POLRMT

Summary

POLRMT (RNA polymerase mitochondrial, HGNC:9200) is a protein-coding gene on chromosome 19p13.3, encoding DNA-directed RNA polymerase, mitochondrial (O00411). DNA-dependent RNA polymerase catalyzes the transcription of mitochondrial DNA into RNA using the four ribonucleoside triphosphates as substrates. It is a selective cancer dependency (DepMap: 59.4% of cell lines).

This gene encodes a mitochondrial DNA-directed RNA polymerase. The gene product is responsible for mitochondrial gene expression as well as for providing RNA primers for initiation of replication of the mitochondrial genome. Although this polypeptide has the same function as the three nuclear DNA-directed RNA polymerases, it is more closely related to RNA polymerases of phage and mitochondrial polymerases of lower eukaryotes.

Source: NCBI Gene 5442 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined oxidative phosphorylation deficiency 55 (Strong, GenCC)
• Clinical variants (ClinVar): 519 total — 9 pathogenic, 12 likely-pathogenic (top 6% of genes corpus-wide)
• GTEx eGene: eQTL in 34 tissues, sQTL in 49 (q < 0.05)
• Phenotypes (HPO): 54
• Cancer dependency (DepMap): dependent in 59.4% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.26 (unconstrained)
• MANE Select transcript: NM_005035

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9200
Approved symbol	POLRMT
Name	RNA polymerase mitochondrial
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	h-mtRPOL, APOLMT, MTRNAP, MTRPOL
Ensembl gene	ENSG00000099821
Ensembl biotype	protein_coding
OMIM	601778
Entrez	5442

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 39 protein_coding, 8 nonsense_mediated_decay, 4 retained_intron

MANE Select: ENST00000588649

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 3: 3, TSL 5: 2

ENST00000588649, ENST00000587057, ENST00000589961, ENST00000590336, ENST00000590573, ENST00000590709, ENST00000592633, ENST00000592863, ENST00000878776, ENST00000878777, ENST00000878778, ENST00000878779, ENST00000878780, ENST00000878781, ENST00000878782, ENST00000878783, ENST00000878784, ENST00000878785, ENST00000878786, ENST00000878787, ENST00000878788, ENST00000878789, ENST00000878790, ENST00000927047, ENST00000927048, ENST00000927049, ENST00000927050, ENST00000927051, ENST00000927052, ENST00000927053, ENST00000927054, ENST00000927055, ENST00000927056, ENST00000927057, ENST00000927058, ENST00000927059, ENST00000927060, ENST00000958661, ENST00000958662, ENST00000958663, ENST00000958664, ENST00000958665, ENST00001043660, ENST00001043661, ENST00001043662, ENST00001043665, ENST00001069768, ENST00001069770, ENST00001117821, ENST00001122994, ENST00001138618

RefSeq mRNA: 21 — MANE Select: NM_005035 NM_001407805, NM_001407806, NM_001407807, NM_001407808, NM_001407809, NM_001407810, NM_001407811, NM_001407812, NM_001407813, NM_001407814, NM_001407815, NM_001407816, NM_001407829, NM_001407830, NM_001407831, NM_001407832, NM_001407833, NM_001407834, NM_001407835, NM_001407836, NM_005035

CCDS: CCDS12036

Canonical transcript exons

ENST00000588649 — 21 exons

Exon	Start	End
ENSE00000655271	629540	630168
ENSE00000655279	621058	621846
ENSE00000655281	620365	620487
ENSE00000655282	619958	620080
ENSE00000655283	619586	619765
ENSE00000655284	619210	619296
ENSE00000655286	618997	619110
ENSE00000655289	618705	618760
ENSE00000655290	618488	618586
ENSE00000655291	617777	617849
ENSE00000892315	633425	633537
ENSE00001365093	617221	617323
ENSE00003469219	632834	632938
ENSE00003480125	617570	617655
ENSE00003493611	622149	622373
ENSE00003511131	622821	622985
ENSE00003565651	623454	623603
ENSE00003576012	624719	624905
ENSE00003593025	622582	622752
ENSE00003630656	625124	625254
ENSE00003694502	617419	617480

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 97.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.5471 / max 142.0891, expressed in 1777 samples.

Highest expression (Bgee): testis, apex of heart, male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon, primordial germ cell in gonad.

Genetic regulation across tissues (GTEx eQTL / sQTL)

POLRMT is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 34 tissues and its splicing (sQTL) in 49 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 83 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	sqtl	3.7e-82	+0.95	19:619021:G:C
Nerve Tibial	sqtl	1.9e-53	+0.84	19:618159:A:G
Cells EBV-transformed lymphocytes	eqtl	8.9e-45	-0.75	19:636375:A:G
Lung	sqtl	2.1e-41	+0.78	19:618159:A:G
Pituitary	sqtl	4.5e-40	+1.08	19:624683:A:G
Muscle Skeletal	eqtl	4.2e-37	-0.18	19:633381:A:G
Cells Cultured fibroblasts	eqtl	3.0e-36	-0.23	19:633381:A:G
Skin Not Sun Exposed Suprapubic	sqtl	4.9e-34	+0.72	19:618159:A:G
Skin Sun Exposed Lower leg	sqtl	2.2e-31	+0.63	19:624502:C:G
Esophagus Mucosa	eqtl	1.1e-30	-0.40	19:634095:A:G
Breast Mammary Tissue	sqtl	7.9e-28	+0.69	19:618159:A:G
Testis	eqtl	1.4e-26	-0.31	19:636717:C:A
Adipose Visceral Omentum	sqtl	5.4e-26	+0.70	19:618159:A:G
Brain Cerebellum	sqtl	9.9e-26	+0.97	19:619574:T:G
Brain Cerebellar Hemisphere	sqtl	2.1e-25	+1.00	19:618159:A:G
Esophagus Mucosa	sqtl	3.2e-25	+0.75	19:625081:G:C
Adipose Subcutaneous	sqtl	2.4e-24	+0.67	19:618159:A:G
Esophagus Muscularis	sqtl	4.7e-24	+0.69	19:618159:A:G
Skin Sun Exposed Lower leg	eqtl	1.1e-22	-0.22	19:633529:G:GGCGCCGCCGCCGCCGCCGCC
Brain Caudate basal ganglia	sqtl	1.4e-21	+0.96	19:618159:A:G

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
177906	10.6204	1773
177907	0.7084	360
177908	0.2183	71

Top tissues by expression

showing 100 of 278 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	97.07	gold quality
right testis	UBERON:0004534	96.99	gold quality
apex of heart	UBERON:0002098	96.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.88	gold quality
testis	UBERON:0000473	95.64	gold quality
mucosa of transverse colon	UBERON:0004991	95.59	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.37	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.36	gold quality
lower esophagus mucosa	UBERON:0035834	95.20	gold quality
right lobe of liver	UBERON:0001114	94.63	gold quality
gastrocnemius	UBERON:0001388	94.19	gold quality
adenohypophysis	UBERON:0002196	93.89	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.58	gold quality
right frontal lobe	UBERON:0002810	93.31	gold quality
granulocyte	CL:0000094	93.23	gold quality
muscle of leg	UBERON:0001383	93.09	gold quality
metanephros cortex	UBERON:0010533	93.02	gold quality
anterior cingulate cortex	UBERON:0009835	92.95	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.93	gold quality
cingulate cortex	UBERON:0003027	92.77	gold quality
cerebellar hemisphere	UBERON:0002245	92.73	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.66	gold quality
cerebellar cortex	UBERON:0002129	92.65	gold quality
right lobe of thyroid gland	UBERON:0001119	92.58	gold quality
skin of leg	UBERON:0001511	92.44	gold quality
pituitary gland	UBERON:0000007	92.32	gold quality
prefrontal cortex	UBERON:0000451	92.22	gold quality
tibial nerve	UBERON:0001323	92.18	gold quality
left lobe of thyroid gland	UBERON:0001120	92.15	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.13	gold quality
skin of abdomen	UBERON:0001416	92.04	gold quality
right uterine tube	UBERON:0001302	91.73	gold quality
transverse colon	UBERON:0001157	91.71	gold quality
caudate nucleus	UBERON:0001873	91.63	gold quality
stromal cell of endometrium	CL:0002255	91.61	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.50	gold quality
putamen	UBERON:0001874	91.49	gold quality
amygdala	UBERON:0001876	91.41	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.16	gold quality
left adrenal gland cortex	UBERON:0035825	91.16	gold quality
heart left ventricle	UBERON:0002084	91.15	gold quality
right adrenal gland	UBERON:0001233	91.08	gold quality
nucleus accumbens	UBERON:0001882	91.00	gold quality
body of stomach	UBERON:0001161	90.86	gold quality
right adrenal gland cortex	UBERON:0035827	90.85	gold quality
lower esophagus	UBERON:0013473	90.81	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.81	gold quality
left adrenal gland	UBERON:0001234	90.79	gold quality
cerebellum	UBERON:0002037	90.71	gold quality
left ovary	UBERON:0002119	90.71	gold quality
right ovary	UBERON:0002118	90.69	gold quality
ventricular zone	UBERON:0003053	90.67	gold quality
small intestine	UBERON:0002108	90.65	gold quality
right atrium auricular region	UBERON:0006631	90.63	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.62	gold quality
cardiac ventricle	UBERON:0002082	90.58	gold quality
thyroid gland	UBERON:0002046	90.53	gold quality
cortical plate	UBERON:0005343	90.50	gold quality
body of uterus	UBERON:0009853	90.43	gold quality
spleen	UBERON:0002106	90.42	gold quality
endocervix	UBERON:0000458	90.37	gold quality
left uterine tube	UBERON:0001303	90.09	gold quality
adrenal cortex	UBERON:0001235	90.02	gold quality
neocortex	UBERON:0001950	89.88	gold quality
ectocervix	UBERON:0012249	89.77	gold quality
esophagus	UBERON:0001043	89.75	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.74	gold quality
spinal cord	UBERON:0002240	89.69	gold quality
upper lobe of left lung	UBERON:0008952	89.51	gold quality
minor salivary gland	UBERON:0001830	89.49	gold quality
frontal cortex	UBERON:0001870	89.49	gold quality
adrenal gland	UBERON:0002369	89.44	gold quality
muscle organ	UBERON:0001630	89.25	gold quality
body of pancreas	UBERON:0001150	89.12	gold quality
esophagus mucosa	UBERON:0002469	89.12	gold quality
cardiac atrium	UBERON:0002081	89.00	gold quality
ganglionic eminence	UBERON:0004023	88.99	gold quality
zone of skin	UBERON:0000014	88.92	gold quality
tibial artery	UBERON:0007610	88.92	gold quality
popliteal artery	UBERON:0002250	88.91	gold quality
heart	UBERON:0000948	88.85	gold quality
left coronary artery	UBERON:0001626	88.84	gold quality
forebrain	UBERON:0001890	88.59	gold quality
adult mammalian kidney	UBERON:0000082	88.55	gold quality
omental fat pad	UBERON:0010414	88.52	gold quality
telencephalon	UBERON:0001893	88.51	gold quality
stomach	UBERON:0000945	88.47	gold quality
peritoneum	UBERON:0002358	88.45	gold quality
aorta	UBERON:0000947	88.42	gold quality
mucosa of stomach	UBERON:0001199	88.40	gold quality
cerebral cortex	UBERON:0000956	88.32	gold quality
right coronary artery	UBERON:0001625	88.31	gold quality
coronary artery	UBERON:0001621	88.30	gold quality
Ammon’s horn	UBERON:0001954	88.25	gold quality
colon	UBERON:0001155	88.24	gold quality
right lung	UBERON:0002167	88.24	gold quality
brain	UBERON:0000955	88.23	gold quality
ascending aorta	UBERON:0001496	88.12	gold quality
sural nerve	UBERON:0015488	88.12	gold quality
intestine	UBERON:0000160	88.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	28.08
E-ANND-3	yes	3.21

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Hippocampus	tissue	28.8	high
Nucleus accumbens	tissue	27.2
Skeletal muscle	tissue	26.5	high
Postcentral gyrus	tissue	26.5
Locus coeruleus	tissue	25.9
Choroid plexus	tissue	24.5
Testis	tissue	23.0	high
Pituitary gland	tissue	21.9
Cerebellum	tissue	18.5	high
Vagina	tissue	17.0	low
Skin 1	tissue	14.0	high
Tongue	tissue	13.9
Duodenum	tissue	13.7	high
Cerebral cortex	tissue	13.6	high
Somatosensory cortex	tissue	13.6
Pancreas	tissue	13.1	high
Superior colliculi	tissue	13.0
Liver	tissue	12.6	medium
Midbrain	tissue	12.5
Thalamus	tissue	12.4
Pons	tissue	12.2
Motor cortex	tissue	12.2
Medulla oblongata	tissue	12.0
Hippocampal formation	tissue	12.0
Spinal cord	tissue	11.8
Occipital cortex	tissue	11.8
Substantia nigra	tissue	11.5
Spleen	tissue	11.2	high
Insular cortex	tissue	11.2
Prefrontal cortex	tissue	11.0
Corpus callosum	tissue	11.0
Retrosplenial cortex	tissue	11.0
Temporal cortex	tissue	11.0
Entorhinal cortex	tissue	10.8
Parathyroid gland	tissue	10.7	high
Small intestine	tissue	10.7	high
Retrosplenial and cingulate cortex	tissue	10.7
Frontal cortex	tissue	10.4
Thymus	tissue	10.3
Kidney	tissue	10.1	high
Putamen	tissue	10.0
Ventral forebrain	tissue	9.9
Amygdala	tissue	9.8
Hypothalamus	tissue	9.6
Caudate putamen	tissue	9.6
Colon	tissue	9.5	high
Stomach 1	tissue	9.4	high
Epididymis	tissue	9.4	high
Periaqueductal gray	tissue	9.4
Septum	tissue	9.3
Basal ganglia	tissue	9.1	high
Esophagus	tissue	9.0	medium
Lymph node	tissue	8.9	high
Seminal vesicle	tissue	8.7	high
Appendix	tissue	8.6	high
Adipose tissue	tissue	8.4	low
Olfactory bulb	tissue	8.2
Salivary gland	tissue	8.1	medium
Heart muscle	tissue	8.0	high
Adrenal gland	tissue	7.6	high

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Nucleus ambiguus (40.3), Parieto-temporal junction (white matter) (38.4), Temporal white matter (37.0), Occipital cortex (white matter) (35.9), Piriform cortex (35.5).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 3.42e-43, LOEUF 1.26, missense Z -4.38 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000588649 — one region, missense o/e 1.16. DepMap (CRISPR cell-line fitness): dependent in 59.4% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): HGC-27 (-1.769), SF-295 (-1.668), OCI-AML3 (-1.618), RT4 (-1.491), FU97 (-1.461), SNU-398 (-1.422), SU-DHL-10 (-1.405), KP-4 (-1.35), NCI-H661 (-1.338), SU-DHL-1 (-1.337), SLR 20 (-1.281), SU-DHL-5 (-1.234), SW 1573 (-1.205), U-251 MG (-1.202), GB-1 (-1.191).

Literature-anchored findings (GeneRIF, showing 21)

• human mitochondrial DNA polymerase has a role in autosomal dominant progressive external ophthalmoplegia (PMID:15258572)
• POLRMT recognizes promoter elements in a sequence specific manner; TFAM induces a structural change of the promoter that is required for POLRMT-dependent promoter recognition (PMID:15526033)
• transcription of some mRNAs in humans and rodents is mediated by a previously unknown single-polypeptide nuclear RNA polymerase (spRNAP-IV), expressed from an alternative transcript of the mitochondrial RNA polymerase gene POLRMT (PMID:16079853)
• the MRPL12 interaction with POLRMT is likely part of a novel regulatory mechanism that coordinates mitochondrial transcription with translation (PMID:17337445)
• Promoter-independent DNA conformation-dependent transcription required TFB2M and was suppressed by TFAM, while promoter-dependent transcription was inhibited to a lesser extent BY TFAM. (PMID:19624753)
• POLRMT can function as an origin-specific primase in mammalian mitochondria. (PMID:20129056)
• Human mitochondrial RNA polymerase: evaluation of the single-nucleotide-addition cycle on synthetic RNA/DNA scaffolds (PMID:21548588)
• muscle actin genes are transcribed by nuclear isoform of mitochondrial RNA polymerase (spRNAP-IV) whereas the non-muscle actin genes are transcribed by the conventional RNA polymerase II (PolII) (PMID:21799907)
• X-ray structure of human mtRNAP at 2.5 A resolution, which reveals a T7-like catalytic carboxy-terminal domain, an amino-terminal domain resembling the T7 promoter-binding domain, a novel pentatricopeptide repeat domain, and flexible N-terminal extension (PMID:21947009)
• Authors propose that POLRMT interacts directly with h-mtTFB1 in 28S mitochondrial ribosomes to augment its 12S rRNA methyltransferase activity. (PMID:23303773)
• Newly synthesized RNA exits toward the pentatricopeptide repeat (PPR) domain, a unique feature of mtRNAP with conserved RNA-recognition motifs. (PMID:24096365)
• The results demonstrate that human TFAM binds to the N-terminal domain of mtRNAP, which results in bending of the promoter DNA around mtRNAP. (PMID:24393772)
• The results reveal the organization of TFAM, POLRMT and TFB2M around the light-strand promoter and represent the first structural characterization of the entire mitochondrial transcriptional initiation complex. (PMID:24413562)
• Results show that polymorphisms at POLG2 and POLRMT increased risk of oral cancer and leukoplakia, respectively, probably modulating synthesis and activity of the enzymes. (PMID:26403317)
• Suggest targeting POLRMT as strategy for treating acute myeloid leukemia. (PMID:26484416)
• knock-down of MRPL12 by RNA interference results in instability of POLRMT. (PMID:26586915)
• the frequency of variation in sequence identity and length at conserved sequence block 2 amongst human mitochondrial genomes and used in vitro transcription to assess the effects of this length heterogeneity on the activity of the mitochondrial RNA polymerase, POLRMT, was examined. (PMID:27436287)
• POLRMT mutations impair mitochondrial transcription causing neurological disease. (PMID:33602924)
• The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth. (PMID:34326320)
• TFB2M and POLRMT are essential for mammalian mitochondrial DNA replication. (PMID:34744028)
• SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression. (PMID:38649537)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	polrmt	ENSDARG00000101220
mus_musculus	Polrmt	ENSMUSG00000020329
rattus_norvegicus	Polrmt	ENSRNOG00000024879
drosophila_melanogaster	PolrMT	FBGN0261938
caenorhabditis_elegans	rpom-1	WBGENE00013680

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1915843) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 12 distinct phenotype terms.

Mouse phenotype (MP)	Records
embryonic lethality prior to organogenesis	2
enlarged lymph nodes	1
hydrocephaly	1
premature death	1
abnormal brain morphology	1
abnormal lymph node morphology	1
dilated heart left ventricle	1
dilated cardiomyopathy	1
decreased heart rate variability	1
abnormal mitochondrial morphology	1
abnormal mitochondrial physiology	1
preweaning lethality, incomplete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Nicotiana sylvestris	P69242	100.0%	Diamond
Nicotiana tabacum	P69243	100.0%	Diamond
Arabidopsis thaliana	P92969	81.3%	Diamond
Saccharomyces cerevisiae S288C	P13433	49.2%	Diamond
Neurospora crassa OR74A	P38671	48.4%	Diamond
Schizosaccharomyces pombe 972h-	O13993	46.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
BSG-AS1	ncRNA	105372233
GZMM	protein-coding	3004
HCN2	protein-coding	610
BSG	protein-coding	682
FGF22	protein-coding	27006
RNF126	protein-coding	55658
FSTL3	protein-coding	10272
PRSS57	protein-coding	400668

Protein

Protein identifiers

DNA-directed RNA polymerase, mitochondrial — O00411 (reviewed: O00411)

All UniProt accessions (4): O00411, K7EMH3, K7ESD1, R4GN79

UniProt curated annotations — full annotation on UniProt →

Function. DNA-dependent RNA polymerase catalyzes the transcription of mitochondrial DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT that is required for basal transcription of mitochondrial DNA. In this complex, TFAM recruits POLRMT to a specific promoter whereas TFB2M induces structural changes in POLRMT to enable promoter opening and trapping of the DNA non-template strand. Has DNA primase activity. Catalyzes the synthesis of short RNA primers that are necessary for the initiation of lagging-strand DNA synthesis from the origin of light-strand DNA replication (OriL).

Subunit / interactions. Homodimer. Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT. In this complex TFAM recruits POLRMT to the promoter whereas TFB2M induces structural changes in POLRMT to enable promoter opening and trapping of the DNA non-template strand. Upon metabolic stress, forms a complex composed of FOXO3, SIRT3 and mitochondrial RNA polymerase POLRMT; the complex is recruited to mtDNA in a SIRT3-dependent manner. Also forms a complex composed of FOXO3, SIRT3, TFAM and POLRMT. Interacts with TFB1M and TFB2M, leading to the stimulation of transcription. Interacts with TEFM. Interacts with MTRES1.

Subcellular location. Mitochondrion.

Disease relevance. Combined oxidative phosphorylation deficiency 55 (COXPD55) [MIM:619743] A mitochondrial disease characterized by global developmental delay, hypotonia, short stature, and impaired intellectual development with speech disabilities in childhood. Indolent progressive external ophthalmoplegia may be present in some patients. COXPD55 transmission pattern is consistent with autosomal dominant inheritance in some families, and with autosomal recessive inheritance in others. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the phage and mitochondrial RNA polymerase family.

RefSeq proteins (21): NP_001394734, NP_001394735, NP_001394736, NP_001394737, NP_001394738, NP_001394739, NP_001394740, NP_001394741, NP_001394742, NP_001394743, NP_001394744, NP_001394745, NP_001394758, NP_001394759, NP_001394760, NP_001394761, NP_001394762, NP_001394763, NP_001394764, NP_001394765, NP_005026* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002092	DNA-dir_Rpol_phage-type	Family
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR029262	RPOL_N	Domain
IPR037159	RNA_POL_N_sf	Homologous_superfamily
IPR043502	DNA/RNA_pol_sf	Homologous_superfamily
IPR046950	DNA-dir_Rpol_C_phage-type	Domain

Pfam: PF00940, PF14700

Enzyme classification (BRENDA)

• EC 2.7.7.6 — DNA-directed RNA polymerase (BRENDA: 114 organisms, 118 substrates, 121 inhibitors, 44 Km, 21 kcat entries)

Substrate kinetics (BRENDA)

16 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DGTP	0.015–1.4	8
RGTP	0.0103–0.32	8
ATP	0.0095–0.384	7
DUTP	1.2–1.7	2
GTP	0.1–0.234	2
RUTP	0.036–0.041	2
A10G2A2C2C	0.018	1
A9G3A2C2C	0.041	1
D(AP4T)	0.0021	1
D(TP4C)	0.0022	1
D(TP4G)	0.0017	1
D(TP4T)	0.0007	1
DTTP	0.0004	1
G2CAC2C	0.043	1
PROMOTER COMPLEX	—	1

Catalyzed reactions (Rhea)

• RNA(n) + a ribonucleoside 5’-triphosphate = RNA(n+1) + diphosphate (RHEA:21248)

UniProt features (148 total): helix 68, strand 44, sequence variant 12, turn 12, region of interest 4, active site 3, sequence conflict 2, transit peptide 1, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

25 structures by resolution:

PDB	Title	Method	Resolution (Å)
3SPA	Crystal Structure of Human Mitochondrial RNA Polymerase	X-RAY DIFFRACTION	2.5
9BDC	Cryo-EM Structure of the TEFM-bound Human Mitochondrial Transcription Substrate Rejection …	ELECTRON MICROSCOPY	2.54
4BOC	Structure of mitochondrial RNA polymerase elongation complex	X-RAY DIFFRACTION	2.65
9MN7	Structure of the human mitochondrial late-stage transcription initiation complex, IC8	ELECTRON MICROSCOPY	2.65
9MN8	Structure of the human mitochondrial transcription initiation transitional complex, TC8	ELECTRON MICROSCOPY	2.69
9MN6	Structure of the human mitochondrial late-stage transcription initiation complex, IC8	ELECTRON MICROSCOPY	2.71
8U8V	Cryo-EM structure of Substrate ATP Bound in the Insertion Site (IS) of Human …	ELECTRON MICROSCOPY	2.74
9MN9	Structure of the human mitochondrial promoter-initiated transcription elongation complex …	ELECTRON MICROSCOPY	2.74
9BDD	Cryo-EM Structure of Non-Cognate Substrate Bound in the Entry Site (ES) of Human …	ELECTRON MICROSCOPY	2.86
8U8U	Cryo-EM Structure of Cognate Substrate ATP Bound in the Entry Site (ES) of Human …	ELECTRON MICROSCOPY	2.9
7PZR	Cryo-EM structure of POLRMT in free form.	ELECTRON MICROSCOPY	3
9MN5	Structure of the human mitochondrial open transcription initiation complex, IC0	ELECTRON MICROSCOPY	3.04
9MN4	Structure of the human mitochondrial initially transcribing complex, IC3	ELECTRON MICROSCOPY	3.05
9R96	Cryo-EM structure of the human mitochondrial RNA polymerase transcription initiation …	ELECTRON MICROSCOPY	3.1
9GZO	Cryo-EM structure of the human mitochondrial RNA polymerase transcription initiation …	ELECTRON MICROSCOPY	3.15
9R95	Cryo-EM structure of the human mitochondrial RNA polymerase transcription initiation …	ELECTRON MICROSCOPY	3.2
7ZC4	Cryo-EM structure of POLRMT mutant.	ELECTRON MICROSCOPY	3.24
9GZM	Cryo-EM structure of the human mitochondrial RNA polymerase transcription initiation …	ELECTRON MICROSCOPY	3.4
7A8P	Structure of human mitochondrial RNA polymerase in complex with IMT inhibitor.	ELECTRON MICROSCOPY	3.5
7PZP	Mitochondrial DNA dependent RNA polymerase homodimer.	ELECTRON MICROSCOPY	3.5
9GZN	Cryo-EM structure of the human mitochondrial RNA polymerase transcription initiation …	ELECTRON MICROSCOPY	3.5
9MNA	Structure of the human mitochondrial promoter-initiated transcription elongation complex …	ELECTRON MICROSCOPY	3.77
5OLA	Structure of mitochondrial transcription elongation complex in complex with elongation …	X-RAY DIFFRACTION	3.9
6ERQ	Structure of the human mitochondrial transcription initiation complex at the HSP promoter	X-RAY DIFFRACTION	4.5
6ERP	Structure of the human mitochondrial transcription initiation complex at the LSP promoter	X-RAY DIFFRACTION	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00411-F1	83.99	0.64

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria

Antibody reliability (HPA): IH uncertain · IF supported

Functional residue map

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

Catalytic / active sites (3)

Position	Role
922
991
1151

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-163282	Mitochondrial transcription initiation	curated
R-HSA-9913635	Strand-asynchronous mitochondrial DNA replication	curated
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis	curated
R-HSA-69306	DNA Replication	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-1592230	Mitochondrial biogenesis	—
R-HSA-1852241	Organelle biogenesis and maintenance	—
R-HSA-75944	Transcription from mitochondrial promoters	—

MSigDB gene sets: 219 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, REACTOME_DNA_REPLICATION, GOMF_RNA_NUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, GOBP_MITOCHONDRIAL_DNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, FRASOR_RESPONSE_TO_SERM_OR_FULVESTRANT_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, GOCC_RNA_POLYMERASE_COMPLEX, GOMF_EXONUCLEASE_ACTIVITY, GOBP_DNA_REPLICATION

GO Biological Process (4): mitochondrial DNA replication (GO:0006264), mitochondrial transcription (GO:0006390), transcription initiation at mitochondrial promoter (GO:0006391), DNA-templated transcription (GO:0006351)

GO Molecular Function (10): 3’-5’-RNA exonuclease activity (GO:0000175), mitochondrial promoter sequence-specific DNA binding (GO:0001018), RNA binding (GO:0003723), DNA-directed RNA polymerase activity (GO:0003899), sequence-specific DNA binding (GO:0043565), DNA binding (GO:0003677), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), 5’-3’ RNA polymerase activity (GO:0034062)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), protein-containing complex (GO:0032991), mitochondrial DNA-directed RNA polymerase complex (GO:0034245), mitochondrial nucleoid (GO:0042645), DNA-directed RNA polymerase complex (GO:0000428)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Transcription from mitochondrial promoters	1
Mitochondrial biogenesis	1
DNA Replication	1
Organelle biogenesis and maintenance	1
Gene expression (Transcription)	1

GO top-level categories

30 GO namespaces:

Category	Terms
mitochondrion	5
mitochondrial RNA metabolic process	2
RNA biosynthetic process	2
nucleic acid binding	2
DNA-templated DNA replication	1
mitochondrial DNA metabolic process	1
DNA-templated transcription	1
mitochondrial gene expression	1
DNA-templated transcription initiation	1
mitochondrial transcription	1
gene expression	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
transcription cis-regulatory region binding	1
5’-3’ RNA polymerase activity	1
DNA binding	1
binding	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
RNA polymerase activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
cellular_component	1
DNA-directed RNA polymerase complex	1
mitochondrial protein-containing complex	1
mitochondrial matrix	1
nucleoid	1
intracellular membraneless organelle	1
RNA polymerase complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
mitochondrial transcription	BP	direct assay
transcription initiation at mitochondrial promoter	BP	direct assay
mitochondrial matrix	CC	direct assay
mitochondrial nucleoid	CC	direct assay
mitochondrion	CC	direct assay
protein-containing complex	CC	direct assay
3’-5’-RNA exonuclease activity	MF	direct assay
DNA-directed RNA polymerase activity	MF	direct assay
RNA binding	MF	high-throughput assay
sequence-specific DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,540 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLRMT	TFB2M	Q9H5Q4	990
POLRMT	TFB1M	Q8WVM0	984
POLRMT	TFAM	Q00059	975
POLRMT	TWNK	Q96RR1	822
POLRMT	TEFM	Q96QE5	821
POLRMT	SSBP1	Q04837	808
POLRMT	MTERF1	Q99551	787
POLRMT	POLG2	Q9UHN1	773
POLRMT	MTERF4	Q7Z6M4	717
POLRMT	MTERF3	Q96E29	712
POLRMT	POLG	P54098	701
POLRMT	SP2	Q02086	675
POLRMT	MGME1	Q9BQP7	675
POLRMT	PTCD3	Q96EY7	658
POLRMT	LRPPRC	P42704	648

IntAct

Human interaction partners of POLRMT in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 57 partners by confidence:

Partner	Interaction type	MIscore	Records
MRPL12	physical association	0.800	4
NFKBIA	association	0.670	3
TEFM	association	0.560	5
TFAM	physical association	0.560	2
DHX32	association	0.530	2
MAGEB2	association	0.530	1
TFB1M	direct interaction	0.440	1
ERP29	physical association	0.400	1
CHCHD2	association	0.350	2
CISD3	association	0.350	2
GRB10	association	0.350	2
GRHL1	association	0.350	2
LGR4	association	0.350	2
PPP6C	association	0.350	2
PPP6R2	association	0.350	2
PRKCI	association	0.350	2
PTX3	association	0.350	2
TRIM10	association	0.350	2
BEND3	association	0.350	1
C1orf174	association	0.350	1
CTCF	association	0.350	1
DDB1	association	0.350	1
DDX55	association	0.350	1
ERAL1	association	0.350	1
FAXC	association	0.350	1
FEZ1	association	0.350	1
FGFR1	association	0.350	1
FMC1	association	0.350	1
GRN	association	0.350	1
H1-1	association	0.350	1

BioGRID (267 interactions; top human partners by supporting records): NFKBIA (Affinity Capture-MS; 4 records), CLEC11A (Affinity Capture-MS; 3 records), KCTD17 (Affinity Capture-MS; 3 records), LTBR (Affinity Capture-MS; 3 records), TRIM10 (Affinity Capture-MS; 3 records), ANLN (Affinity Capture-MS; 2 records), CACNG5 (Affinity Capture-MS; 2 records), CLPP (Proximity Label-MS; 2 records), CS (Proximity Label-MS; 2 records), CUL3 (Affinity Capture-MS; 2 records), DHX32 (Affinity Capture-MS; 2 records), GRSF1 (Proximity Label-MS; 2 records), ICT1 (Proximity Label-MS; 2 records), MRPL12 (Affinity Capture-MS; 2 records), NELL1 (Affinity Capture-MS; 2 records)

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 57 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
Mitochondrial translation initiation	7	23.4×	2e-06
Mitochondrial translation elongation	7	23.4×	2e-06
Mitochondrial ribosome-associated quality control	7	22.6×	2e-06
Mitochondrial translation	6	21.7×	2e-05
Mitochondrial translation termination	7	20.2×	3e-06
Translation	7	11.4×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial translation	6	20.1×	2e-04
translation	6	11.9×	2e-03
protein phosphorylation	6	7.8×	9e-03

Disease & clinical

Genetic variants

Variant evidence for POLRMT: 519 ClinVar records (21 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	12
Uncertain significance	358
Likely benign	85
Benign	10

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 21 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3376607	NM_005035.4(POLRMT):c.2424del (p.Cys809fs)	Pathogenic	criteria provided, single submitter	1
4879669	NM_005035.4(POLRMT):c.2201_2205del (p.Pro734fs)	Pathogenic	criteria provided, single submitter	1
1341472	NM_005035.4(POLRMT):c.748C>G (p.His250Asp)	Likely pathogenic	criteria provided, single submitter	2
2671936	NM_005035.4(POLRMT):c.954-1G>C	Likely pathogenic	criteria provided, single submitter	1
3367088	NM_005035.4(POLRMT):c.1753C>T (p.Gln585Ter)	Likely pathogenic	criteria provided, single submitter	1
4277451	NM_005035.4(POLRMT):c.2732_2733delinsT (p.Ala911fs)	Likely pathogenic	criteria provided, single submitter	1
4796499	NM_005035.4(POLRMT):c.2351C>T (p.Ser784Leu)	Likely pathogenic	criteria provided, single submitter	1
4814169	NM_005035.4(POLRMT):c.983dup (p.Lys329fs)	Likely pathogenic	criteria provided, single submitter	1
4850749	NM_005035.4(POLRMT):c.2140del (p.Leu714fs)	Likely pathogenic	criteria provided, single submitter	1
4874333	NM_005035.4(POLRMT):c.3154-2A>G	Likely pathogenic	criteria provided, single submitter	1
4880543	NM_005035.4(POLRMT):c.1714C>T (p.Gln572Ter)	Likely pathogenic	criteria provided, single submitter	1
4884211	NM_005035.4(POLRMT):c.2574_2575insT (p.Lys859Ter)	Likely pathogenic	criteria provided, single submitter	1
4884219	NM_005035.4(POLRMT):c.1444del (p.Met482fs)	Likely pathogenic	criteria provided, single submitter	1
4974995	NM_005035.4(POLRMT):c.3330_3333dup (p.Thr1112fs)	Likely pathogenic	criteria provided, single submitter	1
1341473	NM_005035.4(POLRMT):c.2641-1G>C	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore POLRMT’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 37 predictions of 1,808):

Position(s)	Effect	Δscore	Sites
19:617481–617482	acceptor_loss	1.0000	5
19:617568–617569	donor_loss	1.0000	4
19:618486–618487	donor_loss	1.0000	4
19:618996	donor_loss	1.0000	3
19:619111–619112	acceptor_loss	1.0000	4
19:619208–619209	donor_loss	1.0000	5
19:619297	acceptor_loss	1.0000
19:619584–619585	donor_loss	1.0000	5
19:619603	donor_gain	1.0000
19:619956–619957	donor_loss	1.0000	5

AlphaMissense

2,166 missense substitutions predicted likely pathogenic (of 7,951 scored), across 581 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M995	9	0.980	0.999
M1132	9	0.892	0.992
D801	8	0.998	0.999
D1151	8	0.998	1.000
D1128	8	0.997	0.999
H1150	8	0.996	0.999
H930	8	0.991	0.997
H1125	8	0.990	0.999
D922	8	0.989	0.997
H1131	8	0.985	0.997
D954	8	0.979	0.996
F1171	8	0.979	0.998
F802	8	0.978	0.999
F1229	8	0.978	0.998
F1119	8	0.977	0.998
F1044	8	0.974	0.997
D697	8	0.965	0.985
D819	8	0.956	0.985
F1228	8	0.952	0.993
N926	8	0.951	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	favorable	2.57e-06
Rectum Adenocarcinoma (validation)	favorable	4.67e-05

Disease associations

OMIM: gene MIM:601778 | disease phenotypes: MIM:619743

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
combined oxidative phosphorylation deficiency 55	Strong	Autosomal recessive	6

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (8 panels, 8 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

8 panels:

Panel	Rating
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Mitochondrial disorders	green
Paediatric disorders	green
Possible mitochondrial disorder, nuclear genes	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (2): combined oxidative phosphorylation deficiency 55 (MONDO:0859228), neurodevelopmental disorder (MONDO:0700092)

HPO phenotypes

54 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000114	Proximal tubulopathy
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000577	Exotropia
HP:0000590	Progressive external ophthalmoplegia
HP:0000592	Blue sclerae
HP:0000601	Hypotelorism
HP:0000750	Delayed speech and language development
HP:0000805	Enuresis
HP:0000954	Single transverse palmar crease
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001324	Muscle weakness
HP:0001344	Absent speech
HP:0001488	Bilateral ptosis
HP:0001762	Talipes equinovarus
HP:0001873	Thrombocytopenia
HP:0001903	Anemia
HP:0001992	Organic aciduria
HP:0001994	Renal Fanconi syndrome
HP:0002019	Constipation
HP:0002119	Ventriculomegaly
HP:0002148	Hypophosphatemia
HP:0002151	Increased circulating lactate concentration
HP:0002917	Hypomagnesemia
HP:0002970	Genu varum
HP:0003198	Myopathy
HP:0003202	Skeletal muscle atrophy
HP:0003236	Elevated circulating creatine kinase activity
HP:0003593	Infantile onset
HP:0003596	Middle age onset
HP:0003701	Proximal muscle weakness
HP:0004322	Short stature
HP:0004912	Hypophosphatemic rickets
HP:0005101	High-frequency hearing impairment
HP:0005280	Depressed nasal bridge
HP:0007359	Focal-onset seizure
HP:0008180	Mildly elevated creatine kinase
HP:0010602	Type 2 muscle fiber predominance
HP:0011342	Mild global developmental delay
HP:0011344	Severe global developmental delay
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0012408	Medullary nephrocalcinosis
HP:0012625	Stage 3 chronic kidney disease
HP:0012707	Elevated brain lactate level by MRS
HP:0033725	Thin corpus callosum

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3120041 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

495 measured of 547 human assays (547 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-((R)-1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)acetamide	IC50	9 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
isopropyl N-methyl-N-(2-oxo-4-(o-tolyl)-2H-chromen-7-yl)glycinate	IC50	20 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
ethyl N-methyl-N-(2-oxo-4-(o-tolyl)-2H-chromen-7-yl)glycinate	IC50	20 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
1-(1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)cyclopropane-1-carboxamide	IC50	20 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
2-methyl-2-(1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)propanoic acid	IC50	20 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
3-ethyl-1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidine-3-carboxylic acid	IC50	20 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
(R)-4-(2-((4-(3-fluoro-2-methylphenyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperazine-1-carboxamide	IC50	20 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
2-[4-(2-methylphenyl)-2-oxochromen-7-yl]oxy-3-(trifluoromethoxy)propanoic acid	IC50	30 nM	US-20240368106: HYDROXY AND ALKOXY COUMARINS AS MODULATORS OF POLRMT
2-[4-(2,6-dimethylphenyl)-2-oxochromen-7-yl]oxyacetonitrile	IC50	30 nM	US-20240368106: HYDROXY AND ALKOXY COUMARINS AS MODULATORS OF POLRMT
(S)-1-(N-methyl-N-(2-oxo-4-(o-tolyl)-2H-chromen-7-yl)-D-alanyl)piperidine-3-carboxylic acid	IC50	30 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
2,2-dimethyl-3-(methyl(2-oxo-4-(o-tolyl)-2H-chromen-7-yl)amino)propanoic acid	IC50	30 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
methyl N-methyl-N-(2-oxo-4-(o-tolyl)-2H-chromen-7-yl)glycinate	IC50	30 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
7-((isoxazol-3-ylmethyl)(methyl)amino)-4-(o-tolyl)-2H-chromen-2-one	IC50	30 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
1-(1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)cyclopropane-1-carboxylic acid	IC50	30 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
2-methyl-2-(1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)propanamide	IC50	30 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
(R)-4-(2-((4-(4-fluoro-2-methylphenyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperazine-1-carboxamide	IC50	30 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
methyl 2-[4-(2-methylphenyl)-2-oxochromen-7-yl]oxy-3-(trifluoromethoxy)propanoate	IC50	40 nM	US-20240368106: HYDROXY AND ALKOXY COUMARINS AS MODULATORS OF POLRMT
tert-butyl N-methyl-N-(2-oxo-4-(o-tolyl)-2H-chromen-7-yl)glycinate	IC50	40 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
N-methyl-N-(2-oxo-4-(o-tolyl)-2H-chromen-7-yl)-D-alanine	IC50	40 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
2-((S)-1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)acetamide	IC50	40 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
1-(1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)cyclopropane-1-carboxamide	IC50	40 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
2-methyl-2-(1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)propanamide	IC50	40 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
3-ethyl-1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidine-3-carboxylic acid	IC50	40 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)-3-propylpiperidine-3-carboxylic acid	IC50	40 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
(2R)-2-[4-(2-methylphenyl)-2-oxochromen-7-yl]oxypropanenitrile	IC50	50 nM	US-20240368106: HYDROXY AND ALKOXY COUMARINS AS MODULATORS OF POLRMT
Synthesis of (R)-4-(2-chloro-4-fluorophenyl)-7-(methyl(1-oxo-1-(piperidin-1-yl)propan-2-yl)amino)-2H-chromen-2-one, (R)-2-((4-(2-chloro-4-fluorophenyl)-2-oxo-2H-chromen-7-yl)(methyl)amino)-N,N-dimethylpropanamide	IC50	50 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
7-(benzylamino)-4-(o-tolyl)-2H-chromen-2-one	IC50	50 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
N-methyl-2-(methyl(2-oxo-4-(o-tolyl)-2H-chromen-7-yl)amino)acetamide	IC50	50 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
7-(((1H-pyrazol-5-yl)methyl)(methyl)amino)-4-(o-tolyl)-2H-chromen-2-one	IC50	50 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
2-(methyl(2-oxo-4-(o-tolyl)-2H-chromen-7-yl)amino)propanamide	IC50	50 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
5,5-difluoro-1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidine-3-carboxylic acid	IC50	50 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
1-(1-((R)-2-((4-(2-chloro-4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)cyclopropane-1-carboxylic acid	IC50	50 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
(S)-1-(2-methyl-3-(2-oxo-4-(o-tolyl)-2H-chromen-7-yl)propanoyl)piperidine-3-carbonitrile	IC50	60 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
5,5-difluoro-1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidine-3-carboxylic acid	IC50	60 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
methyl 2-(1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)acetate	IC50	60 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
(R)-4-methyl-1-(2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidine-4-carboxylic acid	IC50	60 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
2-methyl-2-(1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)propanoic acid	IC50	60 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
2-(1-((R)-2-((4-(2-chloro-4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)-2-methylpropanoic acid	IC50	60 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
(R)-4-(2-chloro-4-fluorophenyl)-7-(methyl(1-morpholino-1-oxopropan-2-yl)amino)-2H-chromen-2-one	IC50	70 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
methyl 2-(1-((R)-2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)acetate	IC50	70 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
(R)-1-(1-(2-((1-oxo-4-(o-tolyl)-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-4-yl)urea	IC50	70 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
7-(2-methyl-3-oxo-3-(piperidin-1-yl)propyl)-4-(o-tolyl)-2H-chromen-2-one	IC50	80 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
7-(methyl(oxazol-2-ylmethyl)amino)-4-(o-tolyl)-2H-chromen-2-one	IC50	80 nM	US-20250326732: CHROMEN-2-ONE MODULATORS OF POLRMT
1-(1-((R)-2-((4-(2-chloro-4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperidin-3-yl)cyclopropane-1-carboxylic acid	IC50	80 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
4-(2-(hydroxymethyl)-6-methylphenyl)-7-(2,2,2-trifluoroethoxy)isoquinolin-1(2H)-one	IC50	80 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
(R)-4-(2-((4-(2-(methyl-d3)phenyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)oxy)propanoyl)piperazine-1-carboxamide	IC50	80 nM	US-20250340516: Isoquinolinones as Modulators of POLRMT
4-(2-methylphenyl)-7-propoxychromen-2-one	IC50	90 nM	US-20240368106: HYDROXY AND ALKOXY COUMARINS AS MODULATORS OF POLRMT
2-[4-(2-chlorophenyl)-2-oxochromen-7-yl]oxy-3-methoxy-N,N-dimethylpropanamide	IC50	90 nM	US-20240368106: HYDROXY AND ALKOXY COUMARINS AS MODULATORS OF POLRMT

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.00	IC50	1000	nM	CHEMBL5575683

PubChem BioAssay actives

1 with measured affinity, of 99 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[[(2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	2110144: Inhibition of recombinant human POLRMT by Phosphor imaging analysis	ic50	1.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
quercitrin	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	decreases expression	1
cupric chloride	increases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
theonyltrifluoroacetone	decreases response to substance	1
ICG 001	decreases expression	1
abrine	decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
BMS-986094	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Methyl Methanesulfonate	decreases expression	1
Ozone	increases oxidation, increases abundance, affects cotreatment	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Thiram	increases expression	1
Valproic Acid	increases methylation	1
Genistein	increases expression	1

ChEMBL screening assays

20 unique, capped per target: 12 binding, 7 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3124277	Binding	Inhibition of mitochondrial RNA polymerase (unknown origin) assessed as inhibition of single nucleotide incorporation	Discovery of the first C-nucleoside HCV polymerase inhibitor (GS-6620) with demonstrated antiviral response in HCV infected patients. — *J Med Chem*
CHEMBL4008258	ADMET	Inhibition of human mitochondrial RNA polymerase after 30 mins in presence of [33P]GTP	Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. — *J Med Chem*
CHEMBL6194224	Functional	Inhibition of human POLRMT using Mitochondrial RNA polymerase-DdRp activity	Data for DCP probe JNJ-8003

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 280 trials:

NCT	Phase	Status	Title
NCT02513940	Phase 4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	Phase 4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	Phase 4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	Phase 4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT04586348	Phase 4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	Phase 4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	Phase 3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	Phase 3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	Phase 3	RECRUITING	Reducing Missed Appointments
NCT07377032	Phase 3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT01648205	Phase 2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	Phase 2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	Phase 2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT02909959	Phase 2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	Phase 2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	Phase 2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00316459	Phase 1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	Phase 1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	Phase 1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	Phase 1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	Phase 1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	Phase 1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT00503191	Phase 1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	Phase 1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	Phase 1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05906732	Phase 1/2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT02931695	Not specified	COMPLETED	Ventricular Repolarization During the Pregnancy-to-Postpartum Transition (QuTe)
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea
NCT03775954	Not specified	RECRUITING	Fetal Electrophysiologic Abnormalities in High-Risk Pregnancies Associated With Fetal Demise
NCT03783975	Not specified	TERMINATED	KCNQ1 Cascade Screening
NCT03868657	Not specified	COMPLETED	The Physiological Effects of Human Ether-a-go-go-Related Gene (hERG)Blockade on Metabolism
NCT04074122	Not specified	UNKNOWN	Electromechanical Profiling of the Long-QT Syndrome (LQTS)
NCT04124237	Not specified	COMPLETED	Long Term Monitoring for Risk of Sudden Death
NCT04189822	Not specified	ENROLLING_BY_INVITATION	Hearts in Rhythm Organization (HiRO)National Registry and Bio Bank
NCT04328376	Not specified	COMPLETED	Measurement of the Electromechanical Window to Improve the Diagnosis of Congenital Long QT Syndrome

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for POLRMT across ~30M SureChEMBL compounds — explore on Sugi Predict.