progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2

Summary

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 (MONDO:0014656) is a disease caused by RNASEH1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: RNASEH1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2
Mondo ID	MONDO:0014656
OMIM	616479
DOID	DOID:0111515
UMLS	C4225312
MedGen	901897
GARD	0018450
Is cancer (heuristic)	no

Also known as: PEOB2 · progressive external ophthalmoplegia with mitochondrial DNA deletions caused by mutation in RNASEH1 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive type 2 · RNASEH1 progressive external ophthalmoplegia with mitochondrial DNA deletions

Data availability: 8 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › progressive external ophthalmoplegia › progressive external ophthalmoplegia with mitochondrial DNA deletions › progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2

Related subtypes (7): autosomal dominant progressive external ophthalmoplegia, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1, mitochondrial DNA deletion syndrome with progressive myopathy, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5, progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

8 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
372197	NM_002936.6(RNASEH1):c.424G>A (p.Val142Ile)	RNASEH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372199	NM_002936.6(RNASEH1):c.554C>T (p.Ala185Val)	RNASEH1	Pathogenic	no assertion criteria provided
372198	NM_002936.6(RNASEH1):c.469C>T (p.Arg157Ter)	RNASEH1	Likely pathogenic	criteria provided, single submitter
2627453	NM_002936.6(RNASEH1):c.526C>T (p.Leu176Phe)	RNASEH1	Uncertain significance	criteria provided, single submitter
3341086	NM_002936.6(RNASEH1):c.532G>A (p.Gly178Arg)	RNASEH1	Uncertain significance	criteria provided, single submitter
3896969	NM_002936.6(RNASEH1):c.137G>A (p.Cys46Tyr)	RNASEH1	Uncertain significance	criteria provided, single submitter
683672	NM_002936.6(RNASEH1):c.409+34C>A	RNASEH1	Benign	criteria provided, multiple submitters, no conflicts
683674	NM_002936.6(RNASEH1):c.498A>G (p.Pro166=)	RNASEH1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RNASEH1	Strong	Autosomal recessive	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2	3
RNASEH1P1	Strong	Autosomal recessive	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNASEH1	Orphanet:329336	Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNASEH1P1	HGNC:10049	ENSG00000265790		ribonuclease H1 pseudogene 1	gencc,clinvar
RNASEH1	HGNC:18466	ENSG00000171865	O60930	Ribonuclease H1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNASEH1	Ribonuclease H1	Endonuclease that specifically degrades the RNA of RNA-DNA hybrids.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNASEH1P1	Other/Unknown	no
RNASEH1	Enzyme (other)	yes	3.1.26.4	RNaseH_domain, Ribosomal_bL9/RNase_H1_N, RNase_H1_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
testis	1
endothelial cell	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNASEH1P1	29	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, testis
RNASEH1	271	ubiquitous	marker	secondary oocyte, oocyte, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RNASEH1	2,627
RNASEH1P1	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RNASEH1	O60930	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	1	1142.0×	0.002	RNASEH1
DNA Replication	1	237.9×	0.004	RNASEH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA replication, removal of RNA primer	1	4213.0×	5e-04	RNASEH1
RNA catabolic process	1	455.5×	0.002	RNASEH1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RNASEH1P1	0	0
RNASEH1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RNASEH1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNASEH1	3.1.26.4	ribonuclease H

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	RNASEH1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RNASEH1P1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RNASEH1P1	0	—
RNASEH1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.