TRMT10C

Summary

TRMT10C (tRNA methyltransferase 10C, mitochondrial RNase P subunit, HGNC:26022) is a protein-coding gene on chromosome 3q12.3, encoding tRNA methyltransferase 10 homolog C (Q7L0Y3). Mitochondrial tRNA N(1)-methyltransferase involved in mitochondrial tRNA maturation. It is a selective cancer dependency (DepMap: 35.5% of cell lines).

This gene encodes the precursor of a subunit of the mitochondrial ribonuclease P, which is involved in 5’ processing of mitochondrial tRNAs. The encoded protein may confer RNA-binding capacity to mitochondrial ribonuclease P and may be essential for transcript processing, RNA modification, translation and mitochondrial respiration.

Source: NCBI Gene 54931 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined oxidative phosphorylation defect type 30 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 101 total — 1 pathogenic
• Phenotypes (HPO): 29
• Cancer dependency (DepMap): dependent in 35.5% of screened cell lines
• MANE Select transcript: NM_017819

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26022
Approved symbol	TRMT10C
Name	tRNA methyltransferase 10C, mitochondrial RNase P subunit
Location	3q12.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20432, MRPP1
Ensembl gene	ENSG00000174173
Ensembl biotype	protein_coding
OMIM	615423
Entrez	54931

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000309922, ENST00000495642

RefSeq mRNA: 1 — MANE Select: NM_017819 NM_017819

CCDS: CCDS43122

Canonical transcript exons

ENST00000309922 — 2 exons

Exon	Start	End
ENSE00001209657	101564770	101566446
ENSE00001251564	101561868	101562003

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 94.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.7089 / max 305.8048, expressed in 1806 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37640	39.1996	1806
37641	0.5093	282

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	94.91	gold quality
deltoid	UBERON:0001476	94.06	gold quality
vastus lateralis	UBERON:0001379	93.93	gold quality
quadriceps femoris	UBERON:0001377	93.41	gold quality
biceps brachii	UBERON:0001507	93.32	gold quality
myocardium	UBERON:0002349	93.12	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.79	gold quality
calcaneal tendon	UBERON:0003701	92.52	gold quality
tibialis anterior	UBERON:0001385	91.97	silver quality
adrenal tissue	UBERON:0018303	91.91	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.66	gold quality
skeletal muscle tissue	UBERON:0001134	91.28	gold quality
muscle tissue	UBERON:0002385	91.05	gold quality
epithelial cell of pancreas	CL:0000083	90.92	gold quality
heart right ventricle	UBERON:0002080	90.80	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.47	gold quality
germinal epithelium of ovary	UBERON:0001304	90.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.28	gold quality
skeletal muscle organ	UBERON:0014892	90.07	gold quality
kidney epithelium	UBERON:0004819	89.70	gold quality
tendon	UBERON:0000043	89.53	gold quality
islet of Langerhans	UBERON:0000006	89.50	gold quality
muscle of leg	UBERON:0001383	89.41	gold quality
gastrocnemius	UBERON:0001388	89.41	gold quality
gingival epithelium	UBERON:0001949	89.25	gold quality
gingiva	UBERON:0001828	89.16	gold quality
endometrium	UBERON:0001295	88.79	gold quality
cortical plate	UBERON:0005343	88.45	gold quality
oral cavity	UBERON:0000167	88.43	gold quality
epithelium of nasopharynx	UBERON:0001951	87.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.60

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting TRMT10C, 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-6740-5P	100.00	65.64	932
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4273	99.45	67.93	1206
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-219A-2-3P	98.62	68.78	797
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-4708-5P	97.77	67.82	831
HSA-MIR-6807-5P	97.51	64.25	1046
HSA-MIR-4693-5P	97.35	67.02	1234
HSA-MIR-5579-5P	96.32	68.54	730
HSA-MIR-3912-3P	88.31	65.41	84

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 35.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• MRPP1 is essential for transcript processing, RNA modification, translation and mitochondrial respiration. (PMID:21857155)
• We also identify the 5’ and 3’ transcript ends of the three lncRNAs and show that mitochondrial RNase P protein 1 (MRPP1) is important for the processing of these transcripts. (PMID:22028365)
• Inhibition of mitochondrial RNase P by beta-amyloid is an unspecific effect and is not mediated by beta-amyloid interaction with SDR5C1. (PMID:23755257)
• identifying mutations in TRMT10C as a cause of mitochondrial disease and highlighting the importance of RNA processing for correct mitochondrial function (PMID:27132592)
• in addition to being an essential component of the RNase P reaction, MRPP1/2 serves as a processing platform for several down-stream tRNA maturation steps in human mitochondria. (PMID:29040705)
• This study proposes low-resolution models of the MRPP1-MRPP2 and MRPP1-MRPP2-MRPP3 complexes that suggest the overall architecture, stoichiometry, and orientation of subunits and tRNA substrates. (PMID:29880640)
• m(1)A Regulator TRMT10C Predicts Poorer Survival and Contributes to Malignant Behavior in Gynecological Cancers. (PMID:32833542)
• Disease-associated mutations in mitochondrial precursor tRNAs affect binding, m1R9 methylation, and tRNA processing by mtRNase P. (PMID:33380464)
• Structural basis of RNA processing by human mitochondrial RNase P. (PMID:34489609)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	trmt10c	ENSDARG00000041575
mus_musculus	Trmt10c	ENSMUSG00000044763
rattus_norvegicus	Trmt10c	ENSRNOG00000039567
drosophila_melanogaster	rswl	FBGN0034351
caenorhabditis_elegans		WBGENE00016978
caenorhabditis_elegans	trmt-10C.1	WBGENE00018513

Paralogs (2): TRMT10A (ENSG00000145331), TRMT10B (ENSG00000165275)

Protein

Protein identifiers

tRNA methyltransferase 10 homolog C — Q7L0Y3 (reviewed: Q7L0Y3)

Alternative names: HBV pre-S2 trans-regulated protein 2, Mitochondrial ribonuclease P protein 1, RNA (guanine-9-)-methyltransferase domain-containing protein 1, Renal carcinoma antigen NY-REN-49, mRNA methyladenosine-N(1)-methyltransferase, tRNA (adenine(9)-N(1))-methyltransferase, tRNA (guanine(9)-N(1))-methyltransferase

All UniProt accessions (2): Q7L0Y3, C9JVB6

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial tRNA N(1)-methyltransferase involved in mitochondrial tRNA maturation. Component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3, which cleaves tRNA molecules in their 5’-ends. Together with HSD17B10/MRPP2, forms a subcomplex of the mitochondrial ribonuclease P, named MRPP1-MRPP2 subcomplex, which displays functions that are independent of the ribonuclease P activity. The MRPP1-MRPP2 subcomplex catalyzes the formation of N(1)-methylguanine and N(1)-methyladenine at position 9 (m1G9 and m1A9, respectively) in tRNAs; TRMT10C/MRPP1 acting as the catalytic N(1)-methyltransferase subunit. The MRPP1-MRPP2 subcomplex also acts as a tRNA maturation platform: following 5’-end cleavage by the mitochondrial ribonuclease P complex, the MRPP1-MRPP2 subcomplex enhances the efficiency of 3’-processing catalyzed by ELAC2, retains the tRNA product after ELAC2 processing and presents the nascent tRNA to the mitochondrial CCA tRNA nucleotidyltransferase TRNT1 enzyme. In addition to tRNA N(1)-methyltransferase activity, TRMT10C/MRPP1 also acts as a mRNA N(1)-methyltransferase by mediating methylation of adenosine residues at the N(1) position of MT-ND5 mRNA. Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly.

Subunit / interactions. Component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3. Interacts with HSD17B10/MRPP2; forming the MRPP1-MRPP2 subcomplex of the mitochondrial ribonuclease P complex. Interacts with GRSF1.

Subcellular location. Mitochondrion matrix. Mitochondrion nucleoid.

Disease relevance. Combined oxidative phosphorylation deficiency 30 (COXPD30) [MIM:616974] An autosomal recessive, severe mitochondrial disease characterized by lactic acidosis, hypotonia, feeding difficulties, deafness, and respiratory failure with fatal issue. Patient skeletal muscle cells show decreased activities of mitochondrial complexes I, III and IV. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the class IV-like SAM-binding methyltransferase superfamily. TRM10 family.

RefSeq proteins (1): NP_060289* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007356	tRNA_m1G_MeTrfase_euk	Family
IPR025812	Trm10_C_MTase_dom	Domain
IPR028564	MT_TRM10-typ	Domain
IPR038459	MT_TRM10-typ_sf	Homologous_superfamily

Enzyme classification (BRENDA):

• EC 2.1.1.218 — tRNA (adenine9-N1)-methyltransferase (BRENDA: 4 organisms, 27 substrates, 0 inhibitors, 2 Km, 2 kcat entries)
• EC 2.1.1.221 — tRNA (guanine9-N1)-methyltransferase (BRENDA: 4 organisms, 53 substrates, 0 inhibitors, 11 Km, 9 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GUANINE9 IN TRNAGLY	0.0032–0.0053	2
GUANINE9 IN TRNAGLYGCC	0.0002–0.0024	2
GUANINE9 IN TRNAVALUAC	0.0002–0.0019	2
ADENINE9 IN TRNAPHE	—	0
ADENINE9 IN TRNATHR	—	0
GUANINE9 IN TRNAARG	—	0
GUANINE9 IN TRNAPHE	—	0

Catalyzed reactions (Rhea), 3 shown:

• adenosine(9) in tRNA + S-adenosyl-L-methionine = N(1)-methyladenosine(9) in tRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:43148)
• guanosine(9) in tRNA + S-adenosyl-L-methionine = N(1)-methylguanosine(9) in tRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:43156)
• an adenosine in mRNA + S-adenosyl-L-methionine = an N(1)-methyladenosine in mRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:55392)

UniProt features (38 total): helix 16, strand 12, sequence variant 4, transit peptide 1, chain 1, domain 1, coiled-coil region 1, modified residue 1, mutagenesis site 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
9GCH	ELECTRON MICROSCOPY	1.9
5NFJ	X-RAY DIFFRACTION	1.96
8CBK	ELECTRON MICROSCOPY	2.76
9EY0	ELECTRON MICROSCOPY	2.78
8CBL	ELECTRON MICROSCOPY	2.79
9EY1	ELECTRON MICROSCOPY	2.9
8RR1	ELECTRON MICROSCOPY	2.93
9EY2	ELECTRON MICROSCOPY	2.96
7ONU	ELECTRON MICROSCOPY	3
8CBM	ELECTRON MICROSCOPY	3.14
8CBO	ELECTRON MICROSCOPY	3.2
8RR4	ELECTRON MICROSCOPY	3.2
8RR3	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7L0Y3-F1	78.35	0.54

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): 84

Mutagenesis-validated functional residues (1):

Position	Phenotype
314	abolished mitochondrial trna methylation. does not affect mitochondrial trna 5’-end processing.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6785470	tRNA processing in the mitochondrion
R-HSA-6787450	tRNA modification in the mitochondrion
R-HSA-8868766	rRNA processing in the mitochondrion

MSigDB gene sets: 213 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_TRNA_METABOLIC_PROCESS, GOBP_MITOCHONDRIAL_TRANSLATION, GOBP_RNA_METHYLATION, GOBP_TRANSLATION, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_RNA_MODIFICATION, GOBP_MITOCHONDRIAL_RNA_PROCESSING, GOBP_TRNA_METHYLATION, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, GARY_CD5_TARGETS_DN, GOBP_TRNA_THREONYLCARBAMOYLADENOSINE_METABOLIC_PROCESS, GOBP_METHYLATION, GOBP_TRNA_PROCESSING

GO Biological Process (9): mitochondrial RNA 5’-end processing (GO:0000964), mRNA processing (GO:0006397), positive regulation of mitochondrial translation (GO:0070131), mitochondrial tRNA methylation (GO:0070901), mitochondrial tRNA processing (GO:0090646), mitochondrial tRNA 5’-end processing (GO:0097745), mitochondrial tRNA 3’-end processing (GO:1990180), tRNA processing (GO:0008033), methylation (GO:0032259)

GO Molecular Function (8): tRNA binding (GO:0000049), RNA binding (GO:0003723), identical protein binding (GO:0042802), tRNA (guanosine(9)-N1)-methyltransferase activity (GO:0052905), tRNA (adenine(9)-N1)-methyltransferase activity (GO:0160106), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), mitochondrial ribonuclease P complex (GO:0030678), mitochondrial nucleoid (GO:0042645), tRNA methyltransferase complex (GO:0043527)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
tRNA processing	2
rRNA processing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	6
mitochondrial RNA processing	2
RNA processing	2
mitochondrial tRNA processing	2
intracellular membrane-bounded organelle	2
RNA 5’-end processing	1
mRNA metabolic process	1
mitochondrial translation	1
positive regulation of translation	1
regulation of mitochondrial translation	1
tRNA methylation	1
mitochondrial tRNA modification	1
mitochondrial RNA metabolic process	1
tRNA processing	1
mitochondrial RNA 5’-end processing	1
tRNA 5’-end processing	1
mitochondrial RNA 3’-end processing	1
tRNA 3’-end processing	1
tRNA metabolic process	1
metabolic process	1
RNA binding	1
nucleic acid binding	1
protein binding	1
tRNA (guanine) methyltransferase activity	1
tRNA (adenine) methyltransferase activity	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular organelle lumen	1
ribonuclease P complex	1
mitochondrial protein-containing complex	1
mitochondrial matrix	1
nucleoid	1
intracellular membraneless organelle	1
methyltransferase complex	1

Protein interactions and networks

STRING

1924 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRMT10C	PRORP	O15091	998
TRMT10C	HSD17B10	Q99714	996
TRMT10C	TRMT61B	Q9BVS5	917
TRMT10C	TRMT6	Q9UJA5	850
TRMT10C	FSIP1	Q8NA03	836
TRMT10C	TRMT61A	Q96FX7	821
TRMT10C	ELAC2	Q9BQ52	775
TRMT10C	ALKBH1	Q13686	697
TRMT10C	HSD17B1	P14061	692
TRMT10C	TRMT5	Q32P41	684
TRMT10C	ALKBH3	Q96Q83	643
TRMT10C	PTCD1	O75127	638
TRMT10C	PUS1	Q9Y606	615
TRMT10C	DHX30	Q7L2E3	599
TRMT10C	RRP8	O43159	571

IntAct

132 interactions, top by confidence:

A	B	Type	Score
AKR7A3	AKR7A2	psi-mi:“MI:0914”(association)	0.890
HSD17B10	TRMT10C	psi-mi:“MI:0407”(direct interaction)	0.880
HSD17B10	TRMT10C	psi-mi:“MI:0915”(physical association)	0.880
HSD17B10	PRORP	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HSD17B10		psi-mi:“MI:0915”(physical association)	0.670
HSD17B10		psi-mi:“MI:0213”(methylation reaction)	0.670
HSD17B10		psi-mi:“MI:0902”(rna cleavage)	0.670
ELAC2	RNF123	psi-mi:“MI:0914”(association)	0.640
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
	TRMT10C	psi-mi:“MI:0407”(direct interaction)	0.560
	TRMT10C	psi-mi:“MI:0915”(physical association)	0.540
	TRMT10C	psi-mi:“MI:0407”(direct interaction)	0.540
TRMT10C	ZZEF1	psi-mi:“MI:0914”(association)	0.530
HSD17B10	SSB	psi-mi:“MI:0914”(association)	0.530

BioGRID (255): TRMT10C (Affinity Capture-MS), TRNI (Biochemical Activity), ZZEF1 (Affinity Capture-MS), HECTD3 (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), TRMT10C (Affinity Capture-MS)

ESM2 similar proteins: A0JMA8, A4IHS0, B5DF07, D3ZRC4, D6WMX4, E7EXT2, F7AEX0, F7BJB9, O15091, O93530, Q09287, Q14149, Q1L987, Q24558, Q28C44, Q2KI45, Q2TBE0, Q32NQ8, Q3MHI8, Q3UFY8, Q4KLI2, Q4R366, Q5RDI0, Q5U245, Q5U2R4, Q5VZ89, Q5XTS1, Q66JD1, Q66JJ4, Q6DDV1, Q6GLI9, Q7JUX9, Q7L0Y3, Q7Z401, Q86VD1, Q8C1Z8, Q8JZY4, Q8K1N1, Q8N6Q8, Q8TBZ6

Diamond homologs: A4IHS0, O14214, Q08BM0, Q08DP1, Q2KI45, Q3MHI8, Q3UFY8, Q4I8X0, Q4KLI2, Q4WXA1, Q59Q39, Q5B8X0, Q5U2R4, Q6C1W9, Q6PF06, Q7JUX9, Q7L0Y3, Q8C1Z8, Q8TBZ6, Q9VR56, P0CS10, P0CS11, Q12400, Q5RJK3, Q66JJ4, Q6BWG3, Q6CUM6, Q6FQB2, Q75A17, Q9D075

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	75
Likely benign	18
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
224317	NM_017819.4(TRMT10C):c.814A>G (p.Thr272Ala)	Pathogenic

SpliceAI

206 predictions. Top by Δscore:

Variant	Effect	Δscore
3:101562000:CCTGG:C	donor_loss	1.0000
3:101562003:GGT:G	donor_loss	1.0000
3:101562004:G:GG	donor_gain	1.0000
3:101562004:GTAA:G	donor_loss	1.0000
3:101562005:T:G	donor_loss	1.0000
3:101564764:TTACA:T	acceptor_loss	0.9900
3:101564765:TACA:T	acceptor_loss	0.9900
3:101564767:CA:C	acceptor_loss	0.9900
3:101564768:A:AC	acceptor_loss	0.9900
3:101564768:A:AG	acceptor_gain	0.9900
3:101564768:AG:A	acceptor_gain	0.9900
3:101564768:AGG:A	acceptor_gain	0.9900
3:101564769:G:A	acceptor_loss	0.9900
3:101564769:G:GG	acceptor_gain	0.9900
3:101564769:GG:G	acceptor_gain	0.9900
3:101564769:GGG:G	acceptor_gain	0.9900
3:101564769:GGGGT:G	acceptor_gain	0.9800
3:101561999:TCCTG:T	donor_gain	0.9700
3:101564766:ACAGG:A	acceptor_gain	0.9700
3:101563251:G:GT	donor_gain	0.9600
3:101563251:G:T	donor_gain	0.9600
3:101563302:C:T	donor_gain	0.9600
3:101564766:ACAG:A	acceptor_gain	0.9600
3:101564768:AGGG:A	acceptor_gain	0.9600
3:101564769:GGGG:G	acceptor_gain	0.9600
3:101562001:CTG:C	donor_gain	0.9500
3:101562002:TG:T	donor_gain	0.9500
3:101562003:GG:G	donor_gain	0.9500
3:101562000:CCTG:C	donor_gain	0.9400
3:101562664:G:GT	donor_gain	0.9200

AlphaMissense

2695 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:101565398:T:A	V206D	0.994
3:101565650:T:C	L290S	0.994
3:101565886:T:A	W369R	0.994
3:101565886:T:C	W369R	0.994
3:101565908:T:A	V376D	0.994
3:101565469:A:C	S230R	0.993
3:101565471:T:A	S230R	0.993
3:101565471:T:G	S230R	0.993
3:101565461:T:C	L227P	0.991
3:101565483:C:A	N234K	0.990
3:101565483:C:G	N234K	0.990
3:101565888:G:C	W369C	0.989
3:101565888:G:T	W369C	0.989
3:101565811:T:A	W344R	0.986
3:101565811:T:C	W344R	0.986
3:101565661:T:C	S294P	0.985
3:101565757:G:C	A326P	0.985
3:101565833:T:C	L351P	0.985
3:101565373:G:C	A198P	0.984
3:101565395:T:C	L205S	0.981
3:101565626:T:C	F282S	0.980
3:101565653:C:T	T291I	0.980
3:101565704:T:A	V308E	0.980
3:101565813:G:C	W344C	0.980
3:101565813:G:T	W344C	0.980
3:101565899:T:C	L373P	0.980
3:101565502:T:C	F241L	0.979
3:101565504:C:A	F241L	0.979
3:101565504:C:G	F241L	0.979
3:101565519:C:G	C246W	0.979

dbSNP variants (sampled 300 via entrez): RS1001175090 (3:101561165 G>A,C), RS1001416497 (3:101561227 G>A,C), RS1001573260 (3:101560986 T>G), RS1003325329 (3:101563559 A>G), RS1004584839 (3:101564628 G>A), RS1004934811 (3:101564348 C>T), RS1005125760 (3:101564672 G>T), RS1005366485 (3:101560447 G>A,C), RS1005723933 (3:101566586 T>A), RS1006000797 (3:101566519 T>C,G), RS1006187374 (3:101566217 G>A), RS1006443278 (3:101561467 T>C), RS1007076280 (3:101559907 C>A,T), RS1007386571 (3:101562675 T>A), RS1007433506 (3:101560259 T>A)

Disease associations

OMIM: gene MIM:615423 | disease phenotypes: MIM:616974

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation defect type 30	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR

Mondo (2): combined oxidative phosphorylation defect type 30 (MONDO:0014856), mitochondrial disease (MONDO:0044970)

Orphanet (2): Combined oxidative phosphorylation defect type 30 (Orphanet:478042), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0001252	Hypotonia
HP:0001410	Decreased liver function
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001712	Left ventricular hypertrophy
HP:0002020	Gastroesophageal reflux
HP:0002033	Poor suck
HP:0002126	Polymicrogyria
HP:0002151	Increased circulating lactate concentration
HP:0002490	Increased CSF lactate
HP:0002878	Respiratory failure
HP:0003128	Lactic acidosis
HP:0003200	Ragged-red muscle fibers
HP:0003348	Hyperalaninemia
HP:0003623	Neonatal onset
HP:0003688	Cytochrome C oxidase-negative muscle fibers
HP:0006821	Frontal polymicrogyria
HP:0008314	Decreased activity of mitochondrial complex II
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0011923	Decreased activity of mitochondrial complex I
HP:0011924	Decreased activity of mitochondrial complex III
HP:0011968	Feeding difficulties
HP:0030948	Elevated gamma-glutamyltransferase level
HP:0031956	Elevated circulating aspartate aminotransferase concentration
HP:0031964	Elevated circulating alanine aminotransferase concentration
HP:0032653	Elevated lactate:pyruvate ratio
HP:6000182	Absent otoacoustic emissions

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005038_3	Allergic disease (asthma, hay fever or eczema)	9.000000e-09
GCST006630_56	Diastolic blood pressure	2.000000e-15
GCST007323_65	Risk-taking tendency (4-domain principal component model)	4.000000e-12
GCST007328_84	Alcohol consumption (drinks per week)	1.000000e-08
GCST90002381_178	Eosinophil count	1.000000e-17
GCST90002382_573	Eosinophil percentage of white cells	2.000000e-18

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0008579	risk-taking behaviour
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Acetaminophen	decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
kojic acid	decreases expression	1
methylparaben	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	increases expression	1
zinc chromate	increases abundance, increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1

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