SUCLG1

Summary

SUCLG1 (succinate-CoA ligase GDP/ADP-forming subunit alpha, HGNC:11449) is a protein-coding gene on chromosome 2p11.2, encoding Succinate–CoA ligase [ADP/GDP-forming] subunit alpha, mitochondrial (P53597). Succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of either ATP or GTP and thus represents the only step of substrate-level phosphorylation in the TCA.

This gene encodes the alpha subunit of the heterodimeric enzyme succinate coenzyme A ligase. This enzyme is targeted to the mitochondria and catalyzes the conversion of succinyl CoA and ADP or GDP to succinate and ATP or GTP. Mutations in this gene are the cause of the metabolic disorder fatal infantile lactic acidosis and mitochondrial DNA depletion.

Source: NCBI Gene 8802 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial DNA depletion syndrome 9 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 375 total — 23 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 92
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003849

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11449
Approved symbol	SUCLG1
Name	succinate-CoA ligase GDP/ADP-forming subunit alpha
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000163541
Ensembl biotype	protein_coding
OMIM	611224
Entrez	8802

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 9 protein_coding, 5 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000393868, ENST00000430989, ENST00000442240, ENST00000483605, ENST00000484365, ENST00000487809, ENST00000488234, ENST00000491123, ENST00000491642, ENST00000651342, ENST00000900284, ENST00000900285, ENST00000912790, ENST00000912791, ENST00000912792, ENST00000912793, ENST00000949558, ENST00000949559

RefSeq mRNA: 1 — MANE Select: NM_003849 NM_003849

CCDS: CCDS1967

Canonical transcript exons

ENST00000393868 — 9 exons

Exon	Start	End
ENSE00001075821	84433352	84433435
ENSE00001075823	84441047	84441104
ENSE00001870348	84423528	84423772
ENSE00003506194	84449649	84449752
ENSE00003529757	84443284	84443400
ENSE00003561405	84431508	84431659
ENSE00003618725	84441247	84441459
ENSE00003673122	84425415	84425603
ENSE00003841990	84459173	84459280

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 75.2219 / max 576.1547, expressed in 1823 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29360	75.2219	1823

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nephron tubule	UBERON:0001231	99.70	gold quality
renal glomerulus	UBERON:0000074	99.50	gold quality
metanephric glomerulus	UBERON:0004736	99.46	gold quality
renal medulla	UBERON:0000362	99.42	gold quality
jejunal mucosa	UBERON:0000399	99.40	gold quality
duodenum	UBERON:0002114	99.24	gold quality
mucosa of transverse colon	UBERON:0004991	99.17	gold quality
heart right ventricle	UBERON:0002080	99.15	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.95	gold quality
adult organism	UBERON:0007023	98.94	gold quality
cortex of kidney	UBERON:0001225	98.93	gold quality
apex of heart	UBERON:0002098	98.90	gold quality
colonic mucosa	UBERON:0000317	98.83	gold quality
rectum	UBERON:0001052	98.81	gold quality
body of tongue	UBERON:0011876	98.74	gold quality
right atrium auricular region	UBERON:0006631	98.70	gold quality
jejunum	UBERON:0002115	98.69	gold quality
esophagus squamous epithelium	UBERON:0006920	98.69	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.68	gold quality
metanephros cortex	UBERON:0010533	98.67	gold quality
biceps brachii	UBERON:0001507	98.65	gold quality
cardiac ventricle	UBERON:0002082	98.62	gold quality
transverse colon	UBERON:0001157	98.60	gold quality
heart left ventricle	UBERON:0002084	98.60	gold quality
middle temporal gyrus	UBERON:0002771	98.54	gold quality
epithelium of esophagus	UBERON:0001976	98.51	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.51	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.41	gold quality
squamous epithelium	UBERON:0006914	98.40	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	26.01
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

17 targeting SUCLG1, 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-551B-5P	99.96	71.28	3493
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-3138	98.41	67.53	744
HSA-MIR-3929	98.32	65.58	1026
HSA-MIR-3920	97.75	69.02	1168

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 9)

• This report enlarges the phenotypic spectrum of SUCLG1 mutations and confirms that a characteristic metabolic profile (presence of MMA and C4-DC carnitine in urines) and basal ganglia MRI lesions are the hallmarks of SCS defects. (PMID:20197121)
• A novel mutation in the SUCLG1 gene was found in two newborns having lethal lactic acidosis, multi-organ failure and congenital malformations including interrupted aortic arch. (PMID:20227526)
• Our results suggest that SUCLG1 mutations that lead to complete absence of SUCLG1 protein are responsible for a very severe disorder with antenatal manifestations, whereas a SUCLA2-like phenotype is found in patients with residual SUCLG1 protein. (PMID:20693550)
• 3 novel mutations have been identified in patients with the mitochondrial DNA depletion syndrome (c.1048G>A and c.1049G>T in SUCLA2 and c.531+4A>T in SUCLG1). (PMID:22980518)
• First Chinese report of succinyl-CoA ligase deficiency caused by novel SUCLG1 mutations; five novel pathogenic mutations in SUCLG1 were identified (PMID:26028457)
• Long survival, to age 20 years or older, was reported in 12% of SUCLA2 and in 10% of SUCLG1 patients. (PMID:26475597)
• These abnormal phenotypes are rescued upon ectopic expression of wild-type SUCLG1 in the patient’s fibroblasts, thus functionally confirming the pathogenic nature of the SUCLG1 VUS identified in this patient and expanding the phenotypic spectrum for SUCLG1 deficiency (PMID:27484306)
• We report two Tunisian patients belonging to a consanguineous family with mitochondrial encephalomyopathy. Mutational analysis of SUCLG1 gene showed the presence of c.41T > C in exon 1 in a homozygous state. This mutation substitutes a conserved methionine residue to a threonine at position 14 (p.M14T) located at the SUCLG1 protein mitochondrial targeting sequence. (PMID:29217198)
• SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression. (PMID:38649537)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	suclg1	ENSDARG00000052712
mus_musculus	Suclg1	ENSMUSG00000052738
rattus_norvegicus	Suclg1	ENSRNOG00000005587
drosophila_melanogaster	Scsalpha1	FBGN0004888
drosophila_melanogaster	Scsalpha2	FBGN0038708
caenorhabditis_elegans		WBGENE00007350
caenorhabditis_elegans		WBGENE00017759

Protein

Protein identifiers

Succinate–CoA ligase [ADP/GDP-forming] subunit alpha, mitochondrial — P53597 (reviewed: P53597)

Alternative names: Itaconyl–CoA ligase [ADP/GDP-forming] subunit alpha, Malyl–CoA ligase [ADP/GDP-forming] subunit alpha, Succinyl-CoA synthetase subunit alpha

All UniProt accessions (3): A0A494C0D1, P53597, H7C233

UniProt curated annotations — full annotation on UniProt →

Function. Succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of either ATP or GTP and thus represents the only step of substrate-level phosphorylation in the TCA. The alpha subunit of the enzyme binds the substrates coenzyme A and phosphate, while succinate binding and specificity for either ATP or GTP is provided by different beta subunits. Also able to act as an itaconyl- and malyl-CoA synthetase.

Subunit / interactions. Heterodimer of an alpha and a beta subunit. Different beta subunits determine nucleotide specificity. Together with the ATP-specific beta subunit SUCLA2, forms an ADP-forming succinyl-CoA synthetase (A-SCS). Together with the GTP-specific beta subunit SUCLG2 forms a GDP-forming succinyl-CoA synthetase (G-SCS).

Subcellular location. Mitochondrion.

Disease relevance. Mitochondrial DNA depletion syndrome 9 (MTDPS9) [MIM:245400] A severe disorder due to mitochondrial dysfunction. It is characterized by infantile onset of hypotonia, lactic acidosis, severe psychomotor retardation, progressive neurologic deterioration, and excretion of methylmalonic acid. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by itaconate.

Pathway. Carbohydrate metabolism; tricarboxylic acid cycle; succinate from succinyl-CoA (ligase route): step 1/1.

Similarity. Belongs to the succinate/malate CoA ligase alpha subunit family.

RefSeq proteins (1): NP_003840* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003781	CoA-bd	Domain
IPR005810	CoA_lig_alpha	Family
IPR005811	SUCC_ACL_C	Domain
IPR016102	Succinyl-CoA_synth-like	Homologous_superfamily
IPR017440	Cit_synth/succinyl-CoA_lig_AS	Active_site
IPR033847	Citrt_syn/SCS-alpha_CS	Conserved_site
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily

Pfam: PF00549, PF02629

Enzyme classification (BRENDA):

• EC 6.2.1.4 — succinate-CoA ligase (GDP-forming) (BRENDA: 27 organisms, 37 substrates, 7 inhibitors, 27 Km, 5 kcat entries)
• EC 6.2.1.5 — succinate-CoA ligase (ADP-forming) (BRENDA: 55 organisms, 83 substrates, 41 inhibitors, 96 Km, 47 kcat entries)

Substrate kinetics (BRENDA)

21 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.005–1.6	28
SUCCINATE	0.141–14	21
COA	0.0013–29	17
GTP	0.009–0.63	9
SUCCINATE	0.39–5.1	6
COA	0.004–0.036	5
ITACONATE	0.351–1.509	5
GTP	0.011–0.311	4
ATP	0.145–0.265	3
ADP	0.0077–0.25	3
D-MALATE	3.588–4.243	3
L-MALATE	2.558–3.27	3
SUCCINYL-COA	0.0221–0.041	3
PHOSPHATE	0.72–1.4	2
GDP	0.007	1

Catalyzed reactions (Rhea), 3 shown:

• succinate + ATP + CoA = succinyl-CoA + ADP + phosphate (RHEA:17661)
• GTP + succinate + CoA = succinyl-CoA + GDP + phosphate (RHEA:22120)
• (S)-malate + ATP + CoA = (S)-malyl-CoA + ADP + phosphate (RHEA:26193)

UniProt features (52 total): strand 15, helix 12, modified residue 8, sequence variant 4, sequence conflict 4, binding site 4, turn 2, transit peptide 1, chain 1, active site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6WCV	X-RAY DIFFRACTION	1.52
7MSR	X-RAY DIFFRACTION	1.58
7MST	X-RAY DIFFRACTION	1.61
7MSS	X-RAY DIFFRACTION	1.75
8Z03	X-RAY DIFFRACTION	1.99
8Z02	X-RAY DIFFRACTION	2.32
6G4Q	X-RAY DIFFRACTION	2.59
9SWJ	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53597-F1	91.82	0.88

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 (1): 299 (tele-phosphohistidine intermediate)

Ligand- & substrate-binding residues (4): 64–67; 90; 143–145; 207

Post-translational modifications (8): 66, 66, 81, 105, 338, 54, 57, 57

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-71403	Citric acid cycle (TCA cycle)
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism

MSigDB gene sets: 378 (showing top): GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, WEI_MYCN_TARGETS_WITH_E_BOX, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, GOBP_SULFUR_COMPOUND_CATABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_DETOXIFICATION, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_CATABOLIC_PROCESS, chr2p11, DOUGLAS_BMI1_TARGETS_UP

GO Biological Process (2): tricarboxylic acid cycle (GO:0006099), succinyl-CoA catabolic process (GO:1901289)

GO Molecular Function (8): nucleotide binding (GO:0000166), RNA binding (GO:0003723), succinate-CoA ligase activity (GO:0004774), succinate-CoA ligase (ADP-forming) activity (GO:0004775), succinate-CoA ligase (GDP-forming) activity (GO:0004776), catalytic activity (GO:0003824), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), succinate-CoA ligase complex (ADP-forming) (GO:0009361), succinate-CoA ligase complex (GDP-forming) (GO:0045244)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
succinate-CoA ligase activity	2
succinate-CoA ligase complex	2
aerobic respiration	1
primary metabolic process	1
succinyl-CoA metabolic process	1
sulfur compound catabolic process	1
purine-containing compound catabolic process	1
nucleoside phosphate catabolic process	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
CoA-ligase activity	1
molecular_function	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

3579 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SUCLG1	SUCLG2	Q96I99	996
SUCLG1	SUCLA2	Q9P2R7	991
SUCLG1	DGUOK	P78532	851
SUCLG1	GNAQ	P50148	848
SUCLG1	MPV17	P39210	826
SUCLG1	GNAI1	P04898	804
SUCLG1	OGDH	Q02218	804
SUCLG1	RGS7	P49802	792
SUCLG1	GNAS	Q5JWF2	772
SUCLG1	RRM2B	Q7LG56	771
SUCLG1	RGS18	Q9NS28	754
SUCLG1	TWNK	Q96RR1	736
SUCLG1	RGS4	P49798	732
SUCLG1	GNA11	P29992	731
SUCLG1	GNAO1	P09471	731

IntAct

54 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SUCLG2	SUCLG1	psi-mi:“MI:0914”(association)	0.690
SUCLG1	SUCLG2	psi-mi:“MI:0407”(direct interaction)	0.690
SERPINC1	BTD	psi-mi:“MI:0914”(association)	0.530
SUCLG1	LARS2	psi-mi:“MI:0914”(association)	0.530
HSCB	NDUFS8	psi-mi:“MI:0914”(association)	0.460
	TK2	psi-mi:“MI:0915”(physical association)	0.400
SUCLG1	CHMP1B	psi-mi:“MI:0915”(physical association)	0.370
Tubg1	BDP1	psi-mi:“MI:0914”(association)	0.350
MYC	ILVBL	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
ANG	DDX39A	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
BCL2L14		psi-mi:“MI:0914”(association)	0.350
IFITM3	STX12	psi-mi:“MI:0914”(association)	0.350
NT5C3A	VWA8	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
SH2D3C	TMEM14DP	psi-mi:“MI:0914”(association)	0.350
SMYD2	HSPA4L	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (161): SUCLG1 (Affinity Capture-MS), OGDH (Co-fractionation), SDHB (Co-fractionation), SUCLA2 (Co-fractionation), SUCLG1 (Co-fractionation), SUCLG1 (Affinity Capture-MS), SUCLA2 (Affinity Capture-MS), SUCLG1 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), POLR3C (Affinity Capture-MS), SUCLG1 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), SUCLG1 (Affinity Capture-MS), SUCLG1 (Proximity Label-MS), SUCLG1 (Affinity Capture-MS)

ESM2 similar proteins: A2TLM1, B4G0F3, B8BKI7, B9N1F9, B9SQI7, C1BJB1, C6JS30, D2XV59, E0CSI1, E9Q4Z2, F4JGR5, O00178, O00763, O04059, O08582, O19069, P0DPI2, P11029, P11497, P13086, P19356, P21343, P22907, P28492, P47968, P49247, P53597, Q13085, Q28559, Q2R483, Q3T186, Q571F8, Q58DC5, Q58DR8, Q5I0K3, Q5NAY4, Q5R8Q7, Q5SWU9, Q5XGS8, Q5ZHY5

Diamond homologs: A0A3A6N9V6, B3FHT4, E5Y8P7, O08371, O13750, O19069, O26663, O28098, O28733, O67547, O93988, P09143, P0AGE9, P0AGF0, P0AGF1, P13086, P36967, P45102, P53399, P53400, P53401, P53585, P53591, P53595, P53596, P53597, P53598, P66866, P68209, P80865, P99070, P9WGC6, P9WGC7, Q1RH56, Q4ULQ8, Q51567, Q54YA0, Q58643, Q58DR8, Q5HGI6

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SUCLG1	“form complex”	“Succinyl-CoA ATP variant”	binding
SUCLG1	“form complex”	“Succinyl-CoA GTP variant”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	11
Uncertain significance	140
Likely benign	140
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012244	NM_003849.4(SUCLG1):c.460C>T (p.Arg154Ter)	Pathogenic
1071175	NC_000002.11:g.(?84650850)(84686413_?)del	Pathogenic
1185061	NM_003849.4(SUCLG1):c.724del (p.Ile242fs)	Pathogenic
1325153	NM_003849.4(SUCLG1):c.814C>T (p.Gln272Ter)	Pathogenic
1375896	NM_003849.4(SUCLG1):c.169_170del (p.Lys57fs)	Pathogenic
1686238	NM_003849.4(SUCLG1):c.643C>T (p.Gln215Ter)	Pathogenic
1686239	NM_003849.4(SUCLG1):c.458T>A (p.Val153Glu)	Pathogenic
18409	NM_003849.4(SUCLG1):c.254G>C (p.Gly85Ala)	Pathogenic
18410	NM_003849.4(SUCLG1):c.509C>G (p.Pro170Arg)	Pathogenic
18411	NM_003849.4(SUCLG1):c.97+3G>C	Pathogenic
18412	NM_003849.4(SUCLG1):c.448C>T (p.Gln150Ter)	Pathogenic
212328	NM_003849.4(SUCLG1):c.507del (p.Asn171fs)	Pathogenic
2982185	NM_003849.4(SUCLG1):c.445C>T (p.Gln149Ter)	Pathogenic
3005619	NM_003849.4(SUCLG1):c.835del (p.Ser279fs)	Pathogenic
3651171	NM_003849.4(SUCLG1):c.583_586del (p.Arg195fs)	Pathogenic
3724793	NM_003849.4(SUCLG1):c.199C>T (p.Gln67Ter)	Pathogenic
4688454	NM_003849.4(SUCLG1):c.937G>T (p.Glu313Ter)	Pathogenic
4712015	NM_003849.4(SUCLG1):c.390_393del (p.Asn130fs)	Pathogenic
4721624	NM_003849.4(SUCLG1):c.220C>T (p.Gln74Ter)	Pathogenic
632365	NM_003849.4(SUCLG1):c.152_153del (p.Tyr51fs)	Pathogenic
801730	NM_003849.4(SUCLG1):c.201+1G>T	Pathogenic
818207	NM_003849.4(SUCLG1):c.457_458delinsTA (p.Val153Ter)	Pathogenic
992828	NM_003849.4(SUCLG1):c.626C>A (p.Ala209Glu)	Pathogenic
203972	NM_003849.4(SUCLG1):c.238A>C (p.Thr80Pro)	Likely pathogenic
203974	NM_003849.4(SUCLG1):c.776G>A (p.Gly259Asp)	Likely pathogenic
203975	NM_003849.4(SUCLG1):c.851C>T (p.Ser284Phe)	Likely pathogenic
2130397	NM_003849.4(SUCLG1):c.826-1G>A	Likely pathogenic
2434026	NM_003849.4(SUCLG1):c.790G>T (p.Glu264Ter)	Likely pathogenic
2734239	NM_003849.4(SUCLG1):c.319-1G>A	Likely pathogenic
2850714	NM_003849.4(SUCLG1):c.673+1G>C	Likely pathogenic

SpliceAI

2149 predictions. Top by Δscore:

Variant	Effect	Δscore
2:84424902:A:AC	donor_gain	1.0000
2:84425602:CC:C	acceptor_gain	1.0000
2:84425602:CCCTA:C	acceptor_loss	1.0000
2:84425603:CC:C	acceptor_gain	1.0000
2:84425603:CCTAG:C	acceptor_loss	1.0000
2:84425604:CTAGA:C	acceptor_loss	1.0000
2:84431501:AACT:A	donor_loss	1.0000
2:84431502:ACTT:A	donor_loss	1.0000
2:84431503:CT:C	donor_loss	1.0000
2:84431504:TTACT:T	donor_loss	1.0000
2:84431505:TACTG:T	donor_loss	1.0000
2:84431506:A:AC	donor_gain	1.0000
2:84431506:A:C	donor_loss	1.0000
2:84431507:C:CC	donor_gain	1.0000
2:84431507:CT:C	donor_gain	1.0000
2:84431507:CTG:C	donor_gain	1.0000
2:84431507:CTGA:C	donor_gain	1.0000
2:84431507:CTGAA:C	donor_gain	1.0000
2:84431657:TGC:T	acceptor_gain	1.0000
2:84431660:CTG:C	acceptor_loss	1.0000
2:84441126:A:T	acceptor_gain	1.0000
2:84441240:CACT:C	donor_loss	1.0000
2:84441241:ACTC:A	donor_loss	1.0000
2:84441242:CTCA:C	donor_loss	1.0000
2:84441243:T:TG	donor_loss	1.0000
2:84441244:CA:C	donor_loss	1.0000
2:84441245:A:AC	donor_gain	1.0000
2:84441245:A:C	donor_loss	1.0000
2:84441246:C:CC	donor_gain	1.0000
2:84441246:CA:C	donor_gain	1.0000

AlphaMissense

2241 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:84425530:G:T	A300D	1.000
2:84425536:C:T	G298D	1.000
2:84425537:C:G	G298R	1.000
2:84425566:C:T	G288D	1.000
2:84425569:G:T	A287D	1.000
2:84433400:C:G	A209P	1.000
2:84433411:A:G	L205P	1.000
2:84433417:C:T	G203D	1.000
2:84425476:A:G	L318P	0.999
2:84425527:C:T	G301E	0.999
2:84425528:C:A	G301W	0.999
2:84425532:A:C	H299Q	0.999
2:84425532:A:T	H299Q	0.999
2:84425534:G:C	H299D	0.999
2:84425536:C:A	G298V	0.999
2:84425537:C:A	G298C	0.999
2:84425539:A:G	M297T	0.999
2:84425557:G:T	A291D	0.999
2:84425567:C:G	G288R	0.999
2:84431563:T:A	E257V	0.999
2:84431653:C:T	G227E	0.999
2:84433411:A:T	L205Q	0.999
2:84433418:C:G	G203R	0.999
2:84433421:A:G	S202P	0.999
2:84433427:A:G	S200P	0.999
2:84441257:C:T	G174E	0.999
2:84441262:G:C	C172W	0.999
2:84441265:G:C	N171K	0.999
2:84441265:G:T	N171K	0.999
2:84441272:C:T	G169E	0.999

dbSNP variants (sampled 300 via entrez): RS1000064720 (2:84453371 T>C), RS1000069379 (2:84460515 CATG>C), RS1000084551 (2:84459246 G>A,C,T), RS1000167655 (2:84435857 G>A), RS1000221655 (2:84428588 A>C), RS1000298999 (2:84454431 C>A,T), RS1000480049 (2:84429721 T>C), RS1000517191 (2:84443850 C>A,G,T), RS1000522664 (2:84443508 T>C,G), RS1000638352 (2:84436870 A>G), RS1000657737 (2:84434032 A>G), RS1000815449 (2:84427307 A>C), RS1000826767 (2:84455946 A>C), RS1000880770 (2:84455750 G>A), RS1000899470 (2:84446868 T>C,G)

Disease associations

OMIM: gene MIM:611224 | disease phenotypes: MIM:245400

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial DNA depletion syndrome 9	Definitive	Autosomal recessive
Leigh syndrome	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR

Mondo (2): mitochondrial DNA depletion syndrome 9 (MONDO:0009504), Leigh syndrome (MONDO:0009723)

Orphanet (1): Fatal infantile lactic acidosis with methylmalonic aciduria (Orphanet:17)

HPO phenotypes

92 total (30 of 92 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000202	Orofacial cleft
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000718	Aggressive behavior
HP:0000736	Short attention span
HP:0000975	Hyperhidrosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001284	Areflexia
HP:0001298	Encephalopathy
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001371	Flexion contracture
HP:0001397	Hepatic steatosis
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001639	Hypertrophic cardiomyopathy
HP:0001643	Patent ductus arteriosus

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002097_42	Coronary artery calcification	2.000000e-06
GCST003854_25	Gut microbiota (functional units)	5.000000e-08
GCST010796_5182	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_5183	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_5184	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_5185	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_5186	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0007874	gut microbiome measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
C566885	Lactic Acidosis, Fatal Infantile (supp.)
C538134	Lactic acidosis congenital infantile (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066499 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.25	Kd	56.31	nM	CHEMBL3752910
7.25	ED50	56.31	nM	CHEMBL3752910
6.06	Kd	877.3	nM	CHEMBL5653589
6.06	ED50	877.3	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 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	2149524: Binding affinity to human SUCLG1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0563	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149524: Binding affinity to human SUCLG1 incubated for 45 mins by Kinobead based pull down assay	kd	0.8773	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	8
bisphenol A	increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
dicrotophos	decreases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Benztropine	decreases expression	1
Clozapine	decreases expression	1
Doxorubicin	affects response to substance	1
Fenbendazole	increases expression	1
Furaldehyde	affects cotreatment, decreases expression, affects localization, increases expression	1
Isoniazid	increases expression	1
Ivermectin	decreases expression	1
Fenofibrate	increases expression	1
Sodium Chloride	affects localization, increases expression, affects cotreatment, 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
CHEMBL5652566	Binding	Binding affinity to human SUCLG1 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

Cellosaurus cell lines

4 cell lines: 2 transformed cell line, 1 finite cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3IM	Abcam HEK293T SUCLG1 KO	Transformed cell line	Female
CVCL_B4D5	WG2319	Finite cell line
CVCL_D8WN	Ubigene HCT 116 SUCLG1 KO	Cancer cell line	Male
CVCL_D9TL	Ubigene HEK293 SUCLG1 KO	Transformed cell line	Female

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