DLST

Summary

DLST (dihydrolipoamide S-succinyltransferase, HGNC:2911) is a protein-coding gene on chromosome 14q24.3, encoding Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (P36957). Dihydrolipoamide succinyltransferase (E2) component of the 2-oxoglutarate dehydrogenase complex. It is a selective cancer dependency (DepMap: 27.6% of cell lines).

This gene encodes a mitochondrial protein that belongs to the 2-oxoacid dehydrogenase family. This protein is one of the three components (the E2 component) of the 2-oxoglutarate dehydrogenase complex that catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 1743 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary pheochromocytoma-paraganglioma (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 173 total
• Phenotypes (HPO): 45
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 27.6% of screened cell lines
• MANE Select transcript: NM_001933

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2911
Approved symbol	DLST
Name	dihydrolipoamide S-succinyltransferase
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	OGDC-E2, KGD2
Ensembl gene	ENSG00000119689
Ensembl biotype	protein_coding
OMIM	126063
Entrez	1743

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 17 protein_coding, 6 nonsense_mediated_decay, 6 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000238671, ENST00000334220, ENST00000550473, ENST00000554612, ENST00000554806, ENST00000555071, ENST00000555089, ENST00000555190, ENST00000555459, ENST00000555492, ENST00000555988, ENST00000556190, ENST00000556460, ENST00000556582, ENST00000557012, ENST00000626051, ENST00000875048, ENST00000875049, ENST00000875050, ENST00000875051, ENST00000875052, ENST00000875053, ENST00000875054, ENST00000875055, ENST00000875056, ENST00000875057, ENST00000875058, ENST00000875059, ENST00000875060, ENST00000875061

RefSeq mRNA: 2 — MANE Select: NM_001933 NM_001244883, NM_001933

CCDS: CCDS9833

Canonical transcript exons

ENST00000334220 — 15 exons

Exon	Start	End
ENSE00002430505	74902196	74903743
ENSE00003463257	74889095	74889147
ENSE00003483814	74885586	74885634
ENSE00003492745	74882591	74882624
ENSE00003504830	74889275	74889349
ENSE00003575672	74899923	74899996
ENSE00003579414	74900289	74900372
ENSE00003623164	74901066	74901233
ENSE00003631601	74894312	74894409
ENSE00003644648	74881916	74882016
ENSE00003662356	74891056	74891167
ENSE00003664753	74892834	74892986
ENSE00003680070	74889897	74889952
ENSE00003682850	74898369	74898499
ENSE00003684143	74893348	74893424

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 97.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 66.3122 / max 472.9507, expressed in 1824 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140590	64.2478	1824
140589	2.0645	1459

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.50	gold quality
right adrenal gland cortex	UBERON:0035827	97.38	gold quality
right adrenal gland	UBERON:0001233	97.30	gold quality
heart left ventricle	UBERON:0002084	97.20	gold quality
gastrocnemius	UBERON:0001388	97.19	gold quality
left adrenal gland	UBERON:0001234	97.16	gold quality
cardiac ventricle	UBERON:0002082	97.15	gold quality
muscle of leg	UBERON:0001383	97.03	gold quality
left adrenal gland cortex	UBERON:0035825	96.98	gold quality
right atrium auricular region	UBERON:0006631	96.90	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.87	gold quality
lower esophagus	UBERON:0013473	96.86	gold quality
secondary oocyte	CL:0000655	96.83	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.78	gold quality
skin of leg	UBERON:0001511	96.75	gold quality
rectum	UBERON:0001052	96.74	gold quality
skin of abdomen	UBERON:0001416	96.70	gold quality
mucosa of stomach	UBERON:0001199	96.67	gold quality
transverse colon	UBERON:0001157	96.65	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.57	gold quality
heart	UBERON:0000948	96.40	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.39	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.37	gold quality
adrenal cortex	UBERON:0001235	96.36	gold quality
adrenal gland	UBERON:0002369	96.31	gold quality
endocervix	UBERON:0000458	96.30	gold quality
metanephros cortex	UBERON:0010533	96.24	gold quality
cardiac atrium	UBERON:0002081	96.19	gold quality
body of stomach	UBERON:0001161	96.17	gold quality
omental fat pad	UBERON:0010414	96.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.04

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, AR, ARID4A, BMAL1, CEBPB, CEBPG, CLOCK, CREB1, E2F1, E2F3, ELK1, ESR1, ESR2, ETS1, FOXL2, GLI2, HES1, HSF2, ID1, ISL1, JUN, MYBL2, MYC, MYOD1, NCOA1, NFIL3, NFKB1, NFKB, NFYA, NR1I3, NR2F1, NR3C1, NR4A1, RARB, RELA, SNAI1, SP1, SP3, SREBF1

miRNA regulators (miRDB)

38 targeting DLST, 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-5011-5P	100.00	83.46	5820
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-4460	99.37	68.52	615
HSA-MIR-7158-5P	99.25	67.95	796
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-4712-3P	98.52	65.39	822
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4632-5P	97.82	65.38	1470

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 27.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• Data show that the dihydrolipoamide succinyltransferase gene is bifunctional, and truncated mRNA transcribed from it contributes to the biogenesis of the mitochondrial respiratory complexes. (PMID:12805207)
• Association between late-onset Alzheimer disease shows strong linkage disequilibrium across the DLST locus. (PMID:15038610)
• 2-oxoglutarate dehydrogenase complex (OGDHC), the key regulatory enzyme of Krebs cycle. [review] (PMID:22235656)
• ATP consumption is demonstrated in respiration-impaired isolated and in situ neuronal somal mitochondria from transgenic mice that exhibit a 20-48% decrease in alpha-ketoglutarate dehydrogenase activity. (PMID:23475850)
• RNAi knockdown of DLST led to decreased cell viability and induction of apoptosis in human T-ALL cell lines (PMID:26876595)
• five germline variants affecting DLST in eight unrelated individuals were identified; all except one were diagnosed with multiple pheochromocytomas and paragangliomas (PMID:30929736)
• Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma. (PMID:33180916)
• Metabolic Enzyme DLST Promotes Tumor Aggression and Reveals a Vulnerability to OXPHOS Inhibition in High-Risk Neuroblastoma. (PMID:34233924)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dlst	ENSDARG00000014230
mus_musculus	Dlst	ENSMUSG00000004789
rattus_norvegicus	Dlst	ENSRNOG00000005061
drosophila_melanogaster	CG5214	FBGN0037891
caenorhabditis_elegans		WBGENE00020950

Paralogs (3): PDHX (ENSG00000110435), DBT (ENSG00000137992), DLAT (ENSG00000150768)

Protein

Protein identifiers

Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial — P36957 (reviewed: P36957)

Alternative names: 2-oxoglutarate dehydrogenase complex component E2, Dihydrolipoamide succinyltransferase component of 2-oxoglutarate dehydrogenase complex, E2K

All UniProt accessions (8): P36957, B7ZAZ8, G3V3F0, G3V498, G3V5L9, G3V5M3, H0YJF9, Q86SW4

UniProt curated annotations — full annotation on UniProt →

Function. Dihydrolipoamide succinyltransferase (E2) component of the 2-oxoglutarate dehydrogenase complex. The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion. A fraction of the 2-oxoglutarate dehydrogenase complex also localizes in the nucleus and is required for lysine succinylation of histones: associates with KAT2A on chromatin and provides succinyl-CoA to histone succinyltransferase KAT2A.

Subunit / interactions. The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2), DLD (dihydrolipoamide dehydrogenase; E3) and the assembly factor KGD4. It contains multiple copies of the three enzymatic components (E1, E2 and E3). In the nucleus, the 2-oxoglutarate dehydrogenase complex associates with KAT2A. Interacts with ABHD11; this interaction maintains the functional lipoylation of the 2-oxoglutarate dehydrogenase complex.

Subcellular location. Mitochondrion matrix. Nucleus.

Disease relevance. Pheochromocytoma/paraganglioma syndrome 7 (PPGL7) [MIM:618475] A form of pheochromocytoma/paraganglioma syndrome, a tumor predisposition syndrome characterized by the development of neuroendocrine tumors, usually in adulthood. Pheochromocytomas are catecholamine-producing tumors that arise from chromaffin cells in the adrenal medulla. Paragangliomas develop from sympathetic paraganglia in the thorax, abdomen, and pelvis, as well as from parasympathetic paraganglia in the head and neck. PPGL7 tumors are generally benign, tend to be abdominal, and often secrete normetanephrine. PPGL7 inheritance is autosomal dominant. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Cofactor. Binds 1 lipoyl cofactor covalently.

Pathway. Amino-acid degradation; L-lysine degradation via saccharopine pathway; glutaryl-CoA from L-lysine: step 6/6. Carbohydrate metabolism; tricarboxylic acid cycle.

Similarity. Belongs to the 2-oxoacid dehydrogenase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P36957-1	1	yes
P36957-2	2

RefSeq proteins (2): NP_001231812, NP_001924* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000089	Biotin_lipoyl	Domain
IPR001078	2-oxoacid_DH_actylTfrase	Domain
IPR003016	2-oxoA_DH_lipoyl-BS	Binding_site
IPR006255	SucB	Family
IPR011053	Single_hybrid_motif	Homologous_superfamily
IPR023213	CAT-like_dom_sf	Homologous_superfamily
IPR050537	2-oxoacid_dehydrogenase	Family

Pfam: PF00198, PF00364

Enzyme classification (BRENDA):

• EC 1.2.1.105 — 2-oxoglutarate dehydrogenase system (BRENDA: 28 organisms, 44 substrates, 119 inhibitors, 83 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-OXOGLUTARATE	0.0025–10.1	50
COA	0.0032–0.075	11
NAD+	0.0249–0.3	11
2-OXOVALERATE	0.0063–0.0163	5
2-OXOADIPATE	0.107–0.52	2

Catalyzed reactions (Rhea), 1 shown:

• N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + succinyl-CoA = N(6)-[(R)-S(8)-succinyldihydrolipoyl]-L-lysyl-[protein] + CoA (RHEA:15213)

UniProt features (54 total): helix 11, strand 9, modified residue 8, sequence variant 6, sequence conflict 4, turn 4, splice variant 2, mutagenesis site 2, compositionally biased region 2, active site 2, transit peptide 1, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6H05	ELECTRON MICROSCOPY	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P36957-F1	77.40	0.44

Functional residue map

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

Catalytic / active sites (2): 424; 428

Post-translational modifications (8): 154, 267, 272, 273, 277, 307, 81, 110

Mutagenesis-validated functional residues (2):

Position	Phenotype
224–226	reduced nuclear localization of the 2-oxoglutarate dehydrogenase complex. reduced histone succinylation.
424	loss of dihydrolipoyllysine-residue succinyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-6783984	Glycine degradation
R-HSA-9853506	OGDH complex synthesizes succinyl-CoA from 2-OG
R-HSA-9857492	Protein lipoylation
R-HSA-9858328	OADH complex synthesizes glutaryl-CoA from 2-OA

MSigDB gene sets: 339 (showing top): GGGACCA_MIR133A_MIR133B, E2F_Q4_01, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, CREBP1_Q2, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, PUJANA_CHEK2_PCC_NETWORK, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, BILD_HRAS_ONCOGENIC_SIGNATURE, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, ONKEN_UVEAL_MELANOMA_UP, E2F_Q3

GO Biological Process (6): generation of precursor metabolites and energy (GO:0006091), tricarboxylic acid cycle (GO:0006099), 2-oxoglutarate metabolic process (GO:0006103), succinyl-CoA metabolic process (GO:0006104), obsolete L-lysine catabolic process to acetyl-CoA via L-saccharopine (GO:0033512), 2-oxoglutarate decarboxylation to succinyl-CoA (GO:0120551)

GO Molecular Function (4): dihydrolipoyllysine-residue succinyltransferase activity (GO:0004149), acyltransferase activity (GO:0016746), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), membrane (GO:0016020), oxoglutarate dehydrogenase complex (GO:0045252), oxoadipate dehydrogenase complex (GO:0160167)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Glyoxylate metabolism and glycine degradation	1
Citric acid cycle (TCA cycle)	1
Post-translational protein modification	1
Lysine catabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular membrane-bounded organelle	2
cytoplasm	2
alpha-ketoacid dehydrogenase complex	2
transferase complex	2
metabolic process	1
aerobic respiration	1
primary metabolic process	1
dicarboxylic acid metabolic process	1
acyl-CoA metabolic process	1
tricarboxylic acid cycle	1
2-oxoglutarate metabolic process	1
succinyl-CoA biosynthetic process	1
S-succinyltransferase activity	1
catalytic activity, acting on a protein	1
transferase activity	1
binding	1
catalytic activity	1
nuclear lumen	1
mitochondrion	1
intracellular organelle lumen	1
tricarboxylic acid cycle heteromeric enzyme complex	1

Protein interactions and networks

STRING

2792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLST	OGDH	Q02218	999
DLST	DHTKD1	Q96HY7	981
DLST	DLD	P09622	980
DLST	OGDHL	Q9ULD0	978
DLST	ACO2	Q99798	689
DLST	ACO1	P21399	635
DLST	MDH2	P40926	628
DLST	IDH3A	P50213	623
DLST	IDH2	P48735	605
DLST	SUCLG1	P53597	600
DLST	SUCLA2	Q9P2R7	595
DLST	IDH3B	O43837	588
DLST	FH	P07954	578
DLST	IDH1	O75874	577
DLST	IDH3G	P51553	572

IntAct

347 interactions, top by confidence:

A	B	Type	Score
DLD	PDHX	psi-mi:“MI:0914”(association)	0.880
DLST	PSMC4	psi-mi:“MI:0915”(physical association)	0.670
DLST		psi-mi:“MI:0915”(physical association)	0.560
DNASE1L1	DLST	psi-mi:“MI:0915”(physical association)	0.560
DLST	FUT2	psi-mi:“MI:0915”(physical association)	0.560
DLST	GJA5	psi-mi:“MI:0915”(physical association)	0.560
GNAO1	DLST	psi-mi:“MI:0915”(physical association)	0.560
HLA-DRB3	DLST	psi-mi:“MI:0915”(physical association)	0.560
DLST	HSD3B1	psi-mi:“MI:0915”(physical association)	0.560
DLST	IDH1	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	DLST	psi-mi:“MI:0915”(physical association)	0.560
DLST	LGALS1	psi-mi:“MI:0915”(physical association)	0.560
DLST	LGALS8	psi-mi:“MI:0915”(physical association)	0.560
DLST	EPCAM	psi-mi:“MI:0915”(physical association)	0.560
DLST	MAGEA2	psi-mi:“MI:0915”(physical association)	0.560
CNOT3	DLST	psi-mi:“MI:0915”(physical association)	0.560
PPEF1	DLST	psi-mi:“MI:0915”(physical association)	0.560
DLST	PSMD2	psi-mi:“MI:0915”(physical association)	0.560
DLST	RAP1B	psi-mi:“MI:0915”(physical association)	0.560
	DLST	psi-mi:“MI:0915”(physical association)	0.560
TAFAZZIN	DLST	psi-mi:“MI:0915”(physical association)	0.560
DLST	TDO2	psi-mi:“MI:0915”(physical association)	0.560
DLST	THBS3	psi-mi:“MI:0915”(physical association)	0.560
U2AF1	DLST	psi-mi:“MI:0915”(physical association)	0.560
SLC25A11	DLST	psi-mi:“MI:0915”(physical association)	0.560
DLST	RASSF2	psi-mi:“MI:0915”(physical association)	0.560
DLST	HUWE1	psi-mi:“MI:0915”(physical association)	0.560
DLST	RBM5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (553): DLST (Affinity Capture-MS), DBT (Co-fractionation), DLST (Co-fractionation), DLST (Co-fractionation), DLST (Co-fractionation), DLST (Co-fractionation), STOML2 (Co-fractionation), DLST (Affinity Capture-MS), DLST (Affinity Capture-MS), DLST (Affinity Capture-MS), DLST (Affinity Capture-MS), DLST (Proximity Label-MS), FLOT1 (Affinity Capture-MS), SQSTM1 (Affinity Capture-MS), CHTOP (Affinity Capture-MS)

ESM2 similar proteins: A0A0D2Y5A7, G0S4X6, O00330, O59816, O94681, P08461, P0CN60, P0CN61, P10515, P11141, P11179, P11180, P11961, P12695, P19262, P20285, P21883, P22439, P35489, P36413, P36957, P37900, P45118, P65634, P86197, P9WIS6, P9WIS7, Q01205, Q0WQF7, Q19749, Q1RHI5, Q1RJT3, Q23571, Q4ULG1, Q59638, Q5B0C0, Q5M729, Q5Y223, Q869Y7, Q8BKZ9

Diamond homologs: A0A0D2Y5A7, G0S4X6, G0S5Q0, O00330, O31550, O59816, O66113, O66119, O94709, P06959, P08461, P10515, P11180, P12695, P16263, P16451, P19262, P20285, P20708, P22439, P36413, P36957, P45118, P47514, P52993, P65635, P65636, P75392, P86197, Q0WQF7, Q19749, Q1RJT3, Q49XM4, Q4UKI7, Q4ULG1, Q59098, Q59695, Q59821, Q5HGY9, Q5M729

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
DLST	“form complex”	OGDC	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	100
Likely benign	44
Benign	12

Top pathogenic / likely-pathogenic (0)

SpliceAI

1838 predictions. Top by Δscore:

Variant	Effect	Δscore
14:74882013:GAAG:G	donor_gain	1.0000
14:74882014:AAG:A	donor_loss	1.0000
14:74882017:G:GC	donor_loss	1.0000
14:74889148:G:GG	donor_gain	1.0000
14:74889261:T:A	acceptor_gain	1.0000
14:74889264:A:AG	acceptor_gain	1.0000
14:74889265:T:G	acceptor_gain	1.0000
14:74889270:CCTA:C	acceptor_loss	1.0000
14:74889271:CTA:C	acceptor_loss	1.0000
14:74889272:TA:T	acceptor_loss	1.0000
14:74889273:A:AG	acceptor_gain	1.0000
14:74889273:AGAG:A	acceptor_gain	1.0000
14:74889274:G:GC	acceptor_gain	1.0000
14:74889274:GA:G	acceptor_gain	1.0000
14:74889274:GAGG:G	acceptor_gain	1.0000
14:74889274:GAGGA:G	acceptor_gain	1.0000
14:74889346:AAAG:A	donor_loss	1.0000
14:74889347:AAG:A	donor_loss	1.0000
14:74889350:G:A	donor_loss	1.0000
14:74889351:T:A	donor_loss	1.0000
14:74889896:GCT:G	acceptor_gain	1.0000
14:74889948:ACAAG:A	donor_loss	1.0000
14:74889949:CAAG:C	donor_loss	1.0000
14:74889950:AAG:A	donor_loss	1.0000
14:74889951:AG:A	donor_loss	1.0000
14:74889952:GGTA:G	donor_loss	1.0000
14:74889953:G:A	donor_loss	1.0000
14:74889954:T:G	donor_loss	1.0000
14:74891132:G:GT	donor_gain	1.0000
14:74891157:G:GT	donor_gain	1.0000

AlphaMissense

2936 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:74889335:T:A	V87D	1.000
14:74889912:T:A	V97D	1.000
14:74889930:T:A	V103D	1.000
14:74889952:G:C	K110N	1.000
14:74889952:G:T	K110N	1.000
14:74894352:T:C	L238P	1.000
14:74899973:A:C	S318R	1.000
14:74899975:T:A	S318R	1.000
14:74899975:T:G	S318R	1.000
14:74901120:A:C	S372R	1.000
14:74901122:C:A	S372R	1.000
14:74901122:C:G	S372R	1.000
14:74902242:G:C	R425P	1.000
14:74889293:T:A	V73D	0.999
14:74889320:T:A	V82D	0.999
14:74889328:G:A	G85R	0.999
14:74889328:G:C	G85R	0.999
14:74889329:G:A	G85E	0.999
14:74889340:T:A	W89R	0.999
14:74889340:T:C	W89R	0.999
14:74889932:T:C	C104R	0.999
14:74889934:T:G	C104W	0.999
14:74889939:T:A	I106N	0.999
14:74889945:C:T	T108I	0.999
14:74889950:A:G	K110E	0.999
14:74891069:T:A	V115D	0.999
14:74891093:T:A	I123N	0.999
14:74891126:T:A	V134D	0.999
14:74891144:T:A	L140H	0.999
14:74894342:G:C	A235P	0.999

dbSNP variants (sampled 300 via entrez): RS1000200089 (14:74901591 C>T), RS1000308785 (14:74900937 G>A), RS1000495709 (14:74888429 A>C,G), RS1000534368 (14:74899830 T>C), RS1000870141 (14:74882303 CAG>C), RS1000871305 (14:74882449 G>A), RS1001197520 (14:74899287 T>G), RS1001578781 (14:74880965 A>C,G), RS1001619799 (14:74886093 T>C), RS1001693599 (14:74901771 C>G), RS1001826347 (14:74882709 CATA>C), RS1001912726 (14:74899688 C>T), RS1001936276 (14:74880692 T>C), RS1002039961 (14:74884649 C>T), RS1002447232 (14:74896258 A>G)

Disease associations

OMIM: gene MIM:126063 | disease phenotypes: MIM:168000, MIM:618475, MIM:203740

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary pheochromocytoma-paraganglioma	Supportive	Autosomal dominant
pheochromocytoma/paraganglioma syndrome 7	Limited	Autosomal dominant
pyruvate dehydrogenase E1-alpha deficiency	No Known Disease Relationship	Autosomal recessive

Mondo (4): hereditary pheochromocytoma-paraganglioma (MONDO:0017366), pheochromocytoma/paraganglioma syndrome 7 (MONDO:0032771), oxoglutaricaciduria (MONDO:0008759), pyruvate dehydrogenase E1-alpha deficiency (MONDO:0010717)

Orphanet (2): Hereditary pheochromocytoma-paraganglioma (Orphanet:29072), Oxoglutaric aciduria (Orphanet:31)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000405	Conductive hearing impairment
HP:0000526	Aniridia
HP:0000740	Episodic paroxysmal anxiety
HP:0000790	Hematuria
HP:0000980	Pallor
HP:0001069	Episodic hyperhidrosis
HP:0001095	Hypertensive retinopathy
HP:0001293	Cranial nerve compression
HP:0001337	Tremor
HP:0001342	Cerebral hemorrhage
HP:0001605	Vocal cord paralysis
HP:0001618	Dysphonia
HP:0001635	Congestive heart failure
HP:0001824	Weight loss
HP:0001962	Palpitations
HP:0002018	Nausea
HP:0002331	Recurrent paroxysmal headache
HP:0002574	Episodic abdominal pain
HP:0002640	Hypertension associated with pheochromocytoma
HP:0002666	Pheochromocytoma
HP:0002668	Paraganglioma
HP:0002864	Paraganglioma of head and neck
HP:0003072	Hypercalcemia
HP:0003345	Elevated urinary norepinephrine level
HP:0003528	Elevated circulating calcitonin concentration
HP:0003574	Positive regitine blocking test
HP:0003581	Adult onset

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001734_8	Non-small cell lung cancer	7.000000e-06
GCST005237_3	Mood instability	1.000000e-06
GCST005238_3	Mood instability	3.000000e-09
GCST005839_15	Depression	4.000000e-09
GCST009600_51	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	2.000000e-08
GCST90000025_543	Appendicular lean mass	6.000000e-27
GCST90002381_604	Eosinophil count	5.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008475	mood instability measurement
EFO:0004980	appendicular lean mass
EFO:0004842	eosinophil count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C536582	Alpha-ketoglutarate dehydrogenase deficiency (supp.)
C564071	Pyruvate Dehydrogenase E1 Alpha Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066909 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.73	Kd	1864	nM	CHEMBL5653589
5.73	ED50	1864	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148245: Binding affinity to human DLST incubated for 45 mins by Kinobead based pull down assay	kd	1.8636	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, decreases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
bisphenol S	increases expression	3
Arsenic	increases abundance, increases expression, affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
GSK-J4	increases expression	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	increases expression	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
decabromobiphenyl ether	increases expression	1
arsenite	affects binding, increases reaction	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
acipimox	increases expression	1
beta-methylcholine	affects expression	1
CGP 52608	increases reaction, affects binding	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
bisphenol AF	increases expression	1
Aspirin	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases expression	1
Cannabidiol	decreases expression	1
Clozapine	decreases expression	1
Cuprizone	decreases expression	1
Furaldehyde	affects localization, increases expression, affects cotreatment	1
Isoniazid	increases expression	1
Ivermectin	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
CHEMBL5651287	Binding	Binding affinity to human DLST 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)

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

Trial	Phase	Status	Title
NCT05257005	Not specified	UNKNOWN	Natural History Study of Pyruvate Dehydrogenase Deficiency
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition