GFM2

Summary

GFM2 (GTP dependent ribosome recycling factor mitochondrial 2, HGNC:29682) is a protein-coding gene on chromosome 5q13.3, encoding Ribosome-releasing factor 2, mitochondrial (Q969S9). Mitochondrial GTPase that mediates the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis. It is a selective cancer dependency (DepMap: 12.9% of cell lines).

Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors, which is a GTPase that plays a role at the termination of mitochondrial translation by mediating the disassembly of ribosomes from messenger RNA . Its role in the regulation of normal mitochondrial function and in disease states attributed to mitochondrial dysfunction is not known. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 84340 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined oxidative phosphorylation deficiency 39 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 457 total — 5 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 75
• Cancer dependency (DepMap): dependent in 12.9% of screened cell lines
• MANE Select transcript: NM_032380

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29682
Approved symbol	GFM2
Name	GTP dependent ribosome recycling factor mitochondrial 2
Location	5q13.3
Locus type	gene with protein product
Status	Approved
Aliases	EFG2, FLJ21661, EF-G2mt
Ensembl gene	ENSG00000164347
Ensembl biotype	protein_coding
OMIM	606544
Entrez	84340

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 21 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000296805, ENST00000345239, ENST00000427854, ENST00000506263, ENST00000506778, ENST00000509097, ENST00000509430, ENST00000513331, ENST00000514734, ENST00000515125, ENST00000905366, ENST00000905367, ENST00000905368, ENST00000905369, ENST00000905370, ENST00000905371, ENST00000905372, ENST00000905373, ENST00000925461, ENST00000925462, ENST00000925463, ENST00000925464, ENST00000958296, ENST00000958297, ENST00000958298

RefSeq mRNA: 4 — MANE Select: NM_032380 NM_001281302, NM_032380, NM_170681, NM_170691

CCDS: CCDS4023, CCDS4024, CCDS47232

Canonical transcript exons

ENST00000296805 — 21 exons

Exon	Start	End
ENSE00001083724	74725640	74725755
ENSE00001083733	74747692	74747780
ENSE00001083738	74741529	74741609
ENSE00001083747	74745678	74745857
ENSE00001083752	74738502	74738642
ENSE00001083754	74738318	74738417
ENSE00001083755	74750579	74750667
ENSE00001083756	74751368	74751493
ENSE00001339520	74763680	74763766
ENSE00001814116	74766938	74767117
ENSE00001901034	74721206	74721783
ENSE00003269693	74746105	74746165
ENSE00003468234	74730260	74730398
ENSE00003574438	74760902	74760986
ENSE00003627597	74736796	74736985
ENSE00003629434	74758849	74758946
ENSE00003651191	74759369	74759426
ENSE00003669500	74725941	74726126
ENSE00003674068	74722379	74722561
ENSE00003675764	74739989	74740137
ENSE00003686265	74733022	74733098

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 96.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.3746 / max 315.7795, expressed in 1814 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
62091	19.3054	1808
62089	5.1634	1620
62090	0.4840	256
62092	0.4218	162

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	96.43	gold quality
tibialis anterior	UBERON:0001385	95.68	gold quality
bronchial epithelial cell	CL:0002328	95.13	gold quality
bronchus	UBERON:0002185	94.85	gold quality
deltoid	UBERON:0001476	93.72	gold quality
epithelium of nasopharynx	UBERON:0001951	93.61	gold quality
adrenal tissue	UBERON:0018303	93.61	gold quality
nasopharynx	UBERON:0001728	93.59	gold quality
secondary oocyte	CL:0000655	92.90	gold quality
myocardium	UBERON:0002349	92.59	gold quality
ileal mucosa	UBERON:0000331	92.50	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.06	gold quality
oocyte	CL:0000023	92.05	gold quality
right uterine tube	UBERON:0001302	91.89	gold quality
kidney epithelium	UBERON:0004819	91.83	gold quality
nasal cavity epithelium	UBERON:0005384	91.72	gold quality
thymus	UBERON:0002370	91.22	gold quality
quadriceps femoris	UBERON:0001377	91.16	gold quality
epithelial cell of pancreas	CL:0000083	91.07	gold quality
heart left ventricle	UBERON:0002084	90.73	gold quality
pharyngeal mucosa	UBERON:0000355	90.71	gold quality
cardiac ventricle	UBERON:0002082	90.68	gold quality
body of tongue	UBERON:0011876	90.52	gold quality
oviduct epithelium	UBERON:0004804	90.49	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.48	gold quality
vastus lateralis	UBERON:0001379	90.40	gold quality
right lobe of liver	UBERON:0001114	90.38	gold quality
heart right ventricle	UBERON:0002080	90.23	gold quality
ventricular zone	UBERON:0003053	90.07	gold quality
calcaneal tendon	UBERON:0003701	90.02	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.46
E-MTAB-6142	no	294.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting GFM2, 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-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-4528	99.18	69.77	1936
HSA-MIR-4724-5P	98.87	67.75	1324
HSA-MIR-4703-5P	98.53	70.13	1645
HSA-MIR-3942-5P	98.52	69.51	1517
HSA-MIR-4720-3P	98.50	68.88	988
HSA-MIR-96-3P	97.47	68.03	839
HSA-MIR-6866-5P	96.64	68.06	624
HSA-MIR-151A-3P	95.52	65.29	516

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• Myoblasts isolated from the MELAS patients show A3243G mutation in tRNALeu(UUR) produces a severe respiratory chain deficiency and this phenotype can be partially suppressed by overexpression of EFTu and EFG2. (PMID:18753147)
• EF-G2mt is an exclusive recycling factor in mammalian mitochondrial protein synthesis. (PMID:19716793)
• These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans (PMID:22719265)
• GFM2 mutations could be causative of a phenotype of Leigh syndrome with arthrogryposis multiplex congenita. (PMID:26016410)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gfm2	ENSDARG00000005561
mus_musculus	Gfm2	ENSMUSG00000021666
rattus_norvegicus	Gfm2	ENSRNOG00000025285
drosophila_melanogaster	mRRF2	FBGN0051159
caenorhabditis_elegans		WBGENE00022491

Paralogs (18): MTIF2 (ENSG00000085760), GTPBP1 (ENSG00000100226), EEF1A2 (ENSG00000101210), GSPT1 (ENSG00000103342), EFTUD2 (ENSG00000108883), HBS1L (ENSG00000112339), EIF2S3 (ENSG00000130741), EEFSEC (ENSG00000132394), EFL1 (ENSG00000140598), GUF1 (ENSG00000151806), EEF1A1 (ENSG00000156508), EIF5B (ENSG00000158417), EEF2 (ENSG00000167658), GFM1 (ENSG00000168827), GTPBP2 (ENSG00000172432), TUFM (ENSG00000178952), EIF2S3B (ENSG00000180574), GSPT2 (ENSG00000189369)

Protein

Protein identifiers

Ribosome-releasing factor 2, mitochondrial — Q969S9 (reviewed: Q969S9)

Alternative names: Elongation factor G 2, mitochondrial, Elongation factor G2

All UniProt accessions (3): Q969S9, D6RAL1, D6RF75

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial GTPase that mediates the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis. Acts in collaboration with MRRF. Promotes mitochondrial ribosome recycling by dissolution of intersubunit contacts. GTP hydrolysis follows the ribosome disassembly and probably occurs on the ribosome large subunit. Not involved in the GTP-dependent ribosomal translocation step during translation elongation.

Subcellular location. Mitochondrion.

Tissue specificity. Widely expressed.

Disease relevance. Combined oxidative phosphorylation deficiency 39 (COXPD39) [MIM:618397] An autosomal recessive disorder due to mitochondrial dysfunction and characterized by global developmental delay, axial hypotonia, dystonia, dysarthria, impaired intellectual development with poor speech, and deficiencies of the mitochondrial respiratory chain enzyme complexes. Neuroimaging shows abnormalities in the putamen and caudate nuclei, along with subcortical white matter involvement. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. This protein may be expected to contain an N-terminal transit peptide but none has been predicted.

Similarity. Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EF-G/EF-2 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q969S9-1	1	yes
Q969S9-2	2
Q969S9-3	3
Q969S9-4	4
Q969S9-5	5

RefSeq proteins (4): NP_001268231, NP_115756, NP_733781, NP_733792 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000640	EFG_V-like	Domain
IPR000795	T_Tr_GTP-bd_dom	Domain
IPR005225	Small_GTP-bd	Domain
IPR005517	Transl_elong_EFG/EF2_IV	Domain
IPR009000	Transl_B-barrel_sf	Homologous_superfamily
IPR009022	EFG_III	Domain
IPR014721	Ribsml_uS5_D2-typ_fold_subgr	Homologous_superfamily
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR030851	EFG2	Family
IPR031157	G_TR_CS	Conserved_site
IPR035647	EFG_III/V	Homologous_superfamily
IPR035649	EFG_V	Domain
IPR041095	EFG_II	Domain
IPR053905	EF-G-like_DII	Domain

Pfam: PF00009, PF00679, PF03764, PF14492, PF22042

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (22 total): sequence variant 9, splice variant 6, binding site 3, sequence conflict 2, chain 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7L20	ELECTRON MICROSCOPY	3.15
7NSH	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969S9-F1	78.50	0.23

Functional residue map

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

Ligand- & substrate-binding residues (3): 77–84; 141–145; 195–198

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5419276	Mitochondrial translation termination
R-HSA-392499	Metabolism of proteins
R-HSA-5368287	Mitochondrial translation
R-HSA-72766	Translation

MSigDB gene sets: 310 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, WANG_CLIM2_TARGETS_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_MITOCHONDRIAL_TRANSLATION, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_TRANSLATIONAL_TERMINATION, GOBP_TRANSLATION, GCM_DDX11, GOBP_TRANSLATIONAL_ELONGATION, GCM_NF2, JAZAERI_BREAST_CANCER_BRCA1_VS_BRCA2_DN, GOBP_ORGANELLE_DISASSEMBLY, LEIN_LOCALIZED_TO_PROXIMAL_DENDRITES, GOCC_MITOCHONDRIAL_MATRIX

GO Biological Process (4): mitochondrial translation (GO:0032543), ribosome disassembly (GO:0032790), mitochondrial translational termination (GO:0070126), translation (GO:0006412)

GO Molecular Function (5): GTPase activity (GO:0003924), GTP binding (GO:0005525), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Mitochondrial translation	1
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	3
translational termination	2
translation	1
mitochondrial gene expression	1
organelle disassembly	1
mitochondrial translation	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1762 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GFM2	MRRF	Q96E11	990
GFM2	MIEF2	Q96C03	890
GFM2	TSFM	P43897	831
GFM2	MTRF1	O75570	664
GFM2	MTRF1L	Q9UGC7	642
GFM2	MTIF3	Q9H2K0	619
GFM2	EIF5B	O60841	601
GFM2	MTIF2	P46199	583
GFM2	MRPL58	Q14197	572
GFM2	MTRFR	Q9H3J6	568
GFM2	TUFM	P49411	546
GFM2	GTPBP6	O43824	543
GFM2	METAP1D	Q6UB28	521
GFM2	NPM1	P06748	500
GFM2	PTCD3	Q96EY7	490

IntAct

43 interactions, top by confidence:

A	B	Type	Score
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
TRIM27	GFM2	psi-mi:“MI:0915”(physical association)	0.560
GFM2	VPS52	psi-mi:“MI:0915”(physical association)	0.560
BANP	GFM2	psi-mi:“MI:0915”(physical association)	0.560
GFM2	TRIM9	psi-mi:“MI:0915”(physical association)	0.560
TRIM9	GFM2	psi-mi:“MI:0915”(physical association)	0.560
GFM2	TRIM27	psi-mi:“MI:0915”(physical association)	0.560
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
HSCB	GFM2	psi-mi:“MI:0915”(physical association)	0.370
GFM2		psi-mi:“MI:0915”(physical association)	0.370
GFM2	PTCHD1	psi-mi:“MI:0915”(physical association)	0.370
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
NT5C3A	VWA8	psi-mi:“MI:0914”(association)	0.350
TNFRSF10A	NAP1L4	psi-mi:“MI:0914”(association)	0.350
SLX4	SMAP	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
MALSU1	VWA8	psi-mi:“MI:0914”(association)	0.350
PTCD1	VWA8	psi-mi:“MI:0914”(association)	0.350
ATP5MGL	GTPBP10	psi-mi:“MI:0914”(association)	0.350
NPTN	RTL8C	psi-mi:“MI:0914”(association)	0.350

BioGRID (192): GFM2 (Two-hybrid), GFM2 (Two-hybrid), GFM2 (Two-hybrid), TRIM9 (Two-hybrid), GFM2 (Affinity Capture-MS), GFM2 (Co-fractionation), GFM2 (Co-fractionation), GFM2 (Co-fractionation), GFM2 (Affinity Capture-MS), GFM2 (Affinity Capture-MS), GFM2 (Affinity Capture-MS), GFM2 (Affinity Capture-MS), GFM2 (Affinity Capture-MS), GFM2 (Affinity Capture-MS), GFM2 (Affinity Capture-MS)

ESM2 similar proteins: A0JMI9, A1CHC3, A1CXG4, A3GHT9, A5DK38, A5PKR8, A6QNM2, A7A0X4, A7RR04, A8QCE7, B0W010, B0Y604, B3LT39, B3M011, B3P8M3, B4GNT0, B4HEQ8, B4JQM7, B4JSI3, B4KKD5, B4LS49, B4M416, B4NAU8, B4PMC6, B5VN01, B6K286, B6K6L6, B8N9M2, P25039, Q07803, Q08BB1, Q16S14, Q1DLM0, Q29BD5, Q2UGQ2, Q4WP57, Q5B6J8, Q5BJP6, Q5R600, Q6BPD3

Diamond homologs: A0JMI9, A0LRL7, A0RQI0, A1T4L5, A1UBL0, A1VYJ8, A3PV95, A4J108, A4T1R3, A4XI36, A5CUB7, A5D5I7, A5IM80, A5USJ2, A6LLL0, A6Q1M7, A6QNM2, A6W5T4, A7H4P5, A7HM55, A7HWQ8, A7I3T6, A7NR66, A8F4Q8, A8FKR7, A8Z6I6, A9BHA8, A9WH62, B0RB35, B0W010, B1GZ80, B1I1I5, B1LBP3, B2GIL1, B2V7L6, B3CLA3, B3E7T2, B3EUF3, B3M011, B3P8M3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	11
Uncertain significance	222
Likely benign	128
Benign	48

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
225205	NM_032380.5(GFM2):c.206+4A>G	Pathogenic
225206	NM_032380.5(GFM2):c.2029-1G>A	Pathogenic
2423202	NC_000005.9:g.(?73980960)(74041702_?)del	Pathogenic
440787	NM_032380.5(GFM2):c.636del (p.Glu213fs)	Pathogenic
440788	NM_032380.5(GFM2):c.275A>C (p.Tyr92Ser)	Pathogenic
1710900	NM_032380.5(GFM2):c.1688_1694del (p.Ala563fs)	Likely pathogenic
2444250	NM_032380.5(GFM2):c.304+1G>A	Likely pathogenic
2630553	NM_032380.5(GFM2):c.1104T>A (p.Cys368Ter)	Likely pathogenic
3234858	NM_032380.5(GFM2):c.1833dup (p.Ala612fs)	Likely pathogenic
372580	NM_032380.5(GFM2):c.1220+2dup	Likely pathogenic
4056493	NM_032380.5(GFM2):c.1113del (p.Phe372fs)	Likely pathogenic
4277858	NM_032380.5(GFM2):c.2028+1G>A	Likely pathogenic
4292341	NM_032380.5(GFM2):c.1400del (p.Lys467fs)	Likely pathogenic
4755559	NM_032380.5(GFM2):c.2195C>T (p.Pro732Leu)	Likely pathogenic
4755560	NM_032380.5(GFM2):c.2029-741_2029-521dup	Likely pathogenic
4845765	NM_032380.5(GFM2):c.349C>T (p.Arg117Ter)	Likely pathogenic

SpliceAI

3103 predictions. Top by Δscore:

Variant	Effect	Δscore
5:74722561:CCTAA:C	acceptor_loss	1.0000
5:74722562:C:CC	acceptor_gain	1.0000
5:74722562:CTAA:C	acceptor_loss	1.0000
5:74725937:TTACC:T	donor_loss	1.0000
5:74725938:TA:T	donor_loss	1.0000
5:74725938:TAC:T	donor_gain	1.0000
5:74725939:A:AC	donor_gain	1.0000
5:74725940:C:CC	donor_gain	1.0000
5:74725940:CCTTG:C	donor_loss	1.0000
5:74726122:GGTAT:G	acceptor_gain	1.0000
5:74726124:TAT:T	acceptor_gain	1.0000
5:74726127:C:CA	acceptor_loss	1.0000
5:74726127:C:CC	acceptor_gain	1.0000
5:74726128:T:C	acceptor_loss	1.0000
5:74730407:C:CT	acceptor_gain	1.0000
5:74730407:C:T	acceptor_gain	1.0000
5:74730408:A:T	acceptor_gain	1.0000
5:74733020:A:AC	donor_gain	1.0000
5:74733021:C:CC	donor_gain	1.0000
5:74738316:A:AC	donor_gain	1.0000
5:74738317:C:CC	donor_gain	1.0000
5:74738414:CTCC:C	acceptor_gain	1.0000
5:74738415:TCC:T	acceptor_gain	1.0000
5:74738416:CC:C	acceptor_gain	1.0000
5:74738416:CCC:C	acceptor_gain	1.0000
5:74738417:CC:C	acceptor_gain	1.0000
5:74738417:CCTGT:C	acceptor_loss	1.0000
5:74738418:C:CC	acceptor_gain	1.0000
5:74738418:CTGTA:C	acceptor_loss	1.0000
5:74738419:T:A	acceptor_loss	1.0000

AlphaMissense

5069 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:74750654:A:C	F148L	1.000
5:74750654:A:T	F148L	1.000
5:74750656:A:G	F148L	1.000
5:74730349:C:G	R546P	0.999
5:74747753:C:G	A183P	0.999
5:74750667:C:T	G144D	0.999
5:74751382:A:G	L139P	0.999
5:74733055:A:C	S518R	0.998
5:74733055:A:T	S518R	0.998
5:74733057:T:G	S518R	0.998
5:74750655:A:G	F148S	0.998
5:74750659:C:G	D147H	0.998
5:74750663:A:C	H145Q	0.998
5:74750663:A:T	H145Q	0.998
5:74751368:C:G	G144R	0.998
5:74751377:C:G	D141H	0.998
5:74751430:A:T	I123N	0.998
5:74751436:A:C	I121S	0.998
5:74751436:A:G	I121T	0.998
5:74751450:C:A	E116D	0.998
5:74751450:C:G	E116D	0.998
5:74751451:T:A	E116V	0.998
5:74751465:A:C	D111E	0.998
5:74751465:A:T	D111E	0.998
5:74751467:C:G	D111H	0.998
5:74758905:T:A	K83I	0.998
5:74758906:T:G	K83Q	0.998
5:74733074:A:G	L512P	0.997
5:74750657:G:C	D147E	0.997
5:74750657:G:T	D147E	0.997

dbSNP variants (sampled 300 via entrez): RS1000024013 (5:74721926 T>G), RS1000057833 (5:74729922 A>G), RS1000143546 (5:74751663 T>A), RS1000231520 (5:74741066 C>G), RS1000283973 (5:74723004 C>G), RS1000284667 (5:74748414 C>T), RS1000291053 (5:74737187 C>A,T), RS1000441223 (5:74763867 A>G), RS1000546075 (5:74721552 G>A), RS1000594759 (5:74756923 G>A,C), RS1000685799 (5:74756656 AGTGTGTG>A), RS1000700059 (5:74723385 C>T), RS1000736402 (5:74743224 C>T), RS1000737643 (5:74749767 AT>A,ATT), RS1000870999 (5:74728569 C>T)

Disease associations

OMIM: gene MIM:606544 | disease phenotypes: MIM:618397, MIM:609060, MIM:268800, MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation deficiency 39	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR

Mondo (5): combined oxidative phosphorylation deficiency 39 (MONDO:0032726), hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (MONDO:0012191), mitochondrial disease (MONDO:0044970), Sandhoff disease (MONDO:0010006), Leigh syndrome (MONDO:0009723)

Orphanet (5): Combined oxidative phosphorylation defect type 39 (Orphanet:565624), Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (Orphanet:137681), Mitochondrial disease (Orphanet:68380), Sandhoff disease (Orphanet:796), Leigh syndrome (Orphanet:506)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000194	Open mouth
HP:0000252	Microcephaly
HP:0000543	Optic disc pallor
HP:0000750	Delayed speech and language development
HP:0000762	Decreased nerve conduction velocity
HP:0000817	Reduced eye contact
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001273	Abnormal corpus callosum morphology
HP:0001302	Pachygyria
HP:0001317	Abnormal cerebellum morphology
HP:0001321	Cerebellar hypoplasia
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0001511	Intrauterine growth retardation
HP:0001662	Bradycardia
HP:0001688	Sinus bradycardia
HP:0001998	Neonatal hypoglycemia
HP:0002013	Vomiting
HP:0002058	Myopathic facies
HP:0002059	Cerebral atrophy
HP:0002061	Lower limb spasticity

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010727_9	Deep white matter hyperintensities	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005665	white matter hyperintensity measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
D012497	Sandhoff Disease	C10.228.140.163.100.435.825.300.300.249; C16.320.565.189.435.825.300.300.249; C16.320.565.398.641.803.350.300.700; C16.320.565.595.554.825.300.300.800; C18.452.132.100.435.825.300.300.249; C18.452.584.563.641.803.350.300.700; C18.452.648.189.435.825.300.300.249; C18.452.648.398.641.803.350.300.700; C18.452.648.595.554.825.300.300.800
C563797	Combined Oxidative Phosphorylation Deficiency 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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	increases abundance, increases expression, affects cotreatment	2
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
bisphenol B	increases expression	1
bisphenol S	affects expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Air Pollutants, Occupational	affects expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Atrazine	decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Cannabidiol	increases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	increases expression	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, increases expression	1
Valproic Acid	increases expression	1
Vanadates	increases expression	1
Josamycin	affects response to substance	1
Cadmium Chloride	increases abundance, increases expression	1
Acrylamide	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

128 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
NCT02030015	PHASE4	TERMINATED	Synergistic Enteral Regimen for Treatment of the Gangliosidoses
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
NCT00672022	PHASE3	COMPLETED	Pharmacokinetics, Safety and Tolerability of Zavesca (Miglustat) in Patients With Infantile Onset Gangliosidosis: Single and Steady State Oral Doses
NCT04221451	PHASE3	TERMINATED	A Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, and Safety of Venglustat in Late-onset GM2
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
NCT03759665	PHASE2	COMPLETED	N-Acetyl-L-Leucine for GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease)
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
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
NCT02254863	PHASE1	RECRUITING	UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells