TUFM

Summary

TUFM (Tu translation elongation factor, mitochondrial, HGNC:12420) is a protein-coding gene on chromosome 16p11.2, encoding Elongation factor Tu, mitochondrial (P49411). GTP hydrolase that promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis. It is a selective cancer dependency (DepMap: 27.2% of cell lines).

This gene encodes a protein which participates in protein translation in mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency resulting in lactic acidosis and fatal encephalopathy. A pseudogene has been identified on chromosome 17.

Source: NCBI Gene 7284 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined oxidative phosphorylation defect type 4 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 26
• Clinical variants (ClinVar): 219 total — 4 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 19
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 27.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003321

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12420
Approved symbol	TUFM
Name	Tu translation elongation factor, mitochondrial
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	EFTu, EF-TuMT, EFTU
Ensembl gene	ENSG00000178952
Ensembl biotype	protein_coding
OMIM	602389
Entrez	7284

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 21 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000313511, ENST00000561644, ENST00000565012, ENST00000569217, ENST00000864057, ENST00000864058, ENST00000864059, ENST00000864060, ENST00000864061, ENST00000864062, ENST00000864063, ENST00000864064, ENST00000864065, ENST00000864066, ENST00000864067, ENST00000864068, ENST00000916488, ENST00000916489, ENST00000916490, ENST00000916491, ENST00000916492, ENST00000916493, ENST00000916494, ENST00000916495

RefSeq mRNA: 2 — MANE Select: NM_003321 NM_001365360, NM_003321

CCDS: CCDS10642

Canonical transcript exons

ENST00000313511 — 10 exons

Exon	Start	End
ENSE00001251421	28843950	28844101
ENSE00001251451	28845314	28845480
ENSE00001251458	28845912	28846106
ENSE00001321584	28842411	28843148
ENSE00001321717	28846218	28846348
ENSE00003515075	28844230	28844334
ENSE00003585244	28844951	28845055
ENSE00003630535	28844698	28844862
ENSE00003667552	28844419	28844551
ENSE00003693242	28843736	28843855

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 99.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 203.3715 / max 1103.7490, expressed in 1827 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156914	172.8075	1827
156915	14.6348	1784
156913	8.9965	1777
156912	6.9326	1711

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.17	gold quality
apex of heart	UBERON:0002098	98.99	gold quality
right adrenal gland	UBERON:0001233	98.49	gold quality
left adrenal gland	UBERON:0001234	98.49	gold quality
metanephros cortex	UBERON:0010533	98.49	gold quality
body of pancreas	UBERON:0001150	98.48	gold quality
transverse colon	UBERON:0001157	98.48	gold quality
body of stomach	UBERON:0001161	98.47	gold quality
right adrenal gland cortex	UBERON:0035827	98.45	gold quality
left adrenal gland cortex	UBERON:0035825	98.44	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.39	gold quality
granulocyte	CL:0000094	98.34	gold quality
right lobe of liver	UBERON:0001114	98.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.26	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.25	gold quality
right lobe of thyroid gland	UBERON:0001119	98.21	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.21	gold quality
right uterine tube	UBERON:0001302	98.20	gold quality
right atrium auricular region	UBERON:0006631	98.13	gold quality
lower esophagus mucosa	UBERON:0035834	98.12	gold quality
left testis	UBERON:0004533	98.11	gold quality
right testis	UBERON:0004534	98.09	gold quality
rectum	UBERON:0001052	98.07	gold quality
minor salivary gland	UBERON:0001830	98.06	gold quality
embryo	UBERON:0000922	98.02	gold quality
ganglionic eminence	UBERON:0004023	98.02	gold quality
adenohypophysis	UBERON:0002196	98.01	gold quality
left lobe of thyroid gland	UBERON:0001120	97.91	gold quality
gastrocnemius	UBERON:0001388	97.91	gold quality
vermiform appendix	UBERON:0001154	97.70	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	20.52
E-MTAB-6819	no	755.30
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting TUFM, 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-188-3P	100.00	68.76	1240
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-8066	99.05	68.66	1532
HSA-MIR-4536-5P	98.47	64.39	657
HSA-MIR-758-3P	98.42	68.60	1122
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-4659A-5P	98.03	66.42	819
HSA-MIR-4659B-5P	98.03	66.84	979
HSA-MIR-4468	98.01	66.85	1187

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 27.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 14)

• Genetic investigation of patients with defective mitochondrial translation led to the discovery of novel mutations in the mitochondrial elongation factor G1 (EFG1) in one affected baby and in the mitochondrial elongation factor Tu (EFTu) in another one (PMID:17160893)
• 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)
• Results suggest that the R336Q mutant mt-EFTu variant fails to bind to aminoacylated mitochondrial tRNAs, thus explaining the observed impairment of mitochondrial translation. (PMID:19524667)
• By recruiting Atg5-Atg12 and NLRX1, TUFM serves as a nodal checkpoint of the RIG-I-MAVS axis. It acts similarly to NLRX1 by inhibiting RigI-like-receptor-induced IFN-I but promoting autophagy. (PMID:22749352)
• Increased expression of TUFM is a promising new prognostic indicator for colorectal carcinoma. (PMID:22772342)
• NLRX1 and TUFM work in concert to reduce cytokine response and augment autophagy. (PMID:23321557)
• TUFM is a novel regulator of epithelial-mesenchymal transition (EMT); there may be a molecular link between mitochondrial dysfunction and EMT induction (PMID:26781467)
• we identify a novel signaling hub centering on the NLRX1 TUFM protein complex, promoting autophagic flux. Defects in the expression of either NLRX1 or TUFM result in compromised autophagy when treated with EGFR inhibitors.These findings expand our understanding of the components involved in head and neck squamous cell carcinoma autophagy machinery that responds to EGFR inhibitors. (PMID:26876213)
• Novel mutation in mitochondrial Elongation Factor EF-Tu associated to dysplastic leukoencephalopathy and defective mitochondrial DNA translation. (PMID:28132884)
• High expression of TUFM is associated with colorectal cancer. (PMID:28449687)
• study revealed a novel role for TUFM as a host restriction factor that exerts an inhibitory effect on avian-signature PB2627E influenza virus propagation in human cells; found that increased TUFM-dependent autophagy correlates with the inhibitory effect on avian-signature influenza virus replication and may serve as a key intrinsic mechanism to restrict avian influenza virus infection in humans (PMID:28611246)
• Elongation Factor Tu Switch I Element is a Gate for Aminoacyl-tRNA Selection. (PMID:32061931)
• TUFM is involved in Alzheimer’s disease-like pathologies that are associated with ROS. (PMID:33774866)
• Novel Tu translation elongation factor, mitochondrial (TUFM) homozygous variant in a consanguineous family with premature ovarian insufficiency. (PMID:37461298)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tufm	ENSDARG00000104173
mus_musculus	Tufm	ENSMUSG00000073838
rattus_norvegicus	Tufm	ENSRNOG00000018604
drosophila_melanogaster	mEFTu1	FBGN0024556
caenorhabditis_elegans		WBGENE00007000

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), GFM2 (ENSG00000164347), EEF2 (ENSG00000167658), GFM1 (ENSG00000168827), GTPBP2 (ENSG00000172432), EIF2S3B (ENSG00000180574), GSPT2 (ENSG00000189369)

Protein

Protein identifiers

Elongation factor Tu, mitochondrial — P49411 (reviewed: P49411)

Alternative names: P43

All UniProt accessions (3): P49411, A0A384ME17, H3BNU3

UniProt curated annotations — full annotation on UniProt →

Function. GTP hydrolase that promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis. Participates in mitochondrial translation. Also plays a role in the regulation of autophagy and innate immunity. Recruits ATG5-ATG12 and NLRX1 at mitochondria and serves as a checkpoint of the RIGI-MAVS pathway. In turn, inhibits RLR-mediated type I interferon while promoting autophagy.

Subunit / interactions. Interacts with NLRX1. Interacts with ATG16L1. (Microbial infection) Interacts with human parainfluenza virus 3 matrix protein; this interaction inhibits RLR-mediated type I interferon production while promoting autophagy. (Microbial infection) Interacts with Hantaan hantavirus glycoprotein N; this interaction contributes to the virus-induced degradation of mitochondria by autophagy, which leads to degradation of MAVS and inhibition of type I interferon (IFN) responses.

Subcellular location. Mitochondrion matrix.

Disease relevance. Combined oxidative phosphorylation deficiency 4 (COXPD4) [MIM:610678] A mitochondrial disease resulting in neonatal lactic acidosis, rapidly progressive encephalopathy, severely decreased mitochondrial protein synthesis, and combined deficiency of mtDNA-related mitochondrial respiratory chain complexes. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein biosynthesis; polypeptide chain elongation.

Similarity. Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EF-Tu/EF-1A subfamily.

RefSeq proteins (2): NP_001352289, NP_003312* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000795	T_Tr_GTP-bd_dom	Domain
IPR004160	Transl_elong_EFTu/EF1A_C	Domain
IPR004161	EFTu-like_2	Domain
IPR004541	Transl_elong_EFTu/EF1A_bac/org	Family
IPR009000	Transl_B-barrel_sf	Homologous_superfamily
IPR009001	Transl_elong_EF1A/Init_IF2_C	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031157	G_TR_CS	Conserved_site
IPR033720	EFTU_2	Domain
IPR041709	EF-Tu_GTP-bd	Domain
IPR050055	EF-Tu_GTPase	Family

Pfam: PF00009, PF03143, PF03144

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (32 total): binding site 11, modified residue 10, region of interest 5, sequence conflict 2, transit peptide 1, chain 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9PRA	ELECTRON MICROSCOPY	2.83
9PS7	ELECTRON MICROSCOPY	3.08
7O9K	ELECTRON MICROSCOPY	3.1
9PRQ	ELECTRON MICROSCOPY	3.34
7A5G	ELECTRON MICROSCOPY	4.33

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49411-F1	85.33	0.65

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 (11): 73; 74; 74; 75; 184; 187; 222; 223; 224; 70; 72

Post-translational modifications (10): 82, 91, 91, 237, 259, 281, 289, 315, 364, 421

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5389840	Mitochondrial translation elongation
R-HSA-9754560	SARS-CoV-2 modulates autophagy

MSigDB gene sets: 0 (showing top):

GO Biological Process (5): translational elongation (GO:0006414), mitochondrial translation (GO:0032543), mitochondrial translational elongation (GO:0070125), mitochondrial large ribosomal subunit assembly (GO:1902775), translation (GO:0006412)

GO Molecular Function (9): magnesium ion binding (GO:0000287), RNA binding (GO:0003723), translation elongation factor activity (GO:0003746), GTPase activity (GO:0003924), GTP binding (GO:0005525), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), membrane (GO:0016020), mitochondrial nucleoid (GO:0042645), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Mitochondrial translation	1
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	3
translational elongation	3
translation	2
macromolecule biosynthetic process	2
mitochondrial gene expression	1
mitochondrial translation	1
ribosomal large subunit assembly	1
mitochondrial ribosome assembly	1
peptidyltransferase activity	1
translational initiation	1
translational termination	1
protein metabolic process	1
protein biosynthetic process	1
metal ion binding	1
nucleic acid binding	1
translation factor activity	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
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1
organelle outer membrane	1
cellular anatomical structure	1
mitochondrial matrix	1
nucleoid	1
intracellular membraneless organelle	1
extracellular vesicle	1

Protein interactions and networks

STRING

4901 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TUFM	NLRX1	Q86UT6	986
TUFM	TSFM	P43897	978
TUFM	ATG16L1	Q676U5	962
TUFM	ATG12	O94817	946
TUFM	ATG5	Q9H1Y0	941
TUFM	MRPS16	Q9Y3D3	914
TUFM	MTFMT	Q96DP5	907
TUFM	MRPS22	P82650	864
TUFM	HOGA1	Q86XE5	792
TUFM	MRRF	Q96E11	755
TUFM	RABEP2	Q9H5N1	667
TUFM	AIFM1	O95831	650
TUFM	APOBR	Q0VD83	645
TUFM	MIEF2	Q96C03	637
TUFM	TRMU	O75648	625

IntAct

217 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TUFM	FAM9B	psi-mi:“MI:0915”(physical association)	0.670
FAM9B	TUFM	psi-mi:“MI:0915”(physical association)	0.670
PB2	TUFM	psi-mi:“MI:0915”(physical association)	0.600
PB2	TUFM	psi-mi:“MI:0403”(colocalization)	0.600
PB2	TUFM	psi-mi:“MI:0914”(association)	0.600
TUFM	PB2	psi-mi:“MI:0914”(association)	0.600
TUFM	ARL6IP1	psi-mi:“MI:0915”(physical association)	0.560
TUFM	FUNDC1	psi-mi:“MI:0915”(physical association)	0.560
CMTM5	TUFM	psi-mi:“MI:0915”(physical association)	0.560
FUNDC1	TUFM	psi-mi:“MI:0915”(physical association)	0.560
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
TUFM	ZMYM6	psi-mi:“MI:0914”(association)	0.530
TUFM	MTIF2	psi-mi:“MI:0914”(association)	0.530

BioGRID (828): TUFM (Affinity Capture-MS), TUFM (Affinity Capture-MS), ARL6IP1 (Two-hybrid), CMTM5 (Two-hybrid), FUNDC1 (Two-hybrid), FAM9B (Two-hybrid), TUFM (Affinity Capture-MS), TUFM (Affinity Capture-MS), TUFM (Affinity Capture-MS), TUFM (Affinity Capture-MS), TUFM (Affinity Capture-MS), TUFM (Affinity Capture-MS), TUFM (Affinity Capture-MS), TUFM (Affinity Capture-MS), CHMP7 (Co-fractionation)

ESM2 similar proteins: A1USC1, A1USL2, A2CI56, A4G9U0, A5DN78, A5V604, A5VR08, A6W394, A6X0A2, A9ISD9, A9M5Q2, A9NEN4, B0CH34, B1XI63, B8I5N8, C5BQ44, P02992, P17245, P17746, P19457, P49411, P64024, P64025, P85834, Q06J54, Q06SH3, Q0P3M7, Q11HA6, Q134R0, Q134S7, Q1GP97, Q1KVS9, Q20EU5, Q21M86, Q2GD83, Q2HJN9, Q2K9L8, Q2K9N2, Q2YM08, Q54HB2

Diamond homologs: A2RFQ4, A3CP09, A4FWW9, A6UPK8, A6UTL4, A6VGE8, A9AAA4, B0R6Y7, B1MY04, B1YGU8, B4U3U1, B6YW69, B9DRL9, B9LSM6, C4KZP9, C9WPN6, F1QGW6, J9VR81, O26361, O29663, O36041, O50306, O59410, O96719, P0DA82, P0DA83, P20461, P32481, P33170, P33887, P41091, P42476, P45975, P49410, P49411, P50377, P69952, P81795, P85834, Q09130

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PINK1	“down-regulates activity”	TUFM	phosphorylation
TUFM	“down-regulates activity”	ATG5	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 210 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Selective autophagy	6	12.6×	2e-03
Aggrephagy	6	11.2×	3e-03
ESR-mediated signaling	8	7.7×	2e-03
Macroautophagy	8	6.9×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	6	12.0×	5e-03
mitophagy	6	10.9×	6e-03
autophagosome assembly	8	10.3×	2e-03
DNA damage response	13	4.0×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	99
Likely benign	72
Benign	9

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
3243635	NC_000016.9:g.(?28854296)(28857590_?)del	Pathogenic
3650557	NM_003321.5(TUFM):c.722dup (p.Leu242fs)	Pathogenic
372182	NM_003321.5(TUFM):c.440T>A (p.Leu147His)	Pathogenic
372183	NM_003321.5(TUFM):c.162del (p.Thr53_Tyr54insTer)	Pathogenic
215312	NM_003321.5(TUFM):c.1196A>G (p.Glu399Gly)	Likely pathogenic
427129	NM_003321.5(TUFM):c.320G>C (p.Arg107Pro)	Likely pathogenic
488629	NM_003321.5(TUFM):c.989G>C (p.Arg330Pro)	Likely pathogenic

SpliceAI

1206 predictions. Top by Δscore:

Variant	Effect	Δscore
16:28843148:CCTAG:C	acceptor_loss	1.0000
16:28843149:C:CA	acceptor_loss	1.0000
16:28843150:T:G	acceptor_loss	1.0000
16:28843731:CGTA:C	donor_loss	1.0000
16:28843732:GTAC:G	donor_loss	1.0000
16:28843733:TA:T	donor_loss	1.0000
16:28843734:A:AC	donor_gain	1.0000
16:28843735:C:CC	donor_gain	1.0000
16:28843735:CCTT:C	donor_gain	1.0000
16:28843735:CCTTC:C	donor_loss	1.0000
16:28843851:TAAAC:T	acceptor_gain	1.0000
16:28843852:AAAC:A	acceptor_gain	1.0000
16:28843853:AAC:A	acceptor_gain	1.0000
16:28843854:AC:A	acceptor_gain	1.0000
16:28843855:CC:C	acceptor_gain	1.0000
16:28843855:CCTGG:C	acceptor_loss	1.0000
16:28843856:C:CC	acceptor_gain	1.0000
16:28843856:CTG:C	acceptor_loss	1.0000
16:28843944:CCTCA:C	donor_loss	1.0000
16:28843945:CTCA:C	donor_loss	1.0000
16:28843946:TCA:T	donor_loss	1.0000
16:28843947:CA:C	donor_loss	1.0000
16:28844097:AATGC:A	acceptor_gain	1.0000
16:28844098:ATGC:A	acceptor_gain	1.0000
16:28844099:TGC:T	acceptor_gain	1.0000
16:28844099:TGCCT:T	acceptor_loss	1.0000
16:28844100:GC:G	acceptor_gain	1.0000
16:28844101:CC:C	acceptor_gain	1.0000
16:28844102:C:CC	acceptor_gain	1.0000
16:28844102:C:T	acceptor_gain	1.0000

AlphaMissense

2931 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000363752 (16:28847907 C>T), RS1000546483 (16:28842185 T>G), RS1000861490 (16:28844545 C>A,T), RS1001872864 (16:28847610 G>C), RS1002114045 (16:28842129 T>C), RS1002993899 (16:28846445 G>A,T), RS1003290298 (16:28846354 C>T), RS1004386535 (16:28842537 A>G), RS1006289259 (16:28846114 G>A,T), RS1007462272 (16:28844374 A>G), RS1007985611 (16:28843354 TGTTCCTAAG>T), RS1008133307 (16:28846742 C>G), RS1008451512 (16:28847025 G>A), RS1009040233 (16:28845836 C>G,T), RS1009474477 (16:28841967 T>C)

Disease associations

OMIM: gene MIM:602389 | disease phenotypes: MIM:610678

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation defect type 4	Strong	Autosomal recessive
inherited primary ovarian failure	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR

Mondo (3): combined oxidative phosphorylation defect type 4 (MONDO:0012534), mitochondrial disease (MONDO:0044970), inherited primary ovarian failure (MONDO:0019852)

Orphanet (2): Combined oxidative phosphorylation defect type 4 (Orphanet:254925), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000639	Nystagmus
HP:0001257	Spasticity
HP:0001298	Encephalopathy
HP:0001319	Neonatal hypotonia
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001942	Metabolic acidosis
HP:0001987	Hyperammonemia
HP:0002126	Polymicrogyria
HP:0002151	Increased circulating lactate concentration
HP:0002179	Opisthotonus
HP:0002240	Hepatomegaly
HP:0002376	Developmental regression
HP:0002415	Leukodystrophy
HP:0002878	Respiratory failure
HP:0003128	Lactic acidosis
HP:0003593	Infantile onset

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST000830_13	Body mass index	2.000000e-20
GCST002598_62	Educational attainment	1.000000e-06
GCST003435_2	Body fat percentage	8.000000e-08
GCST003435_31	Body fat percentage	1.000000e-08
GCST003435_36	Body fat percentage	5.000000e-06
GCST003435_41	Body fat percentage	7.000000e-07
GCST004067_106	Hip circumference adjusted for BMI	4.000000e-08
GCST004067_38	Hip circumference adjusted for BMI	7.000000e-08
GCST004131_83	Inflammatory bowel disease	2.000000e-12
GCST004132_69	Crohn’s disease	3.000000e-10
GCST004364_11	Intelligence	4.000000e-08
GCST004364_31	Intelligence	1.000000e-08
GCST007044_23	Extremely high intelligence	2.000000e-08
GCST007293_116	Body fat distribution (arm fat ratio)	2.000000e-08
GCST007293_16	Body fat distribution (arm fat ratio)	4.000000e-09
GCST007293_43	Body fat distribution (arm fat ratio)	2.000000e-12
GCST007294_71	Body fat distribution (trunk fat ratio)	2.000000e-12
GCST007294_97	Body fat distribution (trunk fat ratio)	1.000000e-11
GCST007295_20	Body fat distribution (leg fat ratio)	3.000000e-06
GCST007295_44	Body fat distribution (leg fat ratio)	1.000000e-21
GCST007295_79	Body fat distribution (leg fat ratio)	2.000000e-24
GCST007328_28	Alcohol consumption (drinks per week)	3.000000e-11
GCST008058_290	Estimated glomerular filtration rate	1.000000e-11
GCST010133_15	Lamb consumption	3.000000e-08
GCST010703_152	Brain morphology (MOSTest)	3.000000e-09
GCST011122_22	Walking pace	2.000000e-13

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004784	self reported educational attainment
EFO:0007800	body fat percentage
EFO:0008039	BMI-adjusted hip circumference
EFO:0004337	intelligence
EFO:0004341	body fat distribution
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565690	Combined Oxidative Phosphorylation Deficiency 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105970 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,395 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3301622	GILTERITINIB	4	2,395

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 5 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.61	Kd	248.2	nM	CHEMBL3752910
6.61	ED50	248.2	nM	CHEMBL3752910
6.33	Kd	464	nM	GILTERITINIB

PubChem BioAssay actives

2 with measured affinity, of 245 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149688: Binding affinity to human TUFM incubated for 45 mins by Kinobead based pull down assay	kd	0.2482	uM
Gilteritinib	1425206: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.4640	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Quercetin	decreases expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
bisphenol F	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
sodium arsenite	decreases expression	1
butylidenephthalide	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
STA 9090	decreases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	affects response to substance	1
Sunitinib	decreases expression	1
Artesunate	decreases response to substance	1
Acetaminophen	increases expression, affects cotreatment	1
Benzo(a)pyrene	increases expression	1
Carmustine	affects response to substance	1
Dactinomycin	affects cotreatment, increases secretion	1
Dopamine	increases expression	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991919	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

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