RNASEH1

Summary

RNASEH1 (ribonuclease H1, HGNC:18466) is a protein-coding gene on chromosome 2p25.3, encoding Ribonuclease H1 (O60930). Endonuclease that specifically degrades the RNA of RNA-DNA hybrids.

This gene encodes an endonuclease that specifically degrades the RNA of RNA-DNA hybrids and plays a key role in DNA replication and repair. Alternate in-frame start codon initiation results in the production of alternate isoforms that are directed to the mitochondria or to the nucleus. The production of the mitochondrial isoform is modulated by an upstream open reading frame (uORF). Mutations in this gene have been found in individuals with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2. Alternative splicing results in additional coding and non-coding transcript variants. Pseudogenes of this gene have been defined on chromosomes 2 and 17.

Source: NCBI Gene 246243 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 (Strong, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 216 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 69
• Druggable target: yes
• MANE Select transcript: NM_002936

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18466
Approved symbol	RNASEH1
Name	ribonuclease H1
Location	2p25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000171865
Ensembl biotype	protein_coding
OMIM	604123
Entrez	246243

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000315212, ENST00000436842, ENST00000454734, ENST00000464986, ENST00000861506, ENST00000921961, ENST00000921962, ENST00000968504

RefSeq mRNA: 6 — MANE Select: NM_002936 NM_001286834, NM_001286837, NM_001378271, NM_001378272, NM_001378273, NM_002936

CCDS: CCDS1647

Canonical transcript exons

ENST00000315212 — 8 exons

Exon	Start	End
ENSE00001253775	3541430	3545871
ENSE00001253796	3558133	3558333
ENSE00003475044	3548640	3548724
ENSE00003507295	3552144	3552308
ENSE00003557603	3549058	3549112
ENSE00003561454	3556789	3556904
ENSE00003563782	3547931	3548055
ENSE00003635735	3550373	3550472

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 97.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1.9985 / max 43.0608, expressed in 1151 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26716	29.0736	1819
26715	1.5310	959
26714	0.4675	239

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.01	gold quality
oocyte	CL:0000023	94.04	gold quality
endothelial cell	CL:0000115	92.36	gold quality
middle temporal gyrus	UBERON:0002771	92.32	gold quality
nipple	UBERON:0002030	91.88	gold quality
visceral pleura	UBERON:0002401	90.16	gold quality
parietal pleura	UBERON:0002400	89.56	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.33	gold quality
tibia	UBERON:0000979	89.04	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.90	gold quality
pleura	UBERON:0000977	87.85	gold quality
cerebellar vermis	UBERON:0004720	87.66	gold quality
saphenous vein	UBERON:0007318	87.59	gold quality
germinal epithelium of ovary	UBERON:0001304	87.45	gold quality
epithelium of nasopharynx	UBERON:0001951	87.29	gold quality
nasopharynx	UBERON:0001728	87.27	silver quality
penis	UBERON:0000989	86.74	gold quality
corpus epididymis	UBERON:0004359	86.62	gold quality
palpebral conjunctiva	UBERON:0001812	86.60	gold quality
biceps brachii	UBERON:0001507	86.17	gold quality
superficial temporal artery	UBERON:0001614	86.16	silver quality
stromal cell of endometrium	CL:0002255	86.05	gold quality
primary visual cortex	UBERON:0002436	86.05	gold quality
trabecular bone tissue	UBERON:0002483	85.91	gold quality
occipital lobe	UBERON:0002021	85.83	gold quality
gastrocnemius	UBERON:0001388	85.79	gold quality
synovial joint	UBERON:0002217	85.78	gold quality
mammalian vulva	UBERON:0000997	85.76	gold quality
adult organism	UBERON:0007023	85.72	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

31 targeting RNASEH1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-4326	98.97	67.63	962
HSA-MIR-550A-3P	98.37	69.61	632
HSA-MIR-3130-5P	98.14	66.00	711
HSA-MIR-1285-5P	98.01	68.71	779
HSA-MIR-3159	97.94	66.79	1098
HSA-MIR-6765-3P	97.83	64.59	1165
HSA-MIR-1271-3P	97.56	64.85	865
HSA-MIR-550A-3-5P	97.56	65.35	823
HSA-MIR-550A-5P	97.56	65.35	823
HSA-MIR-4482-5P	97.53	65.68	598
HSA-MIR-6894-3P	96.73	65.64	798

Literature-anchored findings (GeneRIF, showing 27)

• The cysteine residues responsible for the redox-dependent activity of RNase H1 were determined by site-directed mutagenesis to involve Cys(147) and Cys(148), producing an inactive enzyme conformation by disulfide bond formation. (PMID:12473655)
• Human RNase H1 uses one tryptophan and two lysines to position the enzyme at the 3’-DNA/5’-RNA terminus of the heteroduplex substrate (PMID:14506260)
• in human cells RNase H1 is responsible for most of the activity of DNA-like antisense drugs (PMID:14960586)
• analysis of catalytic site of human RNase H1 for heteroduplex substrate catalysis (PMID:15205459)
• method for enhancing the human RNase H1 activity of chimeric antisense oligonucleotides (PMID:17028157)
• THE role substrate structure plays in directing human RNase H1 activity as well as the design of effective antisense oligodeoxyribonucleotides. (PMID:17028158)
• Report crystal structures of RNase H1 in complex with RNA/DNA hybrids. (PMID:17964265)
• Characterization of full-length enzymes with defective hybrid binding domain indicates that this domain dramatically enhances both the specific activity and processivity of RNase H1. (PMID:18337749)
• On the basis of its nuclear magnetic resonance (NMR) nucleic acid structure, a boranophosphonate-modified, fully R(P) BH(3) DNA/RNA hybrid is predicted not to be a substrate for RNase H1. (PMID:21443203)
• data implicate the H264 side chain in phosphodiester hydrolysis as well as in product release, and are consistent with a proposed model in which the RNAse H1 H264 side chain interacts with a divalent metal ion to support catalysis (PMID:23078533)
• RNase H1 and protein P32 are involved in mitochondrial pre-rRNA processing (PMID:23990920)
• RNaseH1 maintains regulated levels of telomeric RNA-DNA hybrids at ALT telomeres to trigger homologous recombination without compromising telomere integrity too severely (PMID:25330849)
• Altered RNaseH1 has a reduced capability to remove the RNA from RNA-DNA hybrids leading to impaired mtDNA replication and adult-onset mitochondrial encephalomyopathy. (PMID:26094573)
• found that the 3’ fragments of target pre-mRNA generated by ASO were almost completely degraded from their 5’ ends by nuclear XRN2 after RNase H1-mediated cleavage (PMID:26159921)
• Studies indicate that ribonuclease H1 is essential for mitochondrial DNA replication. (PMID:27402764)
• RPA is a sensor of R loops and a regulator of RNaseH1, extending the versatile role of RPA in suppression of genomic instability. (PMID:28257700)
• Data suggest that ribonuclease H1 (RNASEH1) plays important role in replication fork movement by resolving R-loops (RNA-DNA hybrids); RNASEH1 depletion results in accumulation of RNA-DNA hybrids, slowing of replication forks, and increased DNA damage; RNASEH1 appears to contribute to genome stability and preserves telomere integrity. (PMID:28717002)
• Data show that the catalytic domains of E. coli and human RNase H have nearly identical sequence preferences, which correlate with the efficiency of RNase H-recruiting antisense oligonucleotides. (PMID:29126318)
• RNASEH1 gene variants associate with susceptibility/protection to T1 Diabetes in Colombia. (PMID:29204916)
• A second nuclease is therefore required to remove the last ribonucleotides and we demonstrate that Flap endonuclease 1 (FEN1) can execute this function in vitro. Removal of RNA primers at OriL thus depends on a two-nuclease model, which in addition to RNase H1 requires FEN1 or a FEN1-like activity. These findings define the role of RNase H1 at OriL and help to explain the pathogenic consequences of disease causing mutatio (PMID:30102370)
• In combination with previously published in vivo data, the findings presented here suggest a model, in which R-loop processing by RNase H1 directs origin-specific initiation of DNA replication in human mitochondria. (PMID:30605451)
• The protein-protein interaction between P54nrb and RNase H1 requires the spacer region of RNAse H1, while the P54nrb core domains are required for association with RNase H1. (PMID:31495875)
• A non-coding RNASEH1 gene variant associates with type 1 diabetes and interacts with HLA tagSNPs in families from Colombia. (PMID:32447804)
• Progressive External Ophthalmoplegia in Polish Patients-From Clinical Evaluation to Genetic Confirmation. (PMID:33396418)
• BRCA2 deficiency reveals that oxidative stress impairs RNaseH1 function to cripple mitochondrial DNA maintenance. (PMID:34348152)
• A pan-cancer analysis of RNASEH1, a potential regulator of the tumor microenvironment. (PMID:37022517)
• RNase H1 facilitates recombinase recruitment by degrading DNA-RNA hybrids during meiosis. (PMID:37378420)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnaseh1	ENSDARG00000042571
mus_musculus	Rnaseh1	ENSMUSG00000020630
rattus_norvegicus	Rnaseh1	ENSRNOG00000008584
drosophila_melanogaster	rnh1	FBGN0023171
caenorhabditis_elegans		WBGENE00004382

Protein

Protein identifiers

Ribonuclease H1 — O60930 (reviewed: O60930)

Alternative names: Ribonuclease H type II

All UniProt accessions (4): O60930, E5KN15, F8WBP0, F8WD93

UniProt curated annotations — full annotation on UniProt →

Function. Endonuclease that specifically degrades the RNA of RNA-DNA hybrids. Plays a role in RNA polymerase II (RNAp II) transcription termination by degrading R-loop RNA-DNA hybrid formation at G-rich pause sites located downstream of the poly(A) site and behind the elongating RNAp II.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm.

Tissue specificity. Ubiquitous.

Disease relevance. Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 (PEOB2) [MIM:616479] A form of progressive external ophthalmoplegia, a mitochondrial myopathy characterized by progressive paralysis of the levator palpebrae, orbicularis oculi, and extraocular muscles. PEOB2 patients manifest exercise intolerance, muscle weakness, and signs and symptoms of spinocerebellar ataxia, such as impaired gait and dysarthria. Some patients may have respiratory insufficiency. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. In the presence of magnesium, manganese is inhibitory.

Cofactor. Binds 1 Mg(2+) ion per subunit. May bind a second metal ion at a regulatory site, or after substrate binding.

Similarity. Belongs to the RNase H family.

RefSeq proteins (6): NP_001273763, NP_001273766, NP_001365200, NP_001365201, NP_001365202, NP_002927* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002156	RNaseH_domain	Domain
IPR009027	Ribosomal_bL9/RNase_H1_N	Homologous_superfamily
IPR011320	RNase_H1_N	Domain
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR017067	RNase_H1_euk	Family
IPR036397	RNaseH_sf	Homologous_superfamily
IPR037056	RNase_H1_N_sf	Homologous_superfamily
IPR050092	RNase_H	Family

Pfam: PF00075, PF01693

Enzyme classification (BRENDA):

• EC 3.1.26.4 — ribonuclease H (BRENDA: 55 organisms, 293 substrates, 156 inhibitors, 81 Km, 43 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
RNA*DNA HYBRID	0.0001–0.0084	9
DNA-RNA-DNA HYBRID	0.0011–0.0078	7
RNA-DNA HETERODUPLEX	0.0001–0.2	7
RNA-DNA*DNA HYBRID	0.0001–0.0036	5
M13 DNA/RNA HYBRID	0.0004–0.0014	4
RNA-DNA HYBRID	0.0011–0.0028	4
D14R1D3:DNA18	—	3
M13 DNA-RNA HYBRID	0.071–0.26	3
POLY(RADT)	0.0005–0.0019	3
RNA18:DNA18	0.0001–0.0002	3
DNA-RNA HYBRID DUPLEX	—	2
M13 DNA/RNA	0.0005–0.0011	2
5’-(6-CARBOXY-FLUORESCEIN)-CGGAGAUGACGG-3’/5’-CC	0.0004	1
DNA-(1’,2’-METHYLENE-BRIDGED AZETIDINE-T)-ANTISE	0.0001	1
DNA-(2’-ALKOXY-1’,2’-METHYLENE-BRIDGED AZETIDINE	0.0002	1

UniProt features (37 total): strand 11, helix 7, sequence conflict 6, binding site 5, sequence variant 3, chain 1, domain 1, region of interest 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6VRD	X-RAY DIFFRACTION	1.3
8SWB	X-RAY DIFFRACTION	2
3BSU	X-RAY DIFFRACTION	2.1
2QKB	X-RAY DIFFRACTION	2.4
2QK9	X-RAY DIFFRACTION	2.55
8SWC	X-RAY DIFFRACTION	2.68
2QKK	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60930-F1	79.90	0.63

Functional residue map

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

Ligand- & substrate-binding residues (5): 145; 145; 186; 210; 274

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9913635	Strand-asynchronous mitochondrial DNA replication
R-HSA-69306	DNA Replication

MSigDB gene sets: 210 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, REACTOME_DNA_REPLICATION, ELVIDGE_HYPOXIA_DN, chr2p25, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, PUJANA_CHEK2_PCC_NETWORK, WEI_MYCN_TARGETS_WITH_E_BOX, GOMF_RNA_ENDONUCLEASE_ACTIVITY, DODD_NASOPHARYNGEAL_CARCINOMA_UP, MODULE_360

GO Biological Process (2): RNA catabolic process (GO:0006401), DNA replication, removal of RNA primer (GO:0043137)

GO Molecular Function (10): magnesium ion binding (GO:0000287), nucleic acid binding (GO:0003676), RNA binding (GO:0003723), RNA-DNA hybrid ribonuclease activity (GO:0004523), RNA nuclease activity (GO:0004540), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
DNA Replication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
nuclease activity	2
RNA metabolic process	1
nucleic acid catabolic process	1
DNA replication	1
RNA catabolic process	1
metal ion binding	1
nucleic acid binding	1
RNA endonuclease activity producing 5’-phosphomonoesters, hydrolytic mechanism	1
catalytic activity, acting on RNA	1
catalytic activity, acting on a nucleic acid	1
catalytic activity	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2505 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNASEH1	TWNK	Q96RR1	866
RNASEH1	SETX	Q7Z333	775
RNASEH1	POLRMT	O00411	699
RNASEH1	RNASEH2A	O75792	691
RNASEH1	POLG2	Q9UHN1	671
RNASEH1	PIF1	Q9H611	666
RNASEH1	TOP1	P11387	664
RNASEH1	DNA2	P51530	664
RNASEH1	RAD52	P43351	654
RNASEH1	MGME1	Q9BQP7	648
RNASEH1	SSBP1	Q04837	645
RNASEH1	FEN1	P39748	637
RNASEH1	DHX9	Q08211	580
RNASEH1	XRN2	Q9H0D6	577
RNASEH1	POLG	P54098	576

IntAct

68 interactions, top by confidence:

A	B	Type	Score
ORF4b	KPNA3	psi-mi:“MI:0914”(association)	0.620
TMEM11	RNASEH1	psi-mi:“MI:0915”(physical association)	0.560
EMD	RNASEH1	psi-mi:“MI:0915”(physical association)	0.560
RNASEH1	NRM	psi-mi:“MI:0915”(physical association)	0.560
RNASEH1	ASPH	psi-mi:“MI:0915”(physical association)	0.560
RNASEH1	TMEM11	psi-mi:“MI:0915”(physical association)	0.560
RNASEH1	EMD	psi-mi:“MI:0915”(physical association)	0.560
RNASEH1	FAM3C	psi-mi:“MI:0915”(physical association)	0.560
RNASEH1	NCS1	psi-mi:“MI:0915”(physical association)	0.560
CLEC3A	ZZEF1	psi-mi:“MI:0914”(association)	0.530
RNASEH1	LUC7L	psi-mi:“MI:0915”(physical association)	0.500
TM9SF1	RNASEH1	psi-mi:“MI:0915”(physical association)	0.370
FOXD4	EIF5B	psi-mi:“MI:0914”(association)	0.350
CLEC3A	ZNF593	psi-mi:“MI:0914”(association)	0.350
LUC7L	CASC3	psi-mi:“MI:0914”(association)	0.350
CHCHD10	TIMM44	psi-mi:“MI:0914”(association)	0.350
CHCHD10	RNASEH1	psi-mi:“MI:0914”(association)	0.350
CHCHD10	ACSL4	psi-mi:“MI:0914”(association)	0.350
CHCHD2	ACSL4	psi-mi:“MI:0914”(association)	0.350
CHCHD10	AKR7A2	psi-mi:“MI:0914”(association)	0.350
CHCHD2	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
SLX4IP	RNASEH1	psi-mi:“MI:0914”(association)	0.350
	DDX3Y	psi-mi:“MI:0914”(association)	0.350
SOX2	CBX4	psi-mi:“MI:0914”(association)	0.350
	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
	POLRMT	psi-mi:“MI:0914”(association)	0.350
	POLR3A	psi-mi:“MI:0914”(association)	0.350

BioGRID (54): RNASEH1 (Affinity Capture-MS), RNASEH1 (Affinity Capture-MS), RNASEH1 (Affinity Capture-MS), RNASEH1 (Affinity Capture-MS), RNASEH1 (Affinity Capture-MS), RNASEH1 (Affinity Capture-MS), RNASEH1 (Affinity Capture-RNA), RNASEH1 (Affinity Capture-MS), RNASEH1 (Two-hybrid), RNASEH1 (Two-hybrid), RNASEH1 (Two-hybrid), TMEM11 (Two-hybrid), FAM3C (Two-hybrid), ASPH (Two-hybrid), RNASEH1 (Two-hybrid)

ESM2 similar proteins: A1Z9L3, A4RKC3, A9SDL4, A9W185, B2RR83, B2ZFP3, B3M0F3, B5DXG8, B8AMS4, B8ARK7, C5WU23, O13830, O60930, O70157, O70338, O80983, P17569, P28866, P38935, P39864, P40694, P54789, P69859, Q04740, Q0R4F1, Q13472, Q13555, Q1HGK7, Q2VF18, Q5BK46, Q5ZI74, Q60560, Q6E0V2, Q754C9, Q75LI2, Q7S8J7, Q7SCC1, Q7SD49, Q7XWV4, Q7ZV90

Diamond homologs: A1Z651, O60930, O92815, O92956, P01114, P03330, P03331, P03332, P03333, P03334, P03336, P03337, P03338, P03339, P03340, P03341, P03342, P03354, P03355, P03356, P03358, P03359, P03360, P03975, P04026, P04322, P08361, P0DOG8, P0DOG9, P0DOH0, P0DOH1, P0DOH2, P0DOH3, P0DOH4, P0DOH5, P0DOH6, P0DP83, P10262, P10272, P10273

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	80
Likely benign	100
Benign	17

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
3720299	NM_002936.6(RNASEH1):c.442T>C (p.Cys148Arg)	Pathogenic
372199	NM_002936.6(RNASEH1):c.554C>T (p.Ala185Val)	Pathogenic
372198	NM_002936.6(RNASEH1):c.469C>T (p.Arg157Ter)	Likely pathogenic
4542529	NM_002936.6(RNASEH1):c.344del (p.Ala115fs)	Likely pathogenic
818008	NM_002936.6(RNASEH1):c.325dup (p.Glu109fs)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1888 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:3547933:A:G	W258R	0.999
2:3547933:A:T	W258R	0.999
2:3548017:A:G	W230R	0.998
2:3548017:A:T	W230R	0.998
2:3548032:A:G	W225R	0.998
2:3548032:A:T	W225R	0.998
2:3548656:A:C	S211R	0.998
2:3548656:A:T	S211R	0.998
2:3548658:T:G	S211R	0.998
2:3548659:G:C	D210E	0.998
2:3548659:G:T	D210E	0.998
2:3548660:T:A	D210V	0.998
2:3550457:A:T	V142D	0.998
2:3548030:C:A	W225C	0.997
2:3548030:C:G	W225C	0.997
2:3548055:C:T	G217D	0.997
2:3548650:A:C	F213L	0.997
2:3548650:A:T	F213L	0.997
2:3548652:A:G	F213L	0.997
2:3548660:T:G	D210A	0.997
2:3548700:C:G	A197P	0.997
2:3548661:C:G	D210H	0.996
2:3549076:G:C	N182K	0.996
2:3549076:G:T	N182K	0.996
2:3550392:A:G	W164R	0.996
2:3550392:A:T	W164R	0.996
2:3550447:A:C	D145E	0.996
2:3550447:A:T	D145E	0.996
2:3550448:T:A	D145V	0.996
2:3545816:G:T	A277D	0.995

dbSNP variants (sampled 300 via entrez): RS1000218290 (2:3528211 T>G), RS1000270492 (2:3528357 C>G,T), RS1000334429 (2:3537934 G>A), RS1000342864 (2:3558335 C>T), RS1000386726 (2:3538214 G>C), RS1000502992 (2:3558276 C>A), RS1000555172 (2:3558057 G>A,T), RS1000616527 (2:3533664 A>G), RS1000648049 (2:3523542 A>G), RS1000656907 (2:3528493 G>C), RS1000730177 (2:3534722 T>C), RS1000739279 (2:3553152 G>A), RS1000767091 (2:3523183 C>T), RS1000785562 (2:3558342 G>A), RS1000797451 (2:3558213 C>A,G,T)

Disease associations

OMIM: gene MIM:604123 | disease phenotypes: MIM:616479

GenCC curated gene-disease

Disease	Classification	Inheritance
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2	Strong	Autosomal recessive
adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR

Mondo (2): progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 (MONDO:0014656), adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy (MONDO:0018002)

Orphanet (1): Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy (Orphanet:329336)

HPO phenotypes

69 total (30 of 69 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000365	Hearing impairment
HP:0000508	Ptosis
HP:0000565	Esotropia
HP:0000580	Pigmentary retinopathy
HP:0000590	Progressive external ophthalmoplegia
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001310	Dysmetria
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001488	Bilateral ptosis
HP:0001618	Dysphonia
HP:0001638	Cardiomyopathy
HP:0002015	Dysphagia
HP:0002076	Migraine
HP:0002093	Respiratory insufficiency
HP:0002120	Cerebral cortical atrophy
HP:0002136	Broad-based gait
HP:0002141	Gait imbalance
HP:0002151	Increased circulating lactate concentration
HP:0002169	Clonus
HP:0002172	Postural instability

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5893 (SINGLE PROTEIN)

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

ChEMBL bioactivities

9 potent at pChembl≥5 of 16 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.92	IC50	120	nM	CHEMBL16755
6.77	IC50	170	nM	CHEMBL562080
6.22	IC50	600	nM	BETA-THUJAPLICINOL
6.05	IC50	900	nM	CHEMBL572124
5.92	IC50	1200	nM	CHEMBL551212
5.68	IC50	2100	nM	CHEMBL204900
5.23	IC50	5900	nM	CHEMBL183852
5.19	IC50	6500	nM	CHEMBL557770
5.02	IC50	9600	nM	CHEMBL561881

PubChem BioAssay actives

9 with measured affinity, of 26 total; 9 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-hydroxy-4H-isoquinoline-1,3-dione	431467: Inhibition of human RNase H assessed as substrate cleavage by fluorescence assay	ic50	0.1200	uM
2-[(2-bromo-5-chloro-1-benzothiophen-3-yl)methyl]-5-hydroxy-6-oxo-1H-pyrimidine-4-carboxylic acid	431467: Inhibition of human RNase H assessed as substrate cleavage by fluorescence assay	ic50	0.1700	uM
2,3-dihydroxy-6-propan-2-ylcyclohepta-2,4,6-trien-1-one	431467: Inhibition of human RNase H assessed as substrate cleavage by fluorescence assay	ic50	0.6000	uM
2-[(3-bromo-4-methoxyphenyl)methyl]-5-hydroxy-6-oxo-1H-pyrimidine-4-carboxylic acid	431467: Inhibition of human RNase H assessed as substrate cleavage by fluorescence assay	ic50	0.9000	uM
2-[(3,4-dichlorophenyl)methyl]-5-hydroxy-6-oxo-1H-pyrimidine-4-carboxylic acid	431467: Inhibition of human RNase H assessed as substrate cleavage by fluorescence assay	ic50	1.2000	uM
2-benzyl-5-hydroxy-6-oxo-1H-pyrimidine-4-carboxylic acid	431467: Inhibition of human RNase H assessed as substrate cleavage by fluorescence assay	ic50	2.1000	uM
3-hydroxy-1H-quinazoline-2,4-dione	431467: Inhibition of human RNase H assessed as substrate cleavage by fluorescence assay	ic50	5.9000	uM
4-(5-benzamidothiophen-2-yl)-2,4-dioxobutanoic acid	431467: Inhibition of human RNase H assessed as substrate cleavage by fluorescence assay	ic50	6.5000	uM
5-hydroxy-6-oxo-2-(2-phenylethyl)-1H-pyrimidine-4-carboxylic acid	431467: Inhibition of human RNase H assessed as substrate cleavage by fluorescence assay	ic50	9.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
testosterone undecanoate	decreases expression	1
cobaltous chloride	decreases expression	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
AM 251	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
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Benzo(a)pyrene	increases expression	1
Caffeine	decreases phosphorylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Diethylstilbestrol	decreases expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Mercury	decreases expression	1
Piroxicam	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Polychlorinated Biphenyls	increases expression	1
Selenium	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1058996	Binding	Inhibition of human RNase H assessed as substrate cleavage by fluorescence assay	RNase H active site inhibitors of human immunodeficiency virus type 1 reverse transcriptase: design, biochemical activity, and structural information. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9QN	Ubigene HEK293 RNASEH1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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