0002469	90.26	gold quality
esophagus squamous epithelium	UBERON:0006920	89.94	gold quality
mucosa of transverse colon	UBERON:0004991	89.73	gold quality
epithelial cell of pancreas	CL:0000083	89.69	gold quality
adenohypophysis	UBERON:0002196	89.61	gold quality
left adrenal gland cortex	UBERON:0035825	89.59	gold quality
right adrenal gland cortex	UBERON:0035827	89.49	gold quality
lower esophagus mucosa	UBERON:0035834	89.47	gold quality
thyroid gland	UBERON:0002046	89.45	gold quality
right testis	UBERON:0004534	89.43	gold quality
right adrenal gland	UBERON:0001233	89.40	gold quality
left adrenal gland	UBERON:0001234	89.37	gold quality
left testis	UBERON:0004533	89.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7052	no	237.87
E-HCAD-31	no	1.94
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 10)

• analyzed the kinetics of assembly and elongation of the RNA polymerase I complex on endogenous ribosomal genes in the nuclei of living cells with the use of in vivo microscopy (PMID:12446911)
• mutations in both alleles of POLR1C in three individuals with Treacher Collins syndrome. (PMID:21131976)
• Mutations in TCOF1, POLR1C and POLR1D have all been implicated in causing TCS (PMID:24690222)
• We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. (PMID:25790162)
• This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes’ availability leading to two different clinical conditions. (PMID:26151409)
• Treacher Collins syndrome 3-associated mutation leads to the localization of POLR1C into the lysosome and inhibits chondrogenic differentiation, possibly explaining a portion of the pathological molecular basis underlying Treacher Collins syndrome. (PMID:29567474)
• eport here a new family with two sisters affected by mild TCS carrying compound POLR1C heterozygous mutations, and review the literature on mild forms of TCS, autosomal recessive inheritance in this syndrome and POLR1C mutations (PMID:30957429)
• The clinical and imaging findings of patients with POLR1C hypomyelinating leukodystrophy are reviewed. Interestingly, severe myoclonic dystonia and T2 hypointensity of the substantia nigra and the subthalamic nucleus are not reported yet and could be helpful for the diagnosis of POLR1C hypomyelinating leukodystrophy. (PMID:31368241)
• Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C. (PMID:33005949)
• Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia. (PMID:33804237)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	polr1c	ENSDARG00000039400
mus_musculus	Polr1c	ENSMUSG00000067148
rattus_norvegicus	Polr1c	ENSRNOG00000019079
drosophila_melanogaster	Polr1C	FBGN0031657
caenorhabditis_elegans		WBGENE00019275

Paralogs (2): POLR2C (ENSG00000102978), CRIPT (ENSG00000119878)

Protein

Protein identifiers

DNA-directed RNA polymerases I and III subunit RPAC1 — O15160 (reviewed: O15160)

Alternative names: AC40, DNA-directed RNA polymerases I and III 40 kDa polypeptide, RPA39, RPC40

All UniProt accessions (8): A0A2R8Y5D3, A0A2R8Y8D6, A0A2R8YEY5, A0A2R8YEZ4, D6RDJ3, E7EQB9, O15160, H0Y723

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 and III which synthesize ribosomal RNA precursors and short non-coding RNAs including 5S rRNA, snRNAs, tRNAs and miRNAs, respectively. POLR1C/RPAC1 is part of the polymerase core and may function as a clamp element that moves to open and close the cleft.

Subunit / interactions. Component of the RNA polymerase I and RNA polymerase III complexes consisting of at least 13 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 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. Cytoplasm. Cytosol.

Disease relevance. Treacher Collins syndrome 3 (TCS3) [MIM:248390] A form of Treacher Collins syndrome, a disorder of craniofacial development. Treacher Collins syndrome is characterized by a combination of bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids with a paucity of eyelashes medial to the defect, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss. The disease is caused by variants affecting the gene represented in this entry. Leukodystrophy, hypomyelinating, 11 (HLD11) [MIM:616494] An autosomal recessive neurologic disorder characterized by brain hypomyelination, delayed psychomotor development, intellectual disability, tremor and other neurologic symptoms. Some patients may additionally manifest non-neurologic features, particularly dental abnormalities and hypogonadotropic hypogonadism. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (2)

UniProt ID	Names	Canonical?
O15160-1	1	yes
O15160-2	2

RefSeq proteins (3): NP_001305805, NP_001350587, NP_976035* (*=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
IPR033901	RNAPI/III_AC40	Family
IPR036603	RBP11-like	Homologous_superfamily
IPR036643	RNApol_insert_sf	Homologous_superfamily
IPR050518	Rpo3/RPB3_RNA_Pol_subunit	Family

Pfam: PF01000, PF01193

UniProt features (58 total): strand 22, sequence variant 14, helix 14, turn 3, modified residue 2, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

36 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7OB9	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
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
9FSQ	ELECTRON MICROSCOPY	3.51
7FJI	ELECTRON MICROSCOPY	3.6
7FJJ	ELECTRON MICROSCOPY	3.6
9LXO	ELECTRON MICROSCOPY	3.6
9FSR	ELECTRON MICROSCOPY	3.76

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15160-F1	92.24	0.79

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, 4

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA
R-HSA-427413	NoRC negatively regulates rRNA expression
R-HSA-5250924	B-WICH complex positively regulates rRNA expression
R-HSA-73762	RNA Polymerase I Transcription Initiation
R-HSA-73772	RNA Polymerase I Promoter Escape
R-HSA-73780	RNA Polymerase III Chain Elongation
R-HSA-73863	RNA Polymerase I Transcription Termination
R-HSA-73980	RNA Polymerase III Transcription Termination
R-HSA-749476	RNA Polymerase III Abortive And Retractive Initiation
R-HSA-76061	RNA Polymerase III Transcription Initiation From Type 1 Promoter
R-HSA-76066	RNA Polymerase III Transcription Initiation From Type 2 Promoter
R-HSA-76071	RNA Polymerase III Transcription Initiation From Type 3 Promoter
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-5250913	Positive epigenetic regulation of rRNA expression
R-HSA-5250941	Negative epigenetic regulation of rRNA expression
R-HSA-73854	RNA Polymerase I Promoter Clearance
R-HSA-73864	RNA Polymerase I Transcription
R-HSA-74158	RNA Polymerase III Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-76046	RNA Polymerase III Transcription Initiation

MSigDB gene sets: 396 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_INITIATION_FROM_TYPE_3_PROMOTER, REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_TERMINATION, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_RNA_POLYMERASE_III_CHAIN_ELONGATION, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, REACTOME_RNA_POLYMERASE_I_TRANSCRIPTION_INITIATION, GOBP_TRANSCRIPTION_BY_RNA_POLYMERASE_III, BIOCARTA_ARF_PATHWAY, GOBP_RRNA_TRANSCRIPTION, KEGG_CYTOSOLIC_DNA_SENSING_PATHWAY, MAHAJAN_RESPONSE_TO_IL1A_DN, MUELLER_PLURINET

GO Biological Process (2): transcription by RNA polymerase I (GO:0006360), 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 (9): fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), RNA polymerase III complex (GO:0005666), RNA polymerase I complex (GO:0005736), cytoplasm (GO:0005737), cytosol (GO:0005829), DNA-directed RNA polymerase complex (GO:0000428), nucleolus (GO:0005730)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
RNA Polymerase III Transcription	3
RNA Polymerase III Transcription Initiation	3
Gene expression (Transcription)	3
RNA Polymerase I Promoter Clearance	2
RNA Polymerase I Transcription	2
Epigenetic regulation of gene expression	2
Innate Immune System	1
Negative epigenetic regulation of rRNA expression	1
Positive epigenetic regulation of rRNA expression	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
RNA biosynthetic process	2
nucleolus	2
nuclear lumen	2
DNA-directed RNA polymerase complex	2
nuclear protein-containing complex	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
intracellular anatomical structure	1
cytoplasm	1
RNA polymerase complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

4437 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLR1C	POLR1D	P0DPB6	999
POLR1C	POLR2L	P52436	937
POLR1C	POLR2E	P19388	924
POLR1C	POLR1H	Q9P1U0	911
POLR1C	POLR2K	P53803	889
POLR1C	RRN3	Q9NYV6	880
POLR1C	POLR2F	P41584	859
POLR1C	POLR2H	P52434	854
POLR1C	POLR3D	P05423	827
POLR1C	POLR3K	Q9Y2Y1	822
POLR1C	POLR1F	Q3B726	817
POLR1C	POLR2B	P30876	776
POLR1C	POLI	Q9UNA4	756
POLR1C	POLR2J	P52435	741
POLR1C	POLR1G	O15446	725

IntAct

543 interactions, top by confidence:

A	B	Type	Score
POLR1D	POLR1C	psi-mi:“MI:0915”(physical association)	0.940
POLR1C	POLR1D	psi-mi:“MI:0915”(physical association)	0.940
NME1	POLR1C	psi-mi:“MI:0915”(physical association)	0.870
POLR1C	NME1	psi-mi:“MI:0915”(physical association)	0.870
IKZF3	POLR1C	psi-mi:“MI:0915”(physical association)	0.840
POLR1C	IKZF3	psi-mi:“MI:0915”(physical association)	0.840
POLR1C	POLR2J	psi-mi:“MI:0915”(physical association)	0.830
POLR2J	POLR1C	psi-mi:“MI:0915”(physical association)	0.830
POLR1C	TNFAIP1	psi-mi:“MI:0915”(physical association)	0.780
TNFAIP1	POLR1C	psi-mi:“MI:0915”(physical association)	0.780
POLR1C	TRIM27	psi-mi:“MI:0915”(physical association)	0.720
POLR1C	SMN1	psi-mi:“MI:0915”(physical association)	0.720
KCTD1	POLR1C	psi-mi:“MI:0915”(physical association)	0.720
BIRC7	POLR1C	psi-mi:“MI:0915”(physical association)	0.720
POLR1C	RIMBP3	psi-mi:“MI:0915”(physical association)	0.720
TSC22D4	POLR1C	psi-mi:“MI:0915”(physical association)	0.720
TRIM27	POLR1C	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (515): POLR1C (Two-hybrid), POLR1C (Two-hybrid), POLR1C (Two-hybrid), POLR1C (Two-hybrid), POLR1C (Two-hybrid), POLR1C (Two-hybrid), POLR1C (Two-hybrid), IKZF3 (Two-hybrid), POLR1D (Two-hybrid), MBIP (Two-hybrid), FAM208B (Two-hybrid), PPP2R3C (Two-hybrid), BIRC7 (Two-hybrid), CCDC33 (Two-hybrid), TSC22D4 (Two-hybrid)

ESM2 similar proteins: A0A0G2KTI4, A4FUD3, F1Q749, G0SGK0, O08810, O13473, O14007, O15160, O17919, O43100, O43101, O43102, O44081, O59948, O60832, P09605, P32481, P33322, P40615, P52432, P52780, P55013, P55014, P55015, P55016, P56286, P91926, Q02908, Q13621, Q15029, Q15147, Q1ZXC6, Q28BT8, Q32L22, Q3ZBP1, Q54T81, Q5F3X4, Q5R6E0, Q5ZJH9, Q60YA8

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

2 interactions.

A	Effect	B	Mechanism
POLR1C	“form complex”	“RNA Polymerase III”	binding
POLR1C	“form complex”	“RNA Polymerase I”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 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 Transcription Initiation From Type 2 Promoter	5	32.0×	7e-05
RNA Polymerase III Transcription Initiation From Type 1 Promoter	5	30.9×	7e-05
RNA Polymerase III Transcription Initiation From Type 3 Promoter	5	30.9×	7e-05
Positive epigenetic regulation of rRNA expression	5	26.2×	1e-04
RNA Polymerase III Transcription Initiation	5	25.4×	1e-04
RNA Polymerase I Transcription Termination	5	24.7×	1e-04
RNA Polymerase III Transcription	5	24.7×	1e-04
RNA Polymerase I Promoter Clearance	5	22.2×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	18
Uncertain significance	232
Likely benign	169
Benign	56

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1200831	NM_203290.4(POLR1C):c.400G>T (p.Glu134Ter)	Pathogenic
204588	NM_203290.4(POLR1C):c.95A>T (p.Asn32Ile)	Pathogenic
204589	NM_203290.4(POLR1C):c.436T>C (p.Cys146Arg)	Pathogenic
204591	NM_203290.4(POLR1C):c.77C>T (p.Thr26Ile)	Pathogenic
2072032	NM_203290.4(POLR1C):c.415_416del (p.Gln139fs)	Pathogenic
213960	NM_020745.4(AARS2):c.2681C>A (p.Ser894Ter)	Pathogenic
280857	NM_203290.4(POLR1C):c.699C>G (p.Tyr233Ter)	Pathogenic
30812	NM_203290.4(POLR1C):c.922+3_922+6del	Pathogenic
30813	NM_203290.4(POLR1C):c.979A>T (p.Lys327Ter)	Pathogenic
30814	NM_203290.4(POLR1C):c.87del (p.Gly31fs)	Pathogenic
356873	NM_203290.4(POLR1C):c.229C>T (p.Arg77Ter)	Pathogenic
3696905	NM_203290.4(POLR1C):c.589_590dup (p.Leu198fs)	Pathogenic
375403	NM_203290.4(POLR1C):c.614del (p.Gly205fs)	Pathogenic
4739192	NM_203290.4(POLR1C):c.907C>T (p.Arg303Ter)	Pathogenic
4748461	NM_203290.4(POLR1C):c.571C>T (p.Arg191Ter)	Pathogenic
635140	NM_203290.4(POLR1C):c.281T>C (p.Val94Ala)	Pathogenic
635144	NM_203290.4(POLR1C):c.349G>C (p.Ala117Pro)	Pathogenic
635146	NM_203290.4(POLR1C):c.461_462del (p.Lys154fs)	Pathogenic
635147	NM_203290.4(POLR1C):c.502G>A (p.Val168Met)	Pathogenic
635148	NM_203290.4(POLR1C):c.616del (p.Gln206fs)	Pathogenic
635153	NM_203290.4(POLR1C):c.970G>A (p.Glu324Lys)	Pathogenic
1324948	NM_203290.4(POLR1C):c.793C>T (p.Gln265Ter)	Likely pathogenic
3061134	NM_203290.4(POLR1C):c.685del (p.Ala229fs)	Likely pathogenic
3349434	NM_203290.4(POLR1C):c.438C>A (p.Cys146Ter)	Likely pathogenic
3593632	NM_203290.4(POLR1C):c.70-2A>G	Likely pathogenic
3593634	NM_203290.4(POLR1C):c.243_246del (p.Ala82fs)	Likely pathogenic
3593635	NM_203290.4(POLR1C):c.247G>T (p.Glu83Ter)	Likely pathogenic
3593636	NM_203290.4(POLR1C):c.250-8_253delinsA	Likely pathogenic
3593637	NM_203290.4(POLR1C):c.383-2A>G	Likely pathogenic
3593638	NM_203290.4(POLR1C):c.420dup (p.Arg141fs)	Likely pathogenic

SpliceAI

6069 predictions. Top by Δscore:

Variant	Effect	Δscore
6:43512311:GATCC:G	acceptor_gain	1.0000
6:43512313:TCC:T	acceptor_gain	1.0000
6:43512313:TCCC:T	acceptor_loss	1.0000
6:43512314:CC:C	acceptor_gain	1.0000
6:43512314:CCC:C	acceptor_gain	1.0000
6:43512315:CC:C	acceptor_gain	1.0000
6:43512316:C:A	acceptor_loss	1.0000
6:43512316:C:CC	acceptor_gain	1.0000
6:43512316:C:T	acceptor_gain	1.0000
6:43512317:T:A	acceptor_loss	1.0000
6:43512433:CACTT:C	donor_loss	1.0000
6:43512434:ACTTA:A	donor_loss	1.0000
6:43512435:CTTA:C	donor_loss	1.0000
6:43512437:TAC:T	donor_loss	1.0000
6:43512438:A:AC	donor_gain	1.0000
6:43512438:AC:A	donor_gain	1.0000
6:43512439:C:CA	donor_loss	1.0000
6:43512439:C:CC	donor_gain	1.0000
6:43512439:CC:C	donor_gain	1.0000
6:43512439:CCCT:C	donor_gain	1.0000
6:43512564:C:CC	acceptor_gain	1.0000
6:43512564:CTAGG:C	acceptor_loss	1.0000
6:43512570:CCA:C	acceptor_gain	1.0000
6:43512870:TAGCC:T	acceptor_gain	1.0000
6:43513066:TA:T	donor_loss	1.0000
6:43513067:A:AC	donor_gain	1.0000
6:43513068:C:CC	donor_gain	1.0000
6:43513196:TCCCG:T	acceptor_gain	1.0000
6:43513197:CCCG:C	acceptor_gain	1.0000
6:43513197:CCCGC:C	acceptor_gain	1.0000

AlphaMissense

2277 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:43520642:T:C	F225L	1.000
6:43520644:T:A	F225L	1.000
6:43520644:T:G	F225L	1.000
6:43519413:T:A	N74K	0.999
6:43519413:T:G	N74K	0.999
6:43519782:G:C	R109P	0.999
6:43519791:T:C	L112P	0.999
6:43520661:C:A	A231D	0.999
6:43521188:T:A	V310D	0.999
6:43521232:G:C	A325P	0.999
6:43519409:C:A	A73D	0.998
6:43519414:G:C	A75P	0.998
6:43519718:G:C	A88P	0.998
6:43519747:T:A	N97K	0.998
6:43519747:T:G	N97K	0.998
6:43519751:T:C	S99P	0.998
6:43519752:C:A	S99Y	0.998
6:43519752:C:T	S99F	0.998
6:43519763:G:C	D103H	0.998
6:43519776:C:A	A107D	0.998
6:43519781:C:A	R109S	0.998
6:43519788:G:A	G111E	0.998
6:43520295:T:A	W175R	0.998
6:43520295:T:C	W175R	0.998
6:43520377:T:C	L202P	0.998
6:43520625:G:A	G219D	0.998
6:43520637:C:A	A223D	0.998
6:43520639:A:G	K224E	0.998
6:43520641:G:C	K224N	0.998
6:43520641:G:T	K224N	0.998

dbSNP variants (sampled 300 via entrez): RS1000002169 (6:44081998 G>A), RS1000003052 (6:44014080 C>A,T), RS1000003153 (6:44247997 T>G), RS1000004865 (6:43683208 C>G), RS1000010199 (6:43887790 G>A), RS1000019455 (6:43543015 A>G), RS1000023480 (6:43638366 A>G), RS1000025530 (6:44461692 G>A), RS1000029363 (6:44420486 G>A,T), RS1000029790 (6:43685099 A>G,T), RS1000031778 (6:43994927 G>T), RS1000034553 (6:44040541 C>T), RS1000039368 (6:43761169 A>C,T), RS1000040320 (6:43719515 C>A,T), RS1000042282 (6:44457722 C>T)

Disease associations

OMIM: gene MIM:610060 | disease phenotypes: MIM:248390, MIM:616494

GenCC curated gene-disease

Disease	Classification	Inheritance
Treacher Collins syndrome 3	Strong	Autosomal recessive
hypomyelinating leukodystrophy 11	Strong	Autosomal recessive
Treacher-Collins syndrome	Supportive	Autosomal dominant
hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
POLR1C-related disorder	Definitive	AR
Treacher Collins syndrome 3	Moderate	AR

Mondo (6): hearing loss disorder (MONDO:0005365), Treacher Collins syndrome 3 (MONDO:0009558), hypomyelinating leukodystrophy 11 (MONDO:0014666), POLR1C-related disorder (MONDO:0700278), Treacher-Collins syndrome (MONDO:0002457), (MONDO:0019505)

Orphanet (2): Treacher-Collins syndrome (Orphanet:861), Hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome (Orphanet:88637)

HPO phenotypes

87 total (30 of 87 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000143	Rectovaginal fistula
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000162	Glossoptosis
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000358	Posteriorly rotated ears
HP:0000370	Abnormality of the middle ear
HP:0000384	Preauricular skin tag
HP:0000405	Conductive hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000431	Wide nasal bridge
HP:0000453	Choanal atresia
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000505	Visual impairment
HP:0000518	Cataract

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005164_2	GLP-1 levels in response to oral glucose tolerance test (fasting)	4.000000e-06
GCST005956_58	Waist-to-hip ratio adjusted for BMI	7.000000e-26
GCST005957_1	Waist-to-hip ratio adjusted for BMI (age <50)	2.000000e-14
GCST005958_2	Waist-to-hip ratio adjusted for BMI (age >50)	2.000000e-19
GCST005962_2	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-31

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004307	glucose tolerance test
EFO:0008465	glucagon-like peptide-1 measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C535707	Mandibulofacial dysostosis, Treacher Collins type, autosomal recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725134 (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 variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2396243	MYMX, POLR1C		0.00	0
rs693955	POLR1C, SLC29A1		0.00	0

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.30	Kd	505.5	nM	CHEMBL5653589
6.30	ED50	506.3	nM	CHEMBL5653589
5.44	IC50	3620	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 8 total; 2 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149032: Binding affinity to human POLR1C incubated for 45 mins by Kinobead based pull down assay	kd	0.5055	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178865: Inhibition of POLR1C (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	3.6200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
sodium arsenite	decreases expression	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
Nickel	increases expression	2
Plant Extracts	affects cotreatment, increases expression, decreases expression	2
Tretinoin	decreases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
deoxynivalenol	increases expression	1
decabromobiphenyl ether	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
tetrabromobisphenol A	decreases expression	1
cylindrospermopsin	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Antimycin A	increases expression	1
Atrazine	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652074	Binding	Binding affinity to human POLR1C incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT04931056	Not specified	COMPLETED	A Post Market Clinical Follow-up Study on Biomet Microfixation HTR PEKK (Midface), Facial & Mandibular Plates.
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound