PTCD3

Summary

PTCD3 (pentatricopeptide repeat domain 3, HGNC:24717) is a protein-coding gene on chromosome 2p11.2, encoding Small ribosomal subunit protein mS39 (Q96EY7). Mitochondrial RNA-binding protein that has a role in mitochondrial translation. It is a selective cancer dependency (DepMap: 79.3% of cell lines).

Enables rRNA binding activity and ribosomal small subunit binding activity. Involved in mitochondrial translation. Located in several cellular components, including cytosol; mitochondrial matrix; and nucleoplasm. Implicated in combined oxidative phosphorylation deficiency 51.

Source: NCBI Gene 55037 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined oxidative phosphorylation deficiency 51 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 173 total — 5 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 19
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 79.3% of screened cell lines
• MANE Select transcript: NM_017952

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24717
Approved symbol	PTCD3
Name	pentatricopeptide repeat domain 3
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20758, DKFZp666K071, mS39
Ensembl gene	ENSG00000132300
Ensembl biotype	protein_coding
OMIM	614918
Entrez	55037

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 25 protein_coding, 11 retained_intron, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000254630, ENST00000409326, ENST00000409783, ENST00000418628, ENST00000464541, ENST00000465560, ENST00000467273, ENST00000469585, ENST00000472044, ENST00000473829, ENST00000476215, ENST00000477520, ENST00000480102, ENST00000483925, ENST00000484203, ENST00000487043, ENST00000488801, ENST00000493430, ENST00000494323, ENST00000627371, ENST00000898151, ENST00000898152, ENST00000898153, ENST00000898154, ENST00000898155, ENST00000898156, ENST00000898157, ENST00000898158, ENST00000898159, ENST00000898160, ENST00000898161, ENST00000898162, ENST00000898163, ENST00000898164, ENST00000938578, ENST00000938579, ENST00000938580, ENST00000938581, ENST00000971271, ENST00000971272, ENST00000971273, ENST00000971274

RefSeq mRNA: 1 — MANE Select: NM_017952 NM_017952

CCDS: CCDS33235

Canonical transcript exons

ENST00000254630 — 24 exons

Exon	Start	End
ENSE00000799902	86137469	86142157
ENSE00001616986	86106235	86106351
ENSE00001624316	86136982	86137140
ENSE00001662570	86136521	86136562
ENSE00001684631	86127941	86127991
ENSE00001734128	86127161	86127305
ENSE00003462483	86131078	86131106
ENSE00003474047	86117055	86117159
ENSE00003482653	86130648	86130737
ENSE00003504036	86111113	86111158
ENSE00003507556	86118921	86119044
ENSE00003510387	86125455	86125515
ENSE00003523974	86134292	86134377
ENSE00003528418	86133178	86133256
ENSE00003537325	86132318	86132424
ENSE00003538487	86124995	86125082
ENSE00003568017	86134839	86134987
ENSE00003579904	86123701	86123762
ENSE00003581802	86125795	86125880
ENSE00003585431	86121479	86121594
ENSE00003607019	86133346	86133436
ENSE00003610003	86108500	86108536
ENSE00003645899	86108350	86108402
ENSE00003692125	86116530	86116598

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 98.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 54.6765 / max 832.8301, expressed in 1820 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21284	52.7404	1820
21286	1.9361	757

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.34	gold quality
calcaneal tendon	UBERON:0003701	96.78	gold quality
ventricular zone	UBERON:0003053	96.41	gold quality
rectum	UBERON:0001052	96.39	gold quality
left ovary	UBERON:0002119	96.34	gold quality
right ovary	UBERON:0002118	96.04	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.67	gold quality
right adrenal gland	UBERON:0001233	95.55	gold quality
right uterine tube	UBERON:0001302	95.53	gold quality
right adrenal gland cortex	UBERON:0035827	95.48	gold quality
right testis	UBERON:0004534	95.45	gold quality
adenohypophysis	UBERON:0002196	95.43	gold quality
body of uterus	UBERON:0009853	95.43	gold quality
left testis	UBERON:0004533	95.40	gold quality
left lobe of thyroid gland	UBERON:0001120	95.28	gold quality
nerve	UBERON:0001021	95.21	gold quality
tibial nerve	UBERON:0001323	95.21	gold quality
right lobe of thyroid gland	UBERON:0001119	95.17	gold quality
left adrenal gland	UBERON:0001234	95.16	gold quality
body of pancreas	UBERON:0001150	95.06	gold quality
adrenal gland	UBERON:0002369	95.06	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.06	gold quality
left adrenal gland cortex	UBERON:0035825	95.04	gold quality
colonic epithelium	UBERON:0000397	95.03	gold quality
right atrium auricular region	UBERON:0006631	95.02	gold quality
pituitary gland	UBERON:0000007	94.98	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.93	gold quality
diaphragm	UBERON:0001103	94.83	gold quality
muscle of leg	UBERON:0001383	94.83	gold quality
ovary	UBERON:0000992	94.75	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

116 targeting PTCD3, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-579-3P	99.86	71.66	3628

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 79.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 5)

• PTCD3 associates with the small subunit of the mitochondrial ribosome and is required for efficient translation. (PMID:19427859)
• lowering PTCD3 in 143B osteosarcoma cells decreased mitochondrial protein synthesis, mitochondrial respiration and the activity of Complexes III and IV, suggesting that PTCD3 has a role in mitochondrial translation (PMID:19427859)
• PTCD3 levels may serve as a novel biomarker for prostate cancer prognosis. (PMID:30132530)
• Sanger sequencing of gDNA from the affected individual and unaffected family members confirming the PTCD3 variants (PMID:30607703)
• Leigh syndrome is the main clinical characteristic of PTCD3 deficiency. (PMID:36450274)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ptcd3	ENSDARG00000103856
mus_musculus	Ptcd3	ENSMUSG00000063884
rattus_norvegicus	Ptcd3	ENSRNOG00000009484
drosophila_melanogaster	CG4679	FBGN0033816
caenorhabditis_elegans	let-630	WBGENE00002804

Protein

Protein identifiers

Small ribosomal subunit protein mS39 — Q96EY7 (reviewed: Q96EY7)

Alternative names: 28S ribosomal protein S39, mitochondrial, Pentatricopeptide repeat domain-containing protein 3, mitochondrial, Transformation-related gene 15 protein

All UniProt accessions (4): Q96EY7, B8ZZQ4, F8WBP9, F8WE76

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial RNA-binding protein that has a role in mitochondrial translation.

Subunit / interactions. Component of the mitochondrial small ribosomal subunit (mt-SSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. Associated with the 12S mitochondrial rRNA (12S mt-rRNA).

Subcellular location. Mitochondrion.

Tissue specificity. Abundant in testes, skeletal muscle and heart tissue.

Disease relevance. Combined oxidative phosphorylation deficiency 51 (COXPD51) [MIM:619057] An autosomal recessive, mitochondrial disorder characterized by intrauterine growth retardation, low birth weight, poor overall growth, progressive limb rigidity, delayed psychomotor development, hearing loss, and optic atrophy. Brain imaging shows abnormal bilateral signs at the basal ganglia and brainstem. Patient cells show decreased mitochondrial complex I and IV levels and activities, and generalized mitochondrial translation defects. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the mitochondrion-specific ribosomal protein mS39 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96EY7-1	1	yes
Q96EY7-2	2

RefSeq proteins (1): NP_060422* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002885	PPR_rpt	Repeat
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR037387	PTCD3	Family
IPR055063	Rib_mS39_PPR	Repeat

Pfam: PF13812, PF22330

UniProt features (62 total): helix 37, repeat 10, splice variant 2, sequence variant 2, sequence conflict 2, strand 2, turn 2, transit peptide 1, chain 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

77 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7QI4	ELECTRON MICROSCOPY	2.21
8CSS	ELECTRON MICROSCOPY	2.36
7P2E	ELECTRON MICROSCOPY	2.4
8RRI	ELECTRON MICROSCOPY	2.4
9OLF	ELECTRON MICROSCOPY	2.46
9OJM	ELECTRON MICROSCOPY	2.5
8CSQ	ELECTRON MICROSCOPY	2.54
8CSR	ELECTRON MICROSCOPY	2.54
6ZM6	ELECTRON MICROSCOPY	2.59
7QI5	ELECTRON MICROSCOPY	2.63
8CSP	ELECTRON MICROSCOPY	2.66
7PNX	ELECTRON MICROSCOPY	2.76
8ANY	ELECTRON MICROSCOPY	2.85
8CST	ELECTRON MICROSCOPY	2.85
6ZM5	ELECTRON MICROSCOPY	2.89
7PO0	ELECTRON MICROSCOPY	2.9
8K2A	ELECTRON MICROSCOPY	2.9
9PGL	ELECTRON MICROSCOPY	2.9
7PO1	ELECTRON MICROSCOPY	2.92
7PO3	ELECTRON MICROSCOPY	2.92
9PGF	ELECTRON MICROSCOPY	2.93
6VMI	ELECTRON MICROSCOPY	2.96
6RW4	ELECTRON MICROSCOPY	2.97
6VLZ	ELECTRON MICROSCOPY	2.97
7QI6	ELECTRON MICROSCOPY	2.98
8QRN	ELECTRON MICROSCOPY	2.98
9PSM	ELECTRON MICROSCOPY	2.98
8OIS	ELECTRON MICROSCOPY	3
9G5C	ELECTRON MICROSCOPY	3
9G5D	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96EY7-F1	79.48	0.43

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): 126

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5368286	Mitochondrial translation initiation
R-HSA-5389840	Mitochondrial translation elongation
R-HSA-5419276	Mitochondrial translation termination
R-HSA-9937383	Mitochondrial ribosome-associated quality control

MSigDB gene sets: 185 (showing top): CMYB_01, GOBP_MITOCHONDRIAL_TRANSLATION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, AACYNNNNTTCCS_UNKNOWN, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOCC_MITOCHONDRIAL_ENVELOPE, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_TRANS, APPIERTO_RESPONSE_TO_FENRETINIDE_DN, DODD_NASOPHARYNGEAL_CARCINOMA_UP, chr2p11, GCM_NF2, GATA4_Q3, BURTON_ADIPOGENESIS_5, BERENJENO_TRANSFORMED_BY_RHOA_UP

GO Biological Process (2): regulation of translation (GO:0006417), mitochondrial translation (GO:0032543)

GO Molecular Function (4): RNA binding (GO:0003723), rRNA binding (GO:0019843), ribosomal small subunit binding (GO:0043024), protein binding (GO:0005515)

GO Cellular Component (9): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), mitochondrial small ribosomal subunit (GO:0005763), cytosol (GO:0005829), plasma membrane (GO:0005886), ribosome (GO:0005840), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Mitochondrial translation	4

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translation	2
mitochondrion	2
cellular anatomical structure	2
cytoplasm	2
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
mitochondrial gene expression	1
nucleic acid binding	1
RNA binding	1
ribosome binding	1
binding	1
nuclear lumen	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
intracellular organelle lumen	1
organellar small ribosomal subunit	1
mitochondrial ribosome	1
mitochondrial protein-containing complex	1
membrane	1
cell periphery	1
intracellular membraneless organelle	1
protein-containing complex	1

Protein interactions and networks

STRING

1584 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTCD3	POLRMT	O00411	793
PTCD3	PTCD1	O75127	724
PTCD3	DHX30	Q7L2E3	703
PTCD3	PTCD2	Q8WV60	681
PTCD3	LRPPRC	P42704	670
PTCD3	MRPS7	Q9Y2R9	657
PTCD3	MRPS27	Q92552	623
PTCD3	CHCHD1	Q96BP2	604
PTCD3	PRORP	O15091	594
PTCD3	MRPS34	P82930	571
PTCD3	MTIF3	Q9H2K0	569
PTCD3	DAP3	P51398	544
PTCD3	MRPL42	Q9Y6G3	543
PTCD3	MRPS31	Q92665	540
PTCD3	KGD4	P82909	534

IntAct

246 interactions, top by confidence:

A	B	Type	Score
FBL	NOP56	psi-mi:“MI:0914”(association)	0.800
YBX1	HNRNPR	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PTCD3	LNX2	psi-mi:“MI:0915”(physical association)	0.670
ESR1	TRIM24	psi-mi:“MI:0914”(association)	0.640
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
TEFM	POLRMT	psi-mi:“MI:0914”(association)	0.560
NP	KPNA6	psi-mi:“MI:0914”(association)	0.550
RPS6	IPO7	psi-mi:“MI:0914”(association)	0.530
MRPS18B	MRPS14	psi-mi:“MI:0914”(association)	0.530
SNRNP70	GTPBP1	psi-mi:“MI:0914”(association)	0.530
ZNF689	ZNF593	psi-mi:“MI:0914”(association)	0.530
MRPS34	ZZEF1	psi-mi:“MI:0914”(association)	0.530
ZBTB48	ZBTB24	psi-mi:“MI:0914”(association)	0.530
E4F1	ZBTB24	psi-mi:“MI:0914”(association)	0.530
MRPS18C	MRPS14	psi-mi:“MI:0914”(association)	0.530
TRMT10B	MRPS14	psi-mi:“MI:0914”(association)	0.530
ZFC3H1	HNRNPCL1	psi-mi:“MI:0914”(association)	0.530
PDGFB	DKC1	psi-mi:“MI:0914”(association)	0.530
MRPS15	PRKACG	psi-mi:“MI:0914”(association)	0.530
MRPS27	YBX1	psi-mi:“MI:0914”(association)	0.530

BioGRID (453): PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS), PTCD3 (Affinity Capture-MS)

ESM2 similar proteins: A1A5P5, A1L2L5, A1Z9A8, B5DF07, O15091, P42704, Q07DV3, Q08CK1, Q0IHP3, Q14C51, Q14CX7, Q14CZ7, Q28C74, Q28DE0, Q2KI62, Q32LU7, Q32N55, Q32PI8, Q3SZ55, Q4R366, Q4R6I5, Q53R41, Q566X6, Q58CX2, Q5R503, Q5R8W8, Q5RFI6, Q5SGE0, Q5XIR8, Q5ZKK3, Q5ZLS8, Q68FN9, Q6AYP3, Q6DI86, Q6GQ66, Q6PB66, Q6QI44, Q7L8L6, Q7TMV3, Q7Z3E5

Diamond homologs: A1Z9A8, Q0IHP3, Q14C51, Q2KI62, Q32LU7, Q32N55, Q5R8W8, Q96EY7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PTCD3	“form complex”	“28S mitochondrial small ribosomal subunit”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 217 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
Mitochondrial translation	24	24.1×	4e-25
Mitochondrial translation initiation	25	23.1×	2e-25
Mitochondrial translation elongation	25	23.1×	2e-25
Mitochondrial ribosome-associated quality control	25	22.4×	3e-25
Mitochondrial translation termination	25	20.0×	4e-24
Transport of Mature Transcript to Cytoplasm	5	13.9×	5e-04
Translation	29	13.1×	1e-22
mRNA 3’-end processing	7	10.1×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial translation	25	23.0×	2e-24
cytoplasmic translation	11	10.8×	2e-06
translation	18	9.8×	2e-10
ribosomal small subunit biogenesis	7	8.4×	5e-03
RNA processing	7	8.1×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	7
Uncertain significance	102
Likely benign	10
Benign	1

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
2671852	NM_017952.6(PTCD3):c.1453-1G>C	Pathogenic
2671854	NM_017952.6(PTCD3):c.902C>T (p.Thr301Ile)	Pathogenic
4848068	NM_017952.6(PTCD3):c.640C>T (p.Gln214Ter)	Pathogenic
982042	NM_017952.6(PTCD3):c.415-2A>G	Pathogenic
982043	NM_017952.6(PTCD3):c.1746_1747dup (p.Phe583fs)	Pathogenic
1691029	NM_017952.6(PTCD3):c.710del (p.Thr237fs)	Likely pathogenic
2629227	NM_017952.6(PTCD3):c.1148-2A>G	Likely pathogenic
3065533	NM_017952.6(PTCD3):c.1979+1G>A	Likely pathogenic
3235825	NM_017952.6(PTCD3):c.1431G>A (p.Trp477Ter)	Likely pathogenic
3348111	NM_017952.6(PTCD3):c.1166C>G (p.Ser389Ter)	Likely pathogenic
4818995	NM_017952.6(PTCD3):c.1630-1G>A	Likely pathogenic
4845731	NM_017952.6(PTCD3):c.805-2A>G	Likely pathogenic

SpliceAI

3456 predictions. Top by Δscore:

Variant	Effect	Δscore
2:86108495:ATTAG:A	acceptor_gain	1.0000
2:86108498:A:AG	acceptor_gain	1.0000
2:86108499:G:GG	acceptor_gain	1.0000
2:86108533:CTTG:C	donor_gain	1.0000
2:86108535:TGG:T	donor_loss	1.0000
2:86108536:GGT:G	donor_loss	1.0000
2:86108537:G:A	donor_loss	1.0000
2:86108537:G:GG	donor_gain	1.0000
2:86108538:T:G	donor_loss	1.0000
2:86111111:A:AG	acceptor_gain	1.0000
2:86111111:AG:A	acceptor_gain	1.0000
2:86111112:G:GG	acceptor_gain	1.0000
2:86111112:GG:G	acceptor_gain	1.0000
2:86111154:ACAGG:A	donor_gain	1.0000
2:86111155:CAGG:C	donor_gain	1.0000
2:86111156:AGG:A	donor_gain	1.0000
2:86111157:GG:G	donor_gain	1.0000
2:86111157:GGG:G	donor_gain	1.0000
2:86111158:GG:G	donor_gain	1.0000
2:86116526:ACAG:A	acceptor_gain	1.0000
2:86116527:C:G	acceptor_gain	1.0000
2:86116528:A:AG	acceptor_gain	1.0000
2:86116528:A:C	acceptor_loss	1.0000
2:86116528:AG:A	acceptor_gain	1.0000
2:86116529:G:GT	acceptor_gain	1.0000
2:86116529:GG:G	acceptor_gain	1.0000
2:86116529:GGAT:G	acceptor_gain	1.0000
2:86116594:AATCT:A	donor_gain	1.0000
2:86116595:ATCT:A	donor_gain	1.0000
2:86116596:TCT:T	donor_gain	1.0000

AlphaMissense

4578 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:86132320:C:G	C423W	0.984
2:86134863:G:C	A552P	0.983
2:86132346:C:A	A432D	0.981
2:86133380:T:C	L496P	0.980
2:86133430:T:A	W513R	0.980
2:86133430:T:C	W513R	0.980
2:86131096:C:A	A419D	0.979
2:86134864:C:A	A552D	0.979
2:86131083:T:C	F415L	0.978
2:86131085:T:A	F415L	0.978
2:86131085:T:G	F415L	0.978
2:86127956:C:A	T371K	0.977
2:86131095:G:C	A419P	0.977
2:86131084:T:C	F415S	0.970
2:86132318:T:C	C423R	0.970
2:86136559:C:A	P606H	0.968
2:86111135:G:C	A73P	0.967
2:86137061:G:C	A634P	0.967
2:86134854:G:C	A549P	0.965
2:86121512:T:C	L191P	0.961
2:86125069:G:C	R264P	0.961
2:86127956:C:G	T371R	0.961
2:86133383:T:C	L497P	0.961
2:86133246:T:C	L481P	0.960
2:86137062:C:A	A634E	0.960
2:86130734:G:C	D412H	0.959
2:86133388:G:C	A499P	0.959
2:86125809:T:C	F294L	0.958
2:86125811:T:A	F294L	0.958
2:86125811:T:G	F294L	0.958

dbSNP variants (sampled 300 via entrez): RS1000046984 (2:86122327 A>C,G), RS1000072736 (2:86118871 T>C), RS1000208638 (2:86113000 G>A,T), RS1000222394 (2:86138164 C>T), RS1000239805 (2:86111520 A>G), RS1000252640 (2:86105576 A>T), RS1000287796 (2:86123498 C>T), RS1000299074 (2:86125072 G>C), RS1000337103 (2:86107437 G>A), RS1000376651 (2:86117608 T>G), RS1000569179 (2:86111731 TTTTG>T,TTTTGTTTG), RS1000824186 (2:86136525 A>G), RS1000877889 (2:86129514 C>T), RS1000910517 (2:86129966 C>T), RS1000930679 (2:86137547 T>A,C)

Disease associations

OMIM: gene MIM:614918 | disease phenotypes: MIM:619057

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation deficiency 51	Strong	Autosomal recessive
Leigh syndrome	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR

Mondo (2): combined oxidative phosphorylation deficiency 51 (MONDO:0033631), Leigh syndrome (MONDO:0009723)

Orphanet (0):

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0001336	Myoclonus
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0002059	Cerebral atrophy
HP:0002063	Rigidity
HP:0002376	Developmental regression
HP:0002643	Neonatal respiratory distress
HP:0002878	Respiratory failure
HP:0003510	Severe short stature
HP:0011410	Caesarean section
HP:0011923	Decreased activity of mitochondrial complex I
HP:0011951	Aspiration pneumonia
HP:0012692	Focal T2 hyperintense thalamic lesion
HP:0040288	Nasogastric tube feeding

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000903_7	Response to methylphenidate treatment in attention-deficit/hyperactivity disorder (blood pressure)	3.000000e-06
GCST004730_1	Facial emotion recognition (sad faces)	2.000000e-06
GCST007094_12	Diastolic blood pressure	3.000000e-06
GCST007096_245	Pulse pressure	4.000000e-06
GCST007099_181	Systolic blood pressure	4.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008329	facial emotion recognition measurement
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure

MeSH disease descriptors (1)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067351 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, decreases expression	4
Acetaminophen	decreases expression	2
Doxorubicin	decreases expression, affects response to substance	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects 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 S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Benztropine	increases expression, affects cotreatment, decreases expression	1
Cadmium	increases abundance, increases expression	1
Clozapine	increases expression	1
Coumestrol	increases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Ozone	affects expression, increases abundance	1
Ribonucleotides	affects binding	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652185	Binding	Binding affinity to human PTCD3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells