MPV17

Summary

MPV17 (mitochondrial inner membrane protein MPV17, HGNC:7224) is a protein-coding gene on chromosome 2p23.3, encoding Mitochondrial inner membrane protein Mpv17 (P39210). Non-selective channel that modulates the membrane potential under normal conditions and oxidative stress, and is involved in mitochondrial homeostasis.

This gene encodes a mitochondrial inner membrane protein that is implicated in the metabolism of reactive oxygen species. Mutations in this gene have been associated with the hepatocerebral form of mitochondrial DNA depletion syndrome (MDDS).

Source: NCBI Gene 4358 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 373 total — 34 pathogenic, 33 likely-pathogenic
• Phenotypes (HPO): 196
• MANE Select transcript: NM_002437

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7224
Approved symbol	MPV17
Name	mitochondrial inner membrane protein MPV17
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	SYM1
Ensembl gene	ENSG00000115204
Ensembl biotype	protein_coding
OMIM	137960
Entrez	4358

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 25 protein_coding, 9 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000233545, ENST00000357186, ENST00000380044, ENST00000399052, ENST00000402310, ENST00000402722, ENST00000403262, ENST00000405076, ENST00000405983, ENST00000415514, ENST00000426513, ENST00000428910, ENST00000430991, ENST00000475085, ENST00000486898, ENST00000494436, ENST00000616446, ENST00000616707, ENST00000617583, ENST00000620797, ENST00000621183, ENST00000621470, ENST00000622003, ENST00000911060, ENST00000911061, ENST00000911062, ENST00000911063, ENST00000931180, ENST00000931181, ENST00000931182, ENST00000931183, ENST00000931184, ENST00000931185, ENST00000931186, ENST00000949903, ENST00000949904, ENST00000949905

RefSeq mRNA: 1 — MANE Select: NM_002437 NM_002437

CCDS: CCDS1748

Canonical transcript exons

ENST00000380044 — 8 exons

Exon	Start	End
ENSE00001896657	27323052	27323097
ENSE00003478166	27312214	27312246
ENSE00003510234	27322448	27322522
ENSE00003513406	27312680	27312772
ENSE00003553646	27309492	27309981
ENSE00003660390	27312994	27313109
ENSE00003673140	27311899	27311951
ENSE00003691219	27312494	27312589

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.5904 / max 140.2853, expressed in 1817 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27481	27.8843	1814
202123	1.5371	941
27480	0.1156	51
27479	0.0535	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	98.40	gold quality
right adrenal gland cortex	UBERON:0035827	98.29	gold quality
left adrenal gland	UBERON:0001234	98.26	gold quality
left adrenal gland cortex	UBERON:0035825	98.23	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.61	gold quality
adrenal cortex	UBERON:0001235	97.43	gold quality
cerebellar hemisphere	UBERON:0002245	97.42	gold quality
right lobe of thyroid gland	UBERON:0001119	97.38	gold quality
cerebellar cortex	UBERON:0002129	97.32	gold quality
adenohypophysis	UBERON:0002196	97.23	gold quality
adrenal gland	UBERON:0002369	97.22	gold quality
left lobe of thyroid gland	UBERON:0001120	97.14	gold quality
right frontal lobe	UBERON:0002810	97.11	gold quality
islet of Langerhans	UBERON:0000006	96.94	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.94	gold quality
right ovary	UBERON:0002118	96.89	gold quality
left ovary	UBERON:0002119	96.73	gold quality
body of uterus	UBERON:0009853	96.58	gold quality
stromal cell of endometrium	CL:0002255	96.56	gold quality
body of pancreas	UBERON:0001150	96.54	gold quality
thyroid gland	UBERON:0002046	96.38	gold quality
lower esophagus	UBERON:0013473	96.35	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.35	gold quality
endocervix	UBERON:0000458	96.31	gold quality
pituitary gland	UBERON:0000007	96.29	gold quality
left uterine tube	UBERON:0001303	96.24	gold quality
left coronary artery	UBERON:0001626	96.19	gold quality
right coronary artery	UBERON:0001625	96.17	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.15	gold quality
metanephros cortex	UBERON:0010533	96.09	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.38
E-ENAD-20	no	400.72
E-CURD-10	no	348.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ZNF205

miRNA regulators (miRDB)

43 targeting MPV17, 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-4481	100.00	66.42	1669
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-4796-5P	99.34	70.06	810
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-4744	99.01	69.91	1581
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-12114	98.70	63.45	730
HSA-MIR-423-5P	98.69	67.48	1522

Literature-anchored findings (GeneRIF, showing 27)

• MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17-/- mice (PMID:16582910)
• These results show the existence of the human homolog of M-LP and its participation in reactive oxygen species metabolism. (PMID:16631601)
• Sequencing of the MPV17 gene in six patients with Navajo neurohepatopathy from five families revealed the homozygous R50Q mutation described elsewhere. (PMID:16909392)
• Mutations in the MPV17 gene should be considered in the course of evaluating the molecular etiology for isolated, rapidly progressive infantile hepatic failure. (PMID:17694548)
• Lack of founder effect for an identical mtDNA depletion syndrome (MDS)-associated MPV17 mutation shared by Navajos and Italians. (PMID:18261905)
• Lethal hepatopathy, polyneuropathy, neurological regression and leukodystrophy are associated with mutations in MPV17. (PMID:18329934)
• study describes clinical, molecular morphological & biochemical features of 3 children with hepatocerebral mitochondrial DNA depletion syndrome secondary to novel MPV17 mutations; data confirm MPV17 mutations are associated with a 2-stage syndrome (PMID:18695062)
• describes in detail the specific clinical and biological characteristics of three patients with MPV17 gene mutations, a rare hepatocerebral mitochondrial DNA depletion syndrome (MDS) (PMID:19012992)
• clinical courses of patients with MPV17 mutations are greatly influenced by viral infections & dietary & pharmaceutical treatments targeting mitochondrial respiratory chain complex II may be beneficial in the clinical management of MPV17 mutant patients. (PMID:19520594)
• eight new patients with seven novel mutations in MPV17 (PMID:20074988)
• Case Report: functional splicing assay based on the use of minigenes to support that MPV17 c.70 + 5G > A mutation is disease causing. (PMID:20614188)
• results suggest that M-LPH functions to protect cells from oxidative stress and/or initiation of the mitochondrial apoptotic cascade under stressed conditions (PMID:22306510)
• 12 pathogenic mutations in mitochondrial DNA depletion syndrome in the MPV17 gene, of which 11 are novel, in 17 patients from 12 families. (PMID:23714749)
• A novel c.191C>G (p.Pro64Arg) MPV17 mutation has been identified in two pairs of unrelated Polish siblings with mitochondrial hepatoencephalopathy. (PMID:23829229)
• MPV17 is a Deltapsim-modulating channel that apparently contributes to mitochondrial homeostasis under different conditions (PMID:25861990)
• We report a novel homozygous mutation in MPV17 from two unrelated patients harboring axonal sensorimotor polyneuropathy without hepatoencephalopathy. (PMID:26437932)
• New case of Navajo Neurohepatopathy presented + literature review is provided to assist in diagnosis and management of the disease. (PMID:28209105)
• The authors describe an 11 year old girl, born to consanguineous parents, who presented with rapidly progressive MPV17 hepatocerebral mitochondrial DNA depletion syndrome. Genetic analysis of the patient revealed a homozygous pathogenic mutation c.121C>T (p.R41W) in the MPV17 gene. (PMID:28673863)
• Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in 2 unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. (PMID:29318572)
• This report provides further evidence that MPV17 mutations should be considered in patients with pure, non-syndromic axonal neuropathy. (PMID:30298599)
• Depressed MPV17 expression reduced mitochondrial folate levels by 43% and increased uracil levels, a marker of impaired dTMP synthesis, in mtDNA by 3-fold. (PMID:30385507)
• this study demonstrates that MPV17 does not control neither cell proliferation nor mtDNA content in cancer cells. (PMID:32155188)
• Mitochondrial molecular genetic results in a South African cohort: divergent mitochondrial and nuclear DNA findings. (PMID:33115810)
• NMR Structural and Biophysical Analysis of the Disease-Linked Inner Mitochondrial Membrane Protein MPV17. (PMID:34116124)
• Comprehensive Analysis on the Specific Role and Function of Mitochondrial Inner Membrane Protein MPV17 in Liver Hepatocellular Carcinoma. (PMID:35919033)
• [Genetic testing and prenatal diagnosis for a Chinese pedigree affected with mitochondrial DNA depletion syndrome due to variant of MPV17 gene]. (PMID:36184088)
• MPV17 mutation-related mitochondrial DNA depletion syndrome: A case series in infants. (PMID:36753038)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mpv17	ENSDARG00000032431
mus_musculus	Mpv17	ENSMUSG00000107283
rattus_norvegicus	Mpv17	ENSRNOG00000049430
drosophila_melanogaster	Mpv17	FBGN0039930
caenorhabditis_elegans		WBGENE00011826

Paralogs (3): MPV17L (ENSG00000156968), PXMP2 (ENSG00000176894), MPV17L2 (ENSG00000254858)

Protein

Protein identifiers

Mitochondrial inner membrane protein Mpv17 — P39210 (reviewed: P39210)

Alternative names: Protein Mpv17

All UniProt accessions (12): P39210, A0A0S2Z3Z9, A8MPV4, A8MTD3, B5MC10, B5MC53, B5MCF8, C9J473, E7EX18, F8WEL3, G5E9F5, H0Y6M5

UniProt curated annotations — full annotation on UniProt →

Function. Non-selective channel that modulates the membrane potential under normal conditions and oxidative stress, and is involved in mitochondrial homeostasis. Involved in mitochondrial deoxynucleoside triphosphates (dNTP) pool homeostasis and mitochondrial DNA (mtDNA) maintenance. May be involved in the regulation of reactive oxygen species metabolism and the control of oxidative phosphorylation.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Ubiquitous. Expressed in pancreas, kidney, muscle, liver, lung, placenta, brain and heart.

Disease relevance. Mitochondrial DNA depletion syndrome 6 (MTDPS6) [MIM:256810] A disease due to mitochondrial dysfunction. It is characterized by infantile onset of progressive liver failure, often leading to death in the first year of life, peripheral neuropathy, corneal scarring, acral ulceration and osteomyelitis leading to autoamputation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. The disease is caused by variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, axonal, type 2EE (CMT2EE) [MIM:618400] A recessive axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2EE is a slowly progressive, sensorimotor peripheral axonal neuropathy with onset in the first or second decades of life. The disorder primarily affects the lower limbs, sometimes resulting in loss of ambulation, with later onset of upper limb involvement. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the peroxisomal membrane protein PXMP2/4 family.

RefSeq proteins (1): NP_002428* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007248	Mpv17_PMP22	Family

Pfam: PF04117

UniProt features (37 total): sequence variant 28, transmembrane region 4, mutagenesis site 3, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P39210-F1	90.23	0.64

Functional residue map

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

Catalytic / active sites (1): 92 (determines ion selectivity)

Mutagenesis-validated functional residues (3):

Position	Phenotype
80	does not affect gating properties of the channel.
92	affects ion selectivity of the channel.
99	does not affect conductance and gating properties of the channel.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9033241	Peroxisomal protein import
R-HSA-9609507	Protein localization

MSigDB gene sets: 0 (showing top):

GO Biological Process (8): glomerular basement membrane development (GO:0032836), inner ear development (GO:0048839), regulation of mitochondrial DNA metabolic process (GO:1901858), obsolete mitochondrial genome maintenance (GO:0000002), cellular response to reactive oxygen species (GO:0034614), homeostatic process (GO:0042592), transmembrane transport (GO:0055085), regulation of reactive oxygen species metabolic process (GO:2000377)

GO Molecular Function (2): channel activity (GO:0015267), protein binding (GO:0005515)

GO Cellular Component (7): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), peroxisome (GO:0005777), peroxisomal membrane (GO:0005778), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
anatomical structure development	2
cytoplasm	2
extracellular matrix organization	1
glomerulus development	1
ear development	1
mitochondrial DNA metabolic process	1
regulation of DNA metabolic process	1
response to reactive oxygen species	1
cellular response to oxidative stress	1
cellular response to oxygen-containing compound	1
biological_process	1
transport	1
cellular process	1
regulation of metabolic process	1
reactive oxygen species metabolic process	1
passive transmembrane transporter activity	1
binding	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
microbody	1
peroxisome	1
microbody membrane	1

Protein interactions and networks

STRING

1190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MPV17	DGUOK	P78532	954
MPV17	SUCLA2	Q9P2R7	922
MPV17	POLG	P54098	921
MPV17	RRM2B	Q7LG56	901
MPV17	TWNK	Q96RR1	893
MPV17	IMMT	Q16891	844
MPV17	AGL	P35573	828
MPV17	SUCLG1	P53597	826
MPV17	SCN9A	Q15858	810
MPV17	TYMP	P19971	784
MPV17	TK2	O00142	713
MPV17	POLG2	Q9UHN1	678
MPV17	UCN	P55089	633
MPV17	MGME1	Q9BQP7	585
MPV17	SLC25A4	P12235	573

IntAct

3 interactions, top by confidence:

A	B	Type	Score
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
NDUFA4	COX7A2L	psi-mi:“MI:0914”(association)	0.350

BioGRID (58): MPV17 (Affinity Capture-RNA), MPV17 (Affinity Capture-MS), SYCE1 (Two-hybrid), MPV17 (Affinity Capture-RNA), MPV17 (Affinity Capture-MS), MPV17 (Affinity Capture-MS), MPV17 (Negative Genetic), MPV17 (Negative Genetic), MPV17 (Affinity Capture-MS), MPV17 (Affinity Capture-MS), MPV17 (Affinity Capture-MS), MRPL23 (Co-fractionation), MRPL11 (Co-fractionation), MRPL32 (Co-fractionation), NDUFB9 (Co-fractionation)

ESM2 similar proteins: F1R4U0, F1RFX9, O14817, O46373, O89035, O95258, P02722, P05141, P12235, P12236, P22292, P32007, P32089, P34998, P35250, P35347, P35353, P39210, P48962, P51881, P53007, P79110, P97700, Q000K2, Q02978, Q05962, Q05B83, Q09073, Q0VC00, Q13976, Q15382, Q15B89, Q2KIN6, Q5PQM9, Q5R5A1, Q5RAP3, Q5SVS4, Q5XGI1, Q6GQ22, Q76LL8

Diamond homologs: O14142, P0CQ38, P0CQ39, P19258, P39210, P42925, Q06563, Q07066, Q08743, Q10244, Q2KIN6, Q2KIY1, Q2TXA2, Q4IPX8, Q4P9K6, Q4WDZ0, Q54XX9, Q54ZX5, Q59Q43, Q5BK62, Q5TZ51, Q60SZ2, Q66GV0, Q6BMY0, Q6CAW5, Q6CIY7, Q6FXJ3, Q754F0, Q7SCY7, Q9NR77, Q2QL34, Q7YWV6, Q8VIK2, Q99MS3, Q9V492, Q9ZS51, Q6DIY8, Q567V2, Q68F62, Q6DGV7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	34
Likely pathogenic	33
Uncertain significance	91
Likely benign	151
Benign	4

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1359189	NM_002437.5(MPV17):c.55del (p.Gln19fs)	Pathogenic
1397653	NM_002437.5(MPV17):c.210C>G (p.Tyr70Ter)	Pathogenic
16160	NM_002437.5(MPV17):c.149G>A (p.Arg50Gln)	Pathogenic
16161	NM_002437.5(MPV17):c.498C>A (p.Asn166Lys)	Pathogenic
16162	NM_002437.5(MPV17):c.148C>T (p.Arg50Trp)	Pathogenic
16163	NM_002437.5(MPV17):c.122_147del (p.Arg41fs)	Pathogenic
16166	NC_000002.12:g.27309311_27310884delinsCAGG	Pathogenic
1999988	NM_002437.5(MPV17):c.374delinsAT (p.Arg125fs)	Pathogenic
2203027	NM_002437.5(MPV17):c.461+1G>C	Pathogenic
2415008	NM_002437.5(MPV17):c.477del (p.Gln159fs)	Pathogenic
2424432	NC_000002.11:g.(?27532780)(27532869_?)del	Pathogenic
2424433	NC_000002.11:g.(?27534757)(27535986_?)del	Pathogenic
2424434	NC_000002.11:g.(?27532770)(27535986_?)del	Pathogenic
2430184	NM_002437.5(MPV17):c.210C>A (p.Tyr70Ter)	Pathogenic
2672805	NM_002437.5(MPV17):c.462-18_*60del	Pathogenic
2676672	NM_002437.5(MPV17):c.408T>A (p.Tyr136Ter)	Pathogenic
2702232	NM_002437.5(MPV17):c.48G>A (p.Trp16Ter)	Pathogenic
2710314	NM_002437.5(MPV17):c.136dup (p.His46fs)	Pathogenic
2725770	NM_002437.5(MPV17):c.259A>T (p.Lys87Ter)	Pathogenic
2759967	NM_002437.5(MPV17):c.270_274del (p.Leu91fs)	Pathogenic
2812985	NM_002437.5(MPV17):c.360G>A (p.Trp120Ter)	Pathogenic
290443	NM_002437.5(MPV17):c.280-1dup	Pathogenic
3063945	NC_000002.11:g.(27535977_27545314)(27545965?)del	Pathogenic
3247508	NC_000002.11:g.(?27535860)(27539162_?)del	Pathogenic
3384706	NM_002437.5(MPV17):c.125del (p.Gly42fs)	Pathogenic
3902229	NM_002437.5(MPV17):c.112del (p.Val38fs)	Pathogenic
522374	NM_002437.5(MPV17):c.293del (p.Pro98fs)	Pathogenic
522377	NM_002437.4(MPV17):c.71-2_79delins4	Pathogenic
635346	NM_002437.5(MPV17):c.414dup (p.Pro139fs)	Pathogenic
691983	NM_002437.5(MPV17):c.279+1G>T	Pathogenic

SpliceAI

1094 predictions. Top by Δscore:

Variant	Effect	Δscore
2:27311947:CATAG:C	acceptor_gain	1.0000
2:27311949:TAG:T	acceptor_gain	1.0000
2:27311952:C:CC	acceptor_gain	1.0000
2:27312173:A:AC	donor_gain	1.0000
2:27312212:A:AC	donor_gain	1.0000
2:27312213:C:CC	donor_gain	1.0000
2:27312675:CTCA:C	donor_loss	1.0000
2:27312676:TCA:T	donor_loss	1.0000
2:27312677:CA:C	donor_loss	1.0000
2:27312678:A:AG	donor_loss	1.0000
2:27312679:C:CT	donor_loss	1.0000
2:27313109:CCTA:C	acceptor_gain	1.0000
2:27316110:T:TA	donor_gain	1.0000
2:27316128:C:A	donor_gain	1.0000
2:27322444:TCACC:T	donor_loss	1.0000
2:27322446:ACCA:A	donor_loss	1.0000
2:27322447:CCAG:C	donor_gain	1.0000
2:27311894:CATA:C	donor_loss	0.9900
2:27311895:ATACC:A	donor_loss	0.9900
2:27311896:TACC:T	donor_loss	0.9900
2:27311898:CC:C	donor_loss	0.9900
2:27311948:ATAG:A	acceptor_gain	0.9900
2:27311949:TAGC:T	acceptor_loss	0.9900
2:27311950:AG:A	acceptor_gain	0.9900
2:27311951:GCT:G	acceptor_loss	0.9900
2:27311952:C:CA	acceptor_loss	0.9900
2:27311953:T:G	acceptor_loss	0.9900
2:27312074:C:A	donor_gain	0.9900
2:27312174:A:C	donor_gain	0.9900
2:27312678:A:AC	donor_gain	0.9900

AlphaMissense

1111 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:27311899:C:A	R154M	0.996
2:27309950:A:G	W165R	0.994
2:27309950:A:T	W165R	0.994
2:27311922:G:C	F146L	0.994
2:27311922:G:T	F146L	0.994
2:27311924:A:G	F146L	0.994
2:27311948:A:G	W138R	0.994
2:27311948:A:T	W138R	0.994
2:27313089:C:G	D31H	0.994
2:27311914:A:T	V149D	0.993
2:27311925:G:C	N145K	0.993
2:27311925:G:T	N145K	0.993
2:27312230:A:G	L131P	0.993
2:27312754:A:G	W69R	0.993
2:27312754:A:T	W69R	0.993
2:27313109:C:T	G24E	0.992
2:27313088:T:A	D31V	0.991
2:27313088:T:G	D31A	0.991
2:27322448:C:G	G24R	0.991
2:27322448:C:T	G24R	0.991
2:27309955:A:T	V163D	0.989
2:27311899:C:G	R154T	0.989
2:27311923:A:G	F146S	0.989
2:27311946:C:A	W138C	0.989
2:27311946:C:G	W138C	0.989
2:27313075:C:A	Q35H	0.989
2:27313075:C:G	Q35H	0.989
2:27309945:G:C	N166K	0.988
2:27309945:G:T	N166K	0.988
2:27309948:C:A	W165C	0.988

dbSNP variants (sampled 300 via entrez): RS1000249446 (2:27310816 C>G), RS1000382619 (2:27324276 TAGG>T), RS1000597524 (2:27321936 G>A,T), RS1000669704 (2:27321487 T>A,C,G), RS1000898238 (2:27314772 T>C), RS1000989353 (2:27323198 C>T), RS1001115145 (2:27314978 C>A), RS1001519771 (2:27313207 A>G), RS1001600838 (2:27320497 C>A,T), RS1002485944 (2:27323043 G>A), RS1002503168 (2:27315379 G>A), RS1002541275 (2:27313555 G>A), RS1002620178 (2:27318826 G>A), RS1002672385 (2:27318577 C>T), RS1002787245 (2:27322837 C>T)

Disease associations

OMIM: gene MIM:137960 | disease phenotypes: MIM:256810, MIM:618400, MIM:603041, MIM:617156

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	Definitive	Autosomal recessive
Charcot-Marie-Tooth disease, axonal, type 2EE	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (6): mitochondrial DNA depletion syndrome 6 (hepatocerebral type) (MONDO:0009747), Charcot-Marie-Tooth disease, axonal, type 2EE (MONDO:0032728), mitochondrial DNA depletion syndrome, hepatocerebral form (MONDO:0100512), mitochondrial DNA depletion syndrome (MONDO:0018158), mitochondrial disease (MONDO:0044970), mitochondrial DNA depletion syndrome 15 (hepatocerebral type) (MONDO:0014943)

Orphanet (4): Mitochondrial DNA depletion syndrome, hepatocerebral form (Orphanet:254871), Navajo neurohepatopathy (Orphanet:255229), Mitochondrial DNA depletion syndrome (Orphanet:35698), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

196 total (30 of 196 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000114	Proximal tubulopathy
HP:0000121	Nephrocalcinosis
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000431	Wide nasal bridge
HP:0000495	Recurrent corneal erosions
HP:0000508	Ptosis
HP:0000556	Retinal dystrophy
HP:0000559	Corneal scarring
HP:0000580	Pigmentary retinopathy
HP:0000597	Ophthalmoparesis
HP:0000639	Nystagmus
HP:0000666	Horizontal nystagmus
HP:0000716	Depression
HP:0000787	Nephrolithiasis
HP:0000821	Hypothyroidism
HP:0000829	Hypoparathyroidism
HP:0000869	Secondary amenorrhea
HP:0000952	Jaundice
HP:0001081	Cholelithiasis
HP:0001178	Ulnar claw
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C580039	Deoxyguanosine Kinase Deficiency (supp.)
C538344	Navajo neurohepatopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	3
bisphenol A	decreases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Acetaminophen	increases expression	2
bisphenol F	affects cotreatment, increases methylation	1
methylmercuric chloride	decreases expression	1
W 7	decreases reaction, increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
cerous chloride	affects cotreatment, increases expression, decreases expression	1
lanthanum chloride	increases expression, affects cotreatment	1
cadmium sulfide	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
bisphenol S	increases methylation	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Catechin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Glucose	increases expression	1
Manganese	increases abundance, affects cotreatment, decreases expression	1
Ozone	affects expression, increases abundance	1
Selenium	increases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation, increases expression	1

Cellosaurus cell lines

7 cell lines: 4 cancer cell line, 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B1XH	Abcam HeLa MPV17 KO	Cancer cell line	Female
CVCL_C0J5	JUCTCi018-A	Induced pluripotent stem cell	Female
CVCL_C0J6	JUCTCi018-B	Induced pluripotent stem cell	Female
CVCL_C0J7	JUCTCi018-C	Induced pluripotent stem cell	Female
CVCL_SY85	HAP1 MPV17 (-) 1	Cancer cell line	Male
CVCL_XQ61	HAP1 MPV17 (-) 2	Cancer cell line	Male
CVCL_XQ62	HAP1 MPV17 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.
NCT01001585	Not specified	TERMINATED	Anesthetic Effects in Mitochondrial Disease
NCT01148550	Not specified	SUSPENDED	Longitudinal Study of Mitochondrial Hepatopathies