progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4

Summary

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (MONDO:0012415) is a disease caused by POLG2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: POLG2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 45

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 dominant 4
Mondo ID	MONDO:0012415
MeSH	C566437
OMIM	610131
DOID	DOID:0111525
UMLS	C1864668
MedGen	350480
GARD	0016500
Is cancer (heuristic)	no

Also known as: PEOA4 · POLG2 progressive external ophthalmoplegia with mitochondrial DNA deletions · progressive external ophthalmoplegia with mitochondrial DNA deletions caused by mutation in POLG2 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant type 4

Data availability: 45 ClinVar variants · 3 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 › autosomal dominant progressive external ophthalmoplegia › progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4

Related subtypes (4): progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

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

45 retrieved; paginated sample, class counts are floors:

18 uncertain significance, 9 conflicting classifications of pathogenicity, 7 benign, 4 benign/likely benign, 4 likely pathogenic, 3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
40247	NM_007215.4(POLG2):c.614C>G (p.Pro205Arg)	MILR1	Pathogenic	no assertion criteria provided
40249	NM_007215.4(POLG2):c.1423_1424del (p.Leu475fs)	MILR1	Pathogenic	no assertion criteria provided
3375474	NM_007215.4(POLG2):c.729_730del (p.Pro244fs)	POLG2	Pathogenic	criteria provided, single submitter
3367103	NM_007215.4(POLG2):c.1110+2T>A	MILR1	Likely pathogenic	criteria provided, single submitter
3767175	NM_007215.4(POLG2):c.416del (p.Leu139fs)	MILR1	Likely pathogenic	criteria provided, single submitter
3780477	NM_007215.4(POLG2):c.1192-1G>A	MILR1	Likely pathogenic	criteria provided, single submitter
5276	NM_007215.4(POLG2):c.1352G>A (p.Gly451Glu)	MILR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342575	NM_007215.4(POLG2):c.775C>T (p.Arg259Ter)	MILR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1895400	NM_007215.4(POLG2):c.1030C>T (p.Arg344Ter)	MILR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215022	NM_007215.4(POLG2):c.181G>A (p.Gly61Arg)	MILR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215028	NM_007215.4(POLG2):c.703A>G (p.Thr235Ala)	MILR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
324559	NM_007215.4(POLG2):c.674G>A (p.Arg225Gln)	MILR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
324560	NM_007215.4(POLG2):c.496C>G (p.Gln166Glu)	MILR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215019	NM_007215.4(POLG2):c.1417G>A (p.Asp473Asn)	POLG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
252958	NM_007215.4(POLG2):c.544C>T (p.Arg182Trp)	POLG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
384209	NM_007215.4(POLG2):c.562+11C>T	POLG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1913139	NM_007215.4(POLG2):c.770G>A (p.Arg257His)	MILR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
215027	NM_007215.4(POLG2):c.1444G>T (p.Ala482Ser)	MILR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
215030	NM_007215.4(POLG2):c.734C>T (p.Pro245Leu)	MILR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2664901	NM_007215.4(POLG2):c.1060T>C (p.Phe354Leu)	MILR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065651	NM_007215.4(POLG2):c.1189C>T (p.Gln397Ter)	MILR1	Uncertain significance	criteria provided, single submitter
324561	NM_007215.4(POLG2):c.358G>A (p.Val120Met)	MILR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
324563	NM_007215.4(POLG2):c.-66C>T	MILR1	Uncertain significance	criteria provided, single submitter
324565	NM_007215.4(POLG2):c.-85C>T	MILR1	Uncertain significance	criteria provided, single submitter
889721	NM_007215.4(POLG2):c.970-4G>A	MILR1	Uncertain significance	criteria provided, single submitter
891271	NM_007215.4(POLG2):c.381G>A (p.Pro127=)	MILR1	Uncertain significance	criteria provided, single submitter
1027735	NM_007215.4(POLG2):c.743C>T (p.Ser248Leu)	POLG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033197	NM_007215.4(POLG2):c.749A>G (p.Gln250Arg)	POLG2	Uncertain significance	criteria provided, single submitter
1333959	NM_007215.4(POLG2):c.367G>A (p.Glu123Lys)	POLG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1434611	NM_007215.4(POLG2):c.562G>C (p.Gly188Arg)	POLG2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
POLG2	Strong	Autosomal dominant	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLG2	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POLG2	HGNC:9180	ENSG00000256525	Q9UHN1	DNA polymerase subunit gamma-2	gencc,clinvar
MILR1	HGNC:27570	ENSG00000271605	Q7Z6M3	Allergin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLG2	DNA polymerase subunit gamma-2	Accessory subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).
MILR1	Allergin-1	Immunoglobulin-like receptor which plays an inhibitory role in degranulation of mast cells.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	14.6×	0.135
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLG2	Enzyme (other)	yes	2.7.7.7	Anticodon-bd, Gly-tRNA_synthase/POLG2, Anticodon-bd_dom_sf
MILR1	Antibody/Immunoglobulin	yes		Ig-like_fold, Ig-like_dom_sf, IL-40-like_Ig

Expression context

Cohort genes with no expression data: 0.

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	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
oocyte	1
secondary oocyte	1
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLG2	249	ubiquitous	marker	secondary oocyte, oocyte, left testis
MILR1	189	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLG2	1,557
MILR1	769

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG2	Q9UHN1	38

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MILR1	Q7Z6M3	74.55

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	POLG2
Transcriptional activation of mitochondrial biogenesis	1	203.9×	0.005	POLG2

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
negative regulation of mast cell activation	1	1685.2×	0.004	MILR1
positive regulation of DNA-directed DNA polymerase activity	1	1053.2×	0.004	POLG2
mitochondrial DNA replication	1	766.0×	0.004	POLG2
mast cell degranulation	1	312.1×	0.006	MILR1
DNA-templated DNA replication	1	280.9×	0.006	POLG2
mitochondrion organization	1	75.9×	0.020	POLG2
in utero embryonic development	1	36.0×	0.035	POLG2
cell surface receptor signaling pathway	1	32.0×	0.035	MILR1
immune response	1	23.5×	0.042	MILR1

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
POLG2	0	0
MILR1	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
POLG2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLG2	2.7.7.7	DNA-directed DNA polymerase

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	POLG2
D	Druggable family + AlphaFold only, no drug	1	MILR1
E	Difficult family or no structure, no drug	0

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)
POLG2	1	—
MILR1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.