progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

Summary

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (MONDO:0009783) is a disease caused by POLG (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: POLG (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 208

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 1
Mondo ID	MONDO:0009783
OMIM	258450
DOID	DOID:0111522
UMLS	C4225153
MedGen	897191
GARD	0015215
Is cancer (heuristic)	no

Also known as: arPEO · autosomal recessive progressive external ophthalmoplegia · autosomal recessive progressive external ophthalmoplegia caused by mutation in POLG · cerebellar ataxia infantile with progressive external ophthalmoplegia · PEOB1 · POLG autosomal recessive progressive external ophthalmoplegia · progressive external ophthalmoplegia with cerebellar ataxia infantile · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive type 1

Data availability: 208 ClinVar variants · 1 GenCC gene-disease record.

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 1

Related subtypes (7): autosomal dominant progressive external ophthalmoplegia, mitochondrial DNA deletion syndrome with progressive myopathy, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2, 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

208 retrieved; paginated sample, class counts are floors:

67 uncertain significance, 48 conflicting classifications of pathogenicity, 33 pathogenic/likely pathogenic, 23 likely pathogenic, 18 pathogenic, 11 benign/likely benign, 5 benign, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1163576	NM_002693.3(POLG):c.3104+2_3104+5del	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339608	NM_002693.3(POLG):c.660-2A>G	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341586	NM_002693.3(POLG):c.3601del (p.Ser1201fs)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13496	NM_002693.3(POLG):c.1399G>A (p.Ala467Thr)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13497	NM_002693.3(POLG):c.911T>G (p.Leu304Arg)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13498	NM_002693.3(POLG):c.8G>C (p.Arg3Pro)	POLG	Pathogenic	no assertion criteria provided
13499	NM_002693.3(POLG):c.1879C>T (p.Arg627Trp)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13500	NM_002693.3(POLG):c.2794C>T (p.His932Tyr)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13501	NM_002693.3(POLG):c.3151G>C (p.Gly1051Arg)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13502	NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13506	NM_002693.3(POLG):c.2591A>G (p.Asn864Ser)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13507	NM_002693.3(POLG):c.2243G>C (p.Trp748Ser)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13513	NM_002693.3(POLG):c.2209G>C (p.Gly737Arg)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13515	NM_002693.3(POLG):c.679C>T (p.Arg227Trp)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453904	NM_002693.3(POLG):c.3482+2T>C	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455434	NM_002693.3(POLG):c.1457G>A (p.Trp486Ter)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
1458421	NM_002693.3(POLG):c.1575_1578del (p.Met525fs)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1961036	NM_002693.3(POLG):c.178C>T (p.Gln60Ter)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206523	NM_002693.3(POLG):c.2420G>A (p.Arg807His)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206528	NM_002693.3(POLG):c.2554C>T (p.Arg852Cys)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
206588	NM_002693.3(POLG):c.915C>G (p.Ser305Arg)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206600	NM_002693.3(POLG):c.1716G>A (p.Trp572Ter)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206606	NM_002693.3(POLG):c.1943C>G (p.Pro648Arg)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677947	NM_002693.3(POLG):c.3643+1G>A	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677952	NM_002693.3(POLG):c.3626_3629dup (p.Tyr1210Ter)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677961	NM_002693.3(POLG):c.1356T>G (p.Tyr452Ter)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
279948	NM_002693.3(POLG):c.3014_3057del (p.Val1005fs)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279961	NM_002693.3(POLG):c.2740A>C (p.Thr914Pro)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279982	NM_002693.3(POLG):c.2419C>T (p.Arg807Cys)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
280017	NM_002693.3(POLG):c.1433+1G>A	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 9 · 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
POLG	Definitive	Autosomal dominant	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLG	Orphanet:254881	Spinocerebellar ataxia with epilepsy
POLG	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
POLG	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
POLG	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
POLG	Orphanet:402082	Progressive myoclonic epilepsy type 5
POLG	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
POLG	Orphanet:726	Alpers-Huttenlocher syndrome
POLG	Orphanet:94125	Recessive mitochondrial ataxia syndrome
FANCI	Orphanet:84	Fanconi anemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	gencc,clinvar
FANCI	HGNC:25568	ENSG00000140525	Q9NVI1	Fanconi anemia group I protein	clinvar
POLGARF	HGNC:56246	ENSG00000291307	A0A3B3IS91	POLG alternative reading frame	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).
FANCI	Fanconi anemia group I protein	Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA r…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf
FANCI	Other/Unknown	no		FANCI, FANCI_S1-cap, FANCI_S1
POLGARF	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

2 cohort genes 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	1

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
small intestine Peyer’s patch	1
tibial nerve	1
male germ line stem cell (sensu Vertebrata) in testis	1
secondary oocyte	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve
FANCI	221	ubiquitous	marker	ventricular zone, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
POLGARF

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLG	3,400
FANCI	2,312
POLGARF	0

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG	P54098	36
FANCI	Q9NVI1	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
POLGARF	A0A3B3IS91	40.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 evidence-associated genes (2 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 2 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	571.0×	0.005	POLG
Fanconi Anemia Pathway	1	139.3×	0.011	FANCI
TP53 Regulates Transcription of DNA Repair Genes	1	90.6×	0.011	FANCI

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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 proofreading	1	2808.7×	0.003	POLG
mitochondrial DNA replication	1	766.0×	0.004	POLG
base-excision repair, gap-filling	1	561.7×	0.004	POLG
DNA metabolic process	1	526.6×	0.004	POLG
DNA-templated DNA replication	1	280.9×	0.005	POLG
base-excision repair	1	234.1×	0.005	POLG
interstrand cross-link repair	1	216.1×	0.005	FANCI
positive regulation of protein ubiquitination	1	106.7×	0.009	FANCI

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLG	1	4
FANCI	0	0
POLGARF	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADEFOVIR DIPIVOXIL	4	POLG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
POLG	33	Binding:30, ADMET:2, Functional:1
FANCI	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
ADEFOVIR DIPIVOXIL	4	POLG

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	POLG
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FANCI, POLGARF

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)
FANCI	1	—
POLGARF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.