POLG2

Summary

POLG2 (DNA polymerase gamma 2, accessory subunit, HGNC:9180) is a protein-coding gene on chromosome 17q23.3, encoding DNA polymerase subunit gamma-2 (Q9UHN1). Accessory subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA). It is a selective cancer dependency (DepMap: 39.2% of cell lines).

This gene encodes the processivity subunit of the mitochondrial DNA polymerase gamma. The encoded protein forms a heterotrimer containing one catalytic subunit and two processivity subunits. This protein enhances DNA binding and promotes processive DNA synthesis. Mutations in this gene result in autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions.

Source: NCBI Gene 11232 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 80 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 121
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 39.2% of screened cell lines
• MANE Select transcript: NM_007215

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9180
Approved symbol	POLG2
Name	DNA polymerase gamma 2, accessory subunit
Location	17q23.3
Locus type	gene with protein product
Status	Approved
Aliases	MTPOLB, HP55
Ensembl gene	ENSG00000256525
Ensembl biotype	protein_coding
OMIM	604983
Entrez	11232

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 6 protein_coding, 6 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000539111, ENST00000577506, ENST00000578687, ENST00000578997, ENST00000580490, ENST00000580893, ENST00000581355, ENST00000582501, ENST00000585104, ENST00000585141, ENST00000671755, ENST00000673460, ENST00000910209, ENST00000910210, ENST00000913014, ENST00000913015

RefSeq mRNA: 1 — MANE Select: NM_007215 NM_007215

CCDS: CCDS32706

Canonical transcript exons

ENST00000539111 — 8 exons

Exon	Start	End
ENSE00002476486	64496407	64497054
ENSE00002724226	64477785	64477988
ENSE00003514605	64482919	64482999
ENSE00003547192	64492667	64492772
ENSE00003583025	64485728	64485868
ENSE00003632395	64490796	64490969
ENSE00003641652	64492895	64493021
ENSE00003675516	64480289	64480389

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 95.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8835 / max 197.0913, expressed in 1707 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167568	9.8835	1707

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	95.53	gold quality
oocyte	CL:0000023	94.72	gold quality
left testis	UBERON:0004533	91.38	gold quality
right testis	UBERON:0004534	91.21	gold quality
olfactory bulb	UBERON:0002264	90.87	gold quality
type B pancreatic cell	CL:0000169	90.55	gold quality
testis	UBERON:0000473	89.63	gold quality
left ovary	UBERON:0002119	89.42	gold quality
right ovary	UBERON:0002118	89.24	gold quality
right uterine tube	UBERON:0001302	88.88	gold quality
granulocyte	CL:0000094	88.63	gold quality
monocyte	CL:0000576	88.54	gold quality
lymph node	UBERON:0000029	88.19	gold quality
mononuclear cell	CL:0000842	88.15	gold quality
spleen	UBERON:0002106	87.83	gold quality
leukocyte	CL:0000738	87.72	gold quality
body of pancreas	UBERON:0001150	87.52	gold quality
endocervix	UBERON:0000458	87.11	gold quality
body of uterus	UBERON:0009853	87.02	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.01	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.87	gold quality
male germ cell	CL:0000015	86.80	gold quality
right lobe of thyroid gland	UBERON:0001119	86.66	gold quality
cervix squamous epithelium	UBERON:0006922	86.59	gold quality
left lobe of thyroid gland	UBERON:0001120	86.54	gold quality
ventricular zone	UBERON:0003053	86.50	gold quality
ovary	UBERON:0000992	86.47	gold quality
tibial nerve	UBERON:0001323	86.41	gold quality
sperm	CL:0000019	86.15	gold quality
thyroid gland	UBERON:0002046	86.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.37

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 39.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 15)

• PolB gamma can bind double-stranded DNA and may play a role in DNA replication or repair (PMID:12379656)
• Study represents the first structure-function analysis of the thumb subdomain in pol gamma and examines the consequences of mitochondrial disease mutations in this region. (PMID:19478085)
• Both increased and decreased expression of POLGbeta altered nucleoid structure and precipitated a marked decrease in 7S DNA molecules, which form short displacement-loops on mitochondrial DNA. (PMID:19625489)
• human pol gammaB exhibits a catalytic subunit- and substrate DNA-dependent dimerization. (PMID:19858216)
• The biochemical analysis helps explain the pathogenesis of POLG2 mutations in mitochondrial disease. (PMID:21555342)
• Data show that rs17650301 in POLG2 is a good candidate marker for UBC invasiveness in Japanese males. (PMID:21734712)
• The authors describe the molecular characterization of a potential dominant POLG2 mutation (p.R369G) in a patient with autosomal dominant progressive external ophthalmoplegia and multiple mtDNA deletions. (PMID:22155748)
• Mitochondrial DNA (mtDNA) content plays an important role in energy production and sustaining normal physiological function. (PMID:24524965)
• 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)
• This is the first report of a patient with a homozygous mutation in POLG2 and with a clinical presentation of severe hepatic failure and mitochondrial depletion. (PMID:27592148)
• Compared to control fibroblasts, homozygous R182W p55 primary dermal fibroblasts exhibit a two-fold slower doubling time, reduced mtDNA copy number and reduced levels of POLG and POLG2 transcripts correlating with the reported disease state. Expression of R182W p55 in HEK293 cells impairs oxidative-phosphorylation. Biochemically, R182W p55 displays DNA binding and association with p140 similar to WT p55. (PMID:30157269)
• The accessory subunit of human DNA polymerase gamma is required for mitochondrial DNA maintenance and is able to stabilize the catalytic subunit. (PMID:32470614)
• Consequences of compromised mitochondrial genome integrity. (PMID:33087282)
• POLG2-Linked Mitochondrial Disease: Functional Insights from New Mutation Carriers and Review of the Literature. (PMID:37085601)
• Structure-specific roles for PolG2-DNA complexes in maintenance and replication of mitochondrial DNA. (PMID:37592734)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	polg2	ENSDARG00000074933
mus_musculus	Polg2	ENSMUSG00000020718
rattus_norvegicus	Polg2	ENSRNOG00000013728
drosophila_melanogaster	PolG2	FBGN0004407

Paralogs (1): GARS1 (ENSG00000106105)

Protein

Protein identifiers

DNA polymerase subunit gamma-2 — Q9UHN1 (reviewed: Q9UHN1)

Alternative names: DNA polymerase gamma accessory 55 kDa subunit, Mitochondrial DNA polymerase accessory subunit, MtPolB, PolG-beta

All UniProt accessions (6): A0A5F9ZH93, A0A5F9ZHX9, E5KS15, Q9UHN1, J3KRM2, J3QRU9

UniProt curated annotations — full annotation on UniProt →

Function. Accessory subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA). Acts as an allosteric regulator of the holoenzyme activities. Enhances the polymerase activity and the processivity of POLG by increasing its interactions with the DNA template. Suppresses POLG exonucleolytic proofreading especially toward homopolymeric templates bearing mismatched termini. Binds to single-stranded DNA.

Subunit / interactions. Heterotrimer composed of a catalytic subunit and a homodimer of accessory subunits (POLG:POLG2).

Subcellular location. Mitochondrion. Mitochondrion matrix. Mitochondrion nucleoid.

Disease relevance. Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 4 (PEOA4) [MIM:610131] A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial DNA depletion syndrome 16, hepatic type (MTDPS16) [MIM:618528] An autosomal recessive disorder characterized by poor feeding, difficulty breathing, abdominal distention, an abnormal carnitine profile, metabolic acidosis and hepatic failure in the neonatal period. Severe mtDNA depletion is observed in liver and muscle biopsies. The disease may be caused by variants affecting the gene represented in this entry. Mitochondrial DNA depletion syndrome 16B, neuroophthalmic type (MTDPS16B) [MIM:619425] An autosomal recessive disorder characterized by childhood onset of progressive neuroophthalmic manifestations with optic atrophy, mixed polyneuropathy, spinal and cerebellar ataxia, and generalized chorea associated with mtDNA depletion. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_009146* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004154	Anticodon-bd	Domain
IPR027031	Gly-tRNA_synthase/POLG2	Family
IPR036621	Anticodon-bd_dom_sf	Homologous_superfamily
IPR042064	POLG2_C	Domain
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily

Pfam: PF03129

Enzyme classification (BRENDA):

• EC 2.7.7.7 — DNA-directed DNA polymerase (BRENDA: 139 organisms, 372 substrates, 325 inhibitors, 281 Km, 239 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
DATP	0.0003–3.2	52
DCTP	0.0001–2.5	46
DTTP	0.0003–47.4	46
DGTP	0.0002–2.5	29
DEOXYNUCLEOSIDE TRIPHOSPHATE	0.0012–0.64	12
DNAN	—	7
7-DEAZA-2’-DEOXYADENOSINE 5’-TRIPHOSPHATE	0.0011–0.344	5
N1-METHYL-2’-DEOXYADENOSINE 5’-TRIPHOSPHATE	0.223–0.403	5
2-AMINOPURINE-2’-DEOXY-D-RIBOSE 5’-TRIPHOSPHATE	0.006–0.0144	2
2-THIO-DCTP	0.067–0.98	2
5-METHYL-DCTP	0.013–1.22	2
DAMP:DG	1.153–1.42	2
DCMP:DG	—	2
DGMP:DG	0.263–0.3511	2
DTMP:DG	1.26–1.43	2

UniProt features (66 total): strand 24, helix 23, turn 5, sequence variant 5, sequence conflict 4, transit peptide 1, chain 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

38 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8UDL	ELECTRON MICROSCOPY	2.37
9GGC	ELECTRON MICROSCOPY	2.39
8D33	ELECTRON MICROSCOPY	2.46
9IBX	ELECTRON MICROSCOPY	2.54
8G5M	ELECTRON MICROSCOPY	2.58
8G5O	ELECTRON MICROSCOPY	2.61
9Y4F	ELECTRON MICROSCOPY	2.62
8G5J	ELECTRON MICROSCOPY	2.63
9GGB	ELECTRON MICROSCOPY	2.63
8D37	ELECTRON MICROSCOPY	2.65
9GGF	ELECTRON MICROSCOPY	2.65
9GGD	ELECTRON MICROSCOPY	2.67
9GGE	ELECTRON MICROSCOPY	2.69
8G5N	ELECTRON MICROSCOPY	2.73
8G5I	ELECTRON MICROSCOPY	2.75
8G5P	ELECTRON MICROSCOPY	2.78
8G5K	ELECTRON MICROSCOPY	2.9
8D42	ELECTRON MICROSCOPY	2.91
9Y4D	ELECTRON MICROSCOPY	2.94
8G5L	ELECTRON MICROSCOPY	3
8V5R	ELECTRON MICROSCOPY	3
8D3R	ELECTRON MICROSCOPY	3.04
9Y4E	ELECTRON MICROSCOPY	3.05
8T7E	ELECTRON MICROSCOPY	3.08
9IBZ	ELECTRON MICROSCOPY	3.08
3IKL	X-RAY DIFFRACTION	3.1
2G4C	X-RAY DIFFRACTION	3.15
9Y4C	ELECTRON MICROSCOPY	3.23
3IKM	X-RAY DIFFRACTION	3.24
9IC0	ELECTRON MICROSCOPY	3.24

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHN1-F1	81.73	0.56

Functional residue map

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

Post-translational modifications (1): 38

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-9913635	Strand-asynchronous mitochondrial DNA replication

MSigDB gene sets: 400 (showing top): BROWNE_HCMV_INFECTION_4HR_UP, REACTOME_DNA_REPLICATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, YAATNRNNNYNATT_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_DNA_BIOSYNTHETIC_PROCESS, GOBP_MITOCHONDRIAL_DNA_METABOLIC_PROCESS, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, RACCACAR_AML_Q6, KAUFFMANN_DNA_REPAIR_GENES, GGGTGGRR_PAX4_03, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, MUELLER_PLURINET, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, AML_Q6

GO Biological Process (8): in utero embryonic development (GO:0001701), DNA-templated DNA replication (GO:0006261), mitochondrial DNA replication (GO:0006264), mitochondrion organization (GO:0007005), positive regulation of DNA-directed DNA polymerase activity (GO:1900264), DNA replication (GO:0006260), mitochondrial DNA metabolic process (GO:0032042), DNA biosynthetic process (GO:0071897)

GO Molecular Function (7): double-stranded DNA binding (GO:0003690), DNA-directed DNA polymerase activity (GO:0003887), DNA polymerase processivity factor activity (GO:0030337), identical protein binding (GO:0042802), DNA polymerase binding (GO:0070182), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), gamma DNA polymerase complex (GO:0005760), mitochondrial nucleoid (GO:0042645)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Mitochondrial biogenesis	1
DNA Replication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	4
DNA metabolic process	3
DNA polymerase activity	2
mitochondrial matrix	2
chordate embryonic development	1
DNA replication	1
DNA-templated DNA replication	1
mitochondrial DNA metabolic process	1
organelle organization	1
DNA-directed DNA polymerase activity	1
positive regulation of catalytic activity	1
regulation of transferase activity	1
positive regulation of DNA biosynthetic process	1
DNA biosynthetic process	1
nucleic acid biosynthetic process	1
DNA binding	1
enzyme activator activity	1
protein binding	1
enzyme binding	1
nucleic acid binding	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
DNA polymerase complex	1
mitochondrial protein-containing complex	1
nucleoid	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1467 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLG2	POLG	P54098	997
POLG2	RRM2B	Q7LG56	930
POLG2	TWNK	Q96RR1	916
POLG2	SLC25A4	P12235	911
POLG2	GARS1	P41250	824
POLG2	EPRS1	P07814	799
POLG2	MGME1	Q9BQP7	791
POLG2	DGUOK	P78532	788
POLG2	POLRMT	O00411	759
POLG2	SSBP1	Q04837	756
POLG2	TFAM	Q00059	696
POLG2	MPV17	P39210	678
POLG2	RNASEH1	O60930	671
POLG2	SUCLA2	Q9P2R7	628
POLG2	TFB2M	Q9H5Q4	616

IntAct

40 interactions, top by confidence:

A	B	Type	Score
POLG2	POLG	psi-mi:“MI:0407”(direct interaction)	0.950
POLG	POLG2	psi-mi:“MI:0407”(direct interaction)	0.950
POLG2	POLG	psi-mi:“MI:0914”(association)	0.950
POLG	POLG2	psi-mi:“MI:0915”(physical association)	0.950
POLG2	POLG	psi-mi:“MI:0915”(physical association)	0.950
IFIT2	IFIT3	psi-mi:“MI:0914”(association)	0.780
POLG2	GLDC	psi-mi:“MI:0914”(association)	0.530
ASCC1	TRIP4	psi-mi:“MI:0914”(association)	0.530
TAF1A	TAF1C	psi-mi:“MI:0914”(association)	0.530
POLG2	POLG2	psi-mi:“MI:0407”(direct interaction)	0.440
POLG2	RPS3	psi-mi:“MI:0914”(association)	0.350
SEC22C	ACADS	psi-mi:“MI:0914”(association)	0.350
GRHL1	POLRMT	psi-mi:“MI:0914”(association)	0.350
	POLRMT	psi-mi:“MI:0914”(association)	0.350
	POLR3A	psi-mi:“MI:0914”(association)	0.350
	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
LIAS	CTSV	psi-mi:“MI:0914”(association)	0.350

BioGRID (50): POLG2 (Affinity Capture-MS), POLG (Affinity Capture-MS), RPS3 (Affinity Capture-MS), STXBP1 (Affinity Capture-MS), CCDC6 (Affinity Capture-MS), AP4E1 (Affinity Capture-MS), WRAP53 (Affinity Capture-MS), OSBPL1A (Affinity Capture-MS), POLG (Affinity Capture-MS), ALDH6A1 (Affinity Capture-MS), ADNP (Affinity Capture-MS), POLG2 (Affinity Capture-MS), HOMER3 (Affinity Capture-MS), GLDC (Affinity Capture-MS), POLG2 (Affinity Capture-MS)

ESM2 similar proteins: A0JML8, A0JP70, A2BID5, A2CEI4, A6NNW6, A9JTS5, E7FAW3, F1QNV4, O75153, O75800, O95248, P0CI65, P56192, P97874, Q08CY4, Q0VC30, Q14689, Q17QN2, Q1LWH4, Q1LXZ7, Q29S07, Q2T9L8, Q32PH0, Q3B7U4, Q3U308, Q3UAW9, Q3UH60, Q3UY23, Q4R4F1, Q641Y9, Q68FL6, Q6DG91, Q6GPP1, Q6PJN8, Q6TEN6, Q6ZNJ1, Q6ZPE2, Q6ZQA0, Q7T006, Q8BWT5

Diamond homologs: Q0VC30, Q9QZM2, Q9UHN1, Q9W6G7, O59235

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
clofarabine	“down-regulates activity”	POLG2	“chemical inhibition”
POLG2	“form complex”	“DNA polymerase gamma”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	48
Likely benign	13
Benign	6

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3375474	NM_007215.4(POLG2):c.729_730del (p.Pro244fs)	Pathogenic
2034399	NM_007215.4(POLG2):c.689+2T>C	Likely pathogenic

SpliceAI

1631 predictions. Top by Δscore:

Variant	Effect	Δscore
17:64480283:TCTTA:T	donor_loss	1.0000
17:64480284:CTTAC:C	donor_loss	1.0000
17:64480285:TTA:T	donor_loss	1.0000
17:64480287:A:AC	donor_gain	1.0000
17:64480287:A:C	donor_loss	1.0000
17:64480288:C:CC	donor_gain	1.0000
17:64480288:CTT:C	donor_gain	1.0000
17:64480290:T:TA	donor_gain	1.0000
17:64480385:CAAAC:C	acceptor_gain	1.0000
17:64480391:T:C	acceptor_loss	1.0000
17:64485749:T:A	donor_gain	1.0000
17:64490907:T:TA	donor_gain	1.0000
17:64490912:T:A	donor_gain	1.0000
17:64490970:C:CC	acceptor_gain	1.0000
17:64492773:C:CC	acceptor_gain	1.0000
17:64492774:T:C	acceptor_gain	1.0000
17:64492914:T:C	donor_gain	1.0000
17:64477987:ACCTA:A	acceptor_loss	0.9900
17:64477988:CCTAA:C	acceptor_loss	0.9900
17:64477989:C:T	acceptor_loss	0.9900
17:64477990:T:G	acceptor_loss	0.9900
17:64480288:CT:C	donor_gain	0.9900
17:64480390:C:CC	acceptor_gain	0.9900
17:64482914:CTCA:C	donor_loss	0.9900
17:64482915:TCACC:T	donor_loss	0.9900
17:64482916:CACCT:C	donor_loss	0.9900
17:64482917:A:T	donor_loss	0.9900
17:64490624:AATTT:A	donor_gain	0.9900
17:64490794:A:AC	donor_gain	0.9900
17:64490795:C:CC	donor_gain	0.9900

AlphaMissense

3166 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:64492686:C:G	R259P	0.992
17:64492675:A:G	W263R	0.991
17:64492675:A:T	W263R	0.991
17:64477973:A:C	S436R	0.990
17:64477973:A:T	S436R	0.990
17:64477975:T:G	S436R	0.990
17:64492678:A:G	W262R	0.989
17:64492678:A:T	W262R	0.989
17:64492699:A:G	W255R	0.984
17:64492699:A:T	W255R	0.984
17:64477907:T:A	R458S	0.983
17:64477907:T:G	R458S	0.983
17:64477913:T:A	R456S	0.983
17:64477913:T:G	R456S	0.983
17:64492741:A:G	W241R	0.983
17:64492741:A:T	W241R	0.983
17:64496629:A:G	W114R	0.983
17:64496629:A:T	W114R	0.983
17:64482959:G:T	A384D	0.981
17:64485795:G:T	A348D	0.981
17:64492958:G:T	A209D	0.981
17:64492736:A:C	F242L	0.980
17:64492736:A:T	F242L	0.980
17:64492738:A:G	F242L	0.980
17:64492964:C:T	G207D	0.979
17:64477917:A:G	L455P	0.978
17:64477983:T:A	D433V	0.978
17:64485805:C:G	G345R	0.978
17:64490947:A:G	F273S	0.978
17:64492737:A:G	F242S	0.978

dbSNP variants (sampled 300 via entrez): RS1000039971 (17:64494658 G>A,T), RS1000894670 (17:64488532 A>G), RS1000996583 (17:64481597 G>A), RS1001264737 (17:64488211 T>A), RS1001329935 (17:64479625 A>G), RS1001403478 (17:64480131 A>C), RS1001585107 (17:64497962 G>A), RS1001631629 (17:64487013 A>C), RS1002054984 (17:64491830 G>A), RS1002903885 (17:64485408 T>C), RS1003594913 (17:64496132 C>T), RS1003651270 (17:64483802 C>T), RS1003724624 (17:64490346 G>A), RS1003971148 (17:64495122 G>A), RS1004092710 (17:64489397 T>C)

Disease associations

OMIM: gene MIM:604983 | disease phenotypes: MIM:610131, MIM:619425, MIM:618528, MIM:303350, MIM:170500

GenCC curated gene-disease

Disease	Classification	Inheritance
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4	Strong	Autosomal dominant
mitochondrial DNA depletion syndrome 16 (hepatic type)	Moderate	Autosomal recessive
mitochondrial DNA depletion syndrome	Moderate	Semidominant
mitochondrial dna depletion syndrome 16B (neuroophthalmic type)	Moderate	Autosomal recessive
autosomal dominant progressive external ophthalmoplegia	Supportive	Autosomal dominant

Mondo (8): progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (MONDO:0012415), mitochondrial dna depletion syndrome 16B (neuroophthalmic type) (MONDO:0030326), mitochondrial DNA depletion syndrome 16 (hepatic type) (MONDO:0032799), hereditary spastic paraplegia (MONDO:0019064), acute liver failure (MONDO:0019542), hyperkalemic periodic paralysis (MONDO:0008224), mitochondrial DNA depletion syndrome (MONDO:0018158), autosomal dominant progressive external ophthalmoplegia (MONDO:0008003)

Orphanet (3): Hereditary spastic paraplegia (Orphanet:685), Acute liver failure (Orphanet:90062), Hyperkalemic periodic paralysis (Orphanet:682)

HPO phenotypes

121 total (30 of 121 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000017	Nocturia
HP:0000141	Amenorrhea
HP:0000338	Hypomimic face
HP:0000365	Hearing impairment
HP:0000463	Anteverted nares
HP:0000496	Abnormality of eye movement
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000544	External ophthalmoplegia
HP:0000572	Visual loss
HP:0000590	Progressive external ophthalmoplegia
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000648	Optic atrophy
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000836	Hyperthyroidism
HP:0000853	Goiter
HP:0000939	Osteoporosis
HP:0000952	Jaundice
HP:0000969	Edema
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006979_516	Heel bone mineral density	2.000000e-17
GCST010002_128	Refractive error	2.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D017114	Liver Failure, Acute	C06.552.308.500.750
D020513	Paralysis, Hyperkalemic Periodic	C05.651.701.600; C10.668.491.650.600; C16.320.565.618.711.600; C18.452.648.618.711.600
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C563575	Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Dominant, 1 (supp.)
C566437	Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Dominant, 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3430903 (PROTEIN FAMILY)

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance	2
Temozolomide	affects response to substance, increases expression	2
Acetaminophen	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Cisplatin	increases expression	2
Valproic Acid	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
methylparaben	increases expression	1
cobaltous chloride	decreases expression	1
aflatoxin B2	increases methylation	1
coumarin	increases phosphorylation	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Carmustine	affects response to substance	1
Doxorubicin	increases expression	1
Lipopolysaccharides	increases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tunicamycin	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3428608	Binding	Inhibition of human mitochondrial DNA polymerase gamma large subunit/DNA polymerase gamma accessory subunit using 32P-D19/D36 as DNA primer/template assessed as single nucleotide incorporation rate at 100 uM after 5 to 90 mins by PAGE analy	Discovery of β-D-2’-deoxy-2’-α-fluoro-4’-α-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT00896025	PHASE4	TERMINATED	Study of N-Acetylcysteine in Acute Liver Failure (ALF)
NCT02375867	PHASE4	COMPLETED	Steroids in Fulminant Hepatitis A in the Pediatric Age Group
NCT03667157	PHASE4	COMPLETED	Liver Function After Intravenous Methylprednisolone Administration
NCT00004467	PHASE3	COMPLETED	Randomized Study of Acetylcysteine in Patients With Acute Liver Failure Not Caused by Acetaminophen
NCT00248625	PHASE3	COMPLETED	N-acetylcysteine in Non-Acetaminophen Pediatric Acute Liver Failure
NCT00494507	PHASE3	COMPLETED	Hyper- and Hypokalemic Periodic Paralysis Study
NCT01939561	PHASE3	COMPLETED	Lamotrigine as Treatment of Myotonia
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT00030225	PHASE2	COMPLETED	Phase 2 Evaluation of the ELAD System in the Management of Acute Liver Failure
NCT00470314	PHASE2	UNKNOWN	Therapeutic Efficacy of L-Ornithine L-Aspartate Infusion in Patients With Acute Liver Failure
NCT00832728	PHASE2	WITHDRAWN	Safety and Efficacy of the Extracorporeal Liver Assist Device (ELAD®) In Patients With Fulminant Hepatic Failure (FHF)
NCT01548690	PHASE2	COMPLETED	Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury
NCT01690845	PHASE2	UNKNOWN	Molecular Adsorbent Recirculating System (MARS®) in Hypoxic Hepatitis
NCT01875874	PHASE2	TERMINATED	Safety and Efficacy of the ELAD System (ELAD) to Treat Acute Liver Failure (ALF)
NCT01937130	PHASE2	TERMINATED	Pharmacokinetic and Pharmacodynamic Study of IDN-6556 in ACLF
NCT03882346	PHASE2	UNKNOWN	Study to Evaluate Safety and Efficacy of LifeLiver in Acute or Acute-on-Chronic Liver Failure Patients
NCT04862221	PHASE2	RECRUITING	TReatment for ImmUne Mediated PathopHysiology
NCT05689645	PHASE2	RECRUITING	F573 for Injection for the Treatment of Liver Injury/Failure
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT03629015	PHASE1	WITHDRAWN	Safety Study of Stemchymal® in Acute Liver Failure
NCT06285253	PHASE1	COMPLETED	miroliverELAP® for the Treatment of Acute Liver Failure: A Phase 1 Trial
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia