SUCLA2

Summary

SUCLA2 (succinate-CoA ligase ADP-forming subunit beta, HGNC:11448) is a protein-coding gene on chromosome 13q14.2, encoding Succinate–CoA ligase [ADP-forming] subunit beta, mitochondrial (Q9P2R7). ATP-specific succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of ATP and thus represents the only step of substrate-level phosphorylation in the TCA.

Succinyl-CoA synthetase (SCS) is a mitochondrial matrix enzyme that acts as a heterodimer, being composed of an invariant alpha subunit and a substrate-specific beta subunit. The protein encoded by this gene is an ATP-specific SCS beta subunit that dimerizes with the SCS alpha subunit to form SCS-A, an essential component of the tricarboxylic acid cycle. SCS-A hydrolyzes ATP to convert succinate to succinyl-CoA. Defects in this gene are a cause of myopathic mitochondrial DNA depletion syndrome. A pseudogene of this gene has been found on chromosome 6.

Source: NCBI Gene 8803 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 476 total — 16 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 58
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003850

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11448
Approved symbol	SUCLA2
Name	succinate-CoA ligase ADP-forming subunit beta
Location	13q14.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000136143
Ensembl biotype	protein_coding
OMIM	603921
Entrez	8803

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 23 protein_coding, 4 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay, 1 retained_intron

ENST00000433022, ENST00000434484, ENST00000435617, ENST00000467222, ENST00000470760, ENST00000481279, ENST00000484941, ENST00000493152, ENST00000497202, ENST00000634878, ENST00000642944, ENST00000643023, ENST00000643246, ENST00000643584, ENST00000644338, ENST00000646602, ENST00000646804, ENST00000646932, ENST00000647008, ENST00000647361, ENST00000853362, ENST00000853363, ENST00000853364, ENST00000853365, ENST00000853366, ENST00000853367, ENST00000934768, ENST00000944765, ENST00000944766, ENST00000944767, ENST00000944768, ENST00000944769

RefSeq mRNA: 1 — MANE Select: NM_003850 NM_003850

CCDS: CCDS9406

Canonical transcript exons

ENST00000646932 — 11 exons

Exon	Start	End
ENSE00000923434	47968595	47968733
ENSE00001478261	47942656	47943445
ENSE00002694352	47954140	47954282
ENSE00002708627	47954396	47954557
ENSE00003458765	47988541	47988703
ENSE00003475364	47949483	47949603
ENSE00003568868	47973264	47973392
ENSE00003612075	47996843	47997023
ENSE00003653391	47988882	47988981
ENSE00003678376	47948940	47949028
ENSE00003787881	48001180	48001273

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.4819 / max 301.4259, expressed in 1814 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137237	17.5215	1782
137239	10.1402	1791
137238	2.5201	1257
207029	0.1951	84
137236	0.1050	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	98.28	gold quality
pons	UBERON:0000988	98.21	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.19	gold quality
body of tongue	UBERON:0011876	98.08	gold quality
vastus lateralis	UBERON:0001379	98.03	gold quality
biceps brachii	UBERON:0001507	97.97	gold quality
heart right ventricle	UBERON:0002080	97.82	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.66	gold quality
quadriceps femoris	UBERON:0001377	97.55	gold quality
jejunum	UBERON:0002115	97.55	gold quality
diaphragm	UBERON:0001103	97.42	gold quality
left ventricle myocardium	UBERON:0006566	97.42	gold quality
muscle organ	UBERON:0001630	97.36	gold quality
gastrocnemius	UBERON:0001388	97.32	gold quality
muscle of leg	UBERON:0001383	97.31	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.31	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.31	gold quality
skeletal muscle tissue	UBERON:0001134	97.26	gold quality
deltoid	UBERON:0001476	96.65	gold quality
triceps brachii	UBERON:0001509	96.51	gold quality
cardiac ventricle	UBERON:0002082	96.42	gold quality
substantia nigra pars compacta	UBERON:0001965	96.40	gold quality
heart left ventricle	UBERON:0002084	96.40	gold quality
muscle tissue	UBERON:0002385	96.38	gold quality
pigmented layer of retina	UBERON:0001782	96.30	gold quality
superior vestibular nucleus	UBERON:0007227	96.17	gold quality
prefrontal cortex	UBERON:0000451	96.06	gold quality
myocardium	UBERON:0002349	96.06	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.99	gold quality
dorsal root ganglion	UBERON:0000044	95.96	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)

66 targeting SUCLA2, 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-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-150-3P	99.43	70.51	920

Literature-anchored findings (GeneRIF, showing 18)

• Deficiency of SUCLA2 is associated with encephalomyopathy and mitochondrial DNA depletion. (PMID:15877282)
• Mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria is associated with mutations in SUCLA2, the gene encoding a beta subunit of succinate-CoA ligase. (PMID:19526370)
• X-linked sideroblastic anemia due to carboxyl-terminal ALAS2 mutations that cause loss of binding to the beta-subunit of succinyl-CoA synthetase (SUCLA2). (PMID:22740690)
• 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)
• A novel homozygous mutation in SUCLA2 gene has been associated with severe mitochondrial encephalomyopathies in two Italian siblings. (PMID:23010432)
• Identification of a novel mutation in SUCLA2 in two cousins affected with encephalomyopathy, is reported. (PMID:23759946)
• This study demonstrated that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex. (PMID:24085565)
• SUCLA2 mutations should be analyzed in patients with slowly progressive encephalomyopathy, even in the absence of methylmalonic aciduria or mitochondrial DNA depletion. (PMID:24986829)
• The absence of SUCLA2 and SUCLG2 in human glia is in compliance with the presence of alternative pathways occurring in these cells, namely the GABA shunt and ketone body metabolism (PMID:25370487)
• Long survival, to age 20 years or older, was reported in 12% of SUCLA2 and in 10% of SUCLG1 patients. (PMID:26475597)
• XDH and SUCLA2 genes associated with thiopurine-induced leukopenia can act in a complex interactive manner in patients with Crohn’s disease. (PMID:26863601)
• The patient’s cells lack the SUCLG1 protein, with significantly reduced levels of SUCLA2 and SUCLG2 protein (PMID:27484306)
• Sucla2 is related to the developmental stages of mouse spermatogenesis. Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis via decreased mitochondrial function of the cells. (PMID:27766610)
• SUCLA2 mutation is associated with Down syndrome and mitochondrial depletion syndrome. (PMID:28749033)
• Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion. (PMID:32694611)
• SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease. (PMID:33230181)
• SUCLA2 Arg407Trp mutation can cause a nonprogressive movement disorder - deafness syndrome. (PMID:33231368)
• SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells. (PMID:33991485)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sucla2	ENSDARG00000005359
mus_musculus	Sucla2	ENSMUSG00000022110
rattus_norvegicus	Sucla2	ENSRNOG00000017481
drosophila_melanogaster	ScsbetaA	FBGN0037643
caenorhabditis_elegans		WBGENE00009812

Paralogs (1): SUCLG2 (ENSG00000172340)

Protein

Protein identifiers

Succinate–CoA ligase [ADP-forming] subunit beta, mitochondrial — Q9P2R7 (reviewed: Q9P2R7)

Alternative names: ATP-specific succinyl-CoA synthetase subunit beta, Itaconyl–CoA ligase [ADP-forming] subunit beta, Malyl–CoA ligase [ADP-forming] subunit beta, Succinyl-CoA synthetase beta-A chain

All UniProt accessions (14): A0A0U1RQF8, A0A0U1RQL1, A0A0U1RQU7, A0A0U1RRI1, A0A2R8Y5P4, A0A2R8Y5P6, A0A2R8Y6E6, A0A2R8Y6Y7, Q9P2R7, A0A2R8YDQ9, A0A2R8YF84, E5KS60, Q5T9Q5, Q5T9Q8

UniProt curated annotations — full annotation on UniProt →

Function. ATP-specific succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of ATP and thus represents the only step of substrate-level phosphorylation in the TCA. The beta subunit provides nucleotide specificity of the enzyme and binds the substrate succinate, while the binding sites for coenzyme A and phosphate are found in the alpha subunit. Also able to act as an ATP-specific itaconyl- and malyl-CoA synthetase.

Subunit / interactions. Heterodimer of an alpha and a beta subunit. The beta subunit determines specificity for ATP. Interacts with ALAS2.

Subcellular location. Mitochondrion.

Tissue specificity. Widely expressed. Not expressed in liver and lung.

Disease relevance. Mitochondrial DNA depletion syndrome 5 (MTDPS5) [MIM:612073] A disorder due to mitochondrial dysfunction. It is characterized by infantile onset of hypotonia, neurologic deterioration, a hyperkinetic-dystonic movement disorder, external ophthalmoplegia, deafness, variable renal tubular dysfunction, and mild methylmalonic aciduria in some patients. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by itaconate.

Cofactor. Binds 1 Mg(2+) ion per subunit.

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

Similarity. Belongs to the succinate/malate CoA ligase beta subunit family. ATP-specific subunit beta subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P2R7-1	1	yes
Q9P2R7-2	2

RefSeq proteins (1): NP_003841* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005809	Succ_CoA_ligase-like_bsu	Family
IPR005811	SUCC_ACL_C	Domain
IPR011761	ATP-grasp	Domain
IPR013650	ATP-grasp_succ-CoA_synth-type	Domain
IPR013815	ATP_grasp_subdomain_1	Homologous_superfamily
IPR016102	Succinyl-CoA_synth-like	Homologous_superfamily
IPR017866	Succ-CoA_synthase_bsu_CS	Conserved_site
IPR034723	Succ_CoA_betaA_euk	Family

Pfam: PF00549, PF08442

Enzyme classification (BRENDA):

• 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)

14 substrates with measured Km, best-characterized 14. 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
ITACONATE	0.351–1.509	5
GTP	0.011–0.311	4
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
3-SULFINOPROPIONATE	2.964	1
ACETATE	70	1
ACETYL-COA	0.0223	1
COENZYME A	0.01	1

Catalyzed reactions (Rhea), 2 shown:

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

UniProt features (71 total): strand 20, helix 16, modified residue 11, binding site 6, sequence variant 5, turn 4, sequence conflict 3, site 2, transit peptide 1, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6G4Q	X-RAY DIFFRACTION	2.59
9SWJ	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2R7-F1	87.45	0.75

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): 162 (important for substrate specificity); 94 (important for substrate specificity)

Ligand- & substrate-binding residues (6): 98; 105–107; 258; 272; 323; 380–382

Post-translational modifications (11): 78, 84, 88, 88, 129, 139, 143, 216, 279, 341, 368

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: 297 (showing top): RORA1_01, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MORF_HDAC2, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_SULFUR_COMPOUND_CATABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_DETOXIFICATION

GO Biological Process (5): tricarboxylic acid cycle (GO:0006099), succinyl-CoA metabolic process (GO:0006104), succinate metabolic process (GO:0006105), succinyl-CoA pathway (GO:0006781), succinyl-CoA catabolic process (GO:1901289)

GO Molecular Function (8): magnesium ion binding (GO:0000287), succinate-CoA ligase (ADP-forming) activity (GO:0004775), ATP binding (GO:0005524), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), ligase activity (GO:0016874), metal ion binding (GO:0046872)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), succinate-CoA ligase complex (ADP-forming) (GO:0009361), succinate-CoA ligase complex (GO:0042709), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

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
succinyl-CoA metabolic process	2
aerobic respiration	1
primary metabolic process	1
acyl-CoA metabolic process	1
dicarboxylic acid metabolic process	1
porphyrin-containing compound biosynthetic process	1
uroporphyrinogen III biosynthetic process	1
sulfur compound catabolic process	1
purine-containing compound catabolic process	1
nucleoside phosphate catabolic process	1
metal ion binding	1
succinate-CoA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
catalytic activity	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
succinate-CoA ligase complex	1
tricarboxylic acid cycle heteromeric enzyme complex	1
extracellular vesicle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2840 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SUCLA2	SUCLG1	P53597	991
SUCLA2	MPV17	P39210	922
SUCLA2	DGUOK	P78532	921
SUCLA2	RRM2B	Q7LG56	901
SUCLA2	POLG	P54098	886
SUCLA2	TWNK	Q96RR1	874
SUCLA2	COASY	Q13057	824
SUCLA2	TYMP	P19971	786
SUCLA2	OGDH	Q02218	742
SUCLA2	ACO2	Q99798	723
SUCLA2	IDH3A	P50213	699
SUCLA2	MDH2	P40926	677
SUCLA2	TK2	O00142	668
SUCLA2	SDHA	P31040	665
SUCLA2	PDHB	P11177	665

IntAct

111 interactions, top by confidence:

A	B	Type	Score
SUCLA2	ARL6IP1	psi-mi:“MI:0915”(physical association)	0.720
SUCLA2	AGTRAP	psi-mi:“MI:0915”(physical association)	0.720
SUCLA2	CMTM5	psi-mi:“MI:0915”(physical association)	0.720
AGTRAP	SUCLA2	psi-mi:“MI:0915”(physical association)	0.720
ARL6IP1	SUCLA2	psi-mi:“MI:0915”(physical association)	0.720
CMTM5	SUCLA2	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PSMD14	PSMD11	psi-mi:“MI:0914”(association)	0.650
SEC23A	SUCLA2	psi-mi:“MI:0915”(physical association)	0.560
MAGEA11	SUCLA2	psi-mi:“MI:0915”(physical association)	0.560
MAL2	SUCLA2	psi-mi:“MI:0915”(physical association)	0.560
SUCLA2	FKBP7	psi-mi:“MI:0915”(physical association)	0.560
SUCLA2	TNFRSF10D	psi-mi:“MI:0915”(physical association)	0.560
SUCLA2	OPTN	psi-mi:“MI:0915”(physical association)	0.560
SUCLG1	LARS2	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
	CAND2	psi-mi:“MI:0914”(association)	0.460

BioGRID (248): ARL6IP1 (Two-hybrid), AGTRAP (Two-hybrid), CMTM5 (Two-hybrid), FAM9B (Two-hybrid), SUCLA2 (Affinity Capture-MS), DLST (Co-fractionation), RAB2A (Co-fractionation), SSR4 (Co-fractionation), SUCLA2 (Co-fractionation), SUCLA2 (Co-fractionation), SUCLA2 (Co-fractionation), SUCLA2 (Co-fractionation), SUCLA2 (Co-fractionation), SUCLA2 (Co-fractionation), SUCLA2 (Co-fractionation)

ESM2 similar proteins: A0A7J6F8C5, A0FKE6, B9FK36, B9HBA8, B9N843, F4I1L3, O04983, O42615, O42938, O50046, O94201, O94634, P00927, P05165, P0DTA4, P14671, P14882, P16578, P16638, P16862, P22221, P25269, P25306, P32260, P53396, P53585, P54886, P54889, P59680, P87131, Q148D5, Q2TCH3, Q32PF2, Q39469, Q40545, Q40546, Q42777, Q43086, Q43725, Q5I0C3

Diamond homologs: A1AZH7, A1BE51, A1UQV9, A3PN13, A4SDL6, A4WNM6, A5FYZ9, A5VB78, A5VSQ3, A6U164, A6UDP2, A6WXE8, A7GRG6, A7HT39, A7X1L8, A8F1K7, A8FD73, A8GS29, A8GUV0, A9IZV3, A9M8R2, B0BXJ5, B0CIT0, B0T3D1, B1YIL7, B1ZP17, B2S880, B2UMH5, B3EFL3, B3EN95, B3FHP0, B3Q760, B3QPP2, B4RCH3, B4S612, B4SEH6, B6IP72, B8GYZ1, B9DPG0, B9EBC7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SUCLA2	“form complex”	“Succinyl-CoA ATP variant”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	14
Uncertain significance	183
Likely benign	167
Benign	50

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1383524	NM_003850.3(SUCLA2):c.371+1G>C	Pathogenic
1458811	NM_003850.3(SUCLA2):c.251dup (p.Tyr84Ter)	Pathogenic
2127356	NM_003850.3(SUCLA2):c.21C>G (p.Tyr7Ter)	Pathogenic
2424779	NC_000013.10:g.(?48562656)(48575405_?)del	Pathogenic
2444289	NM_003850.3(SUCLA2):c.964+1G>A	Pathogenic
3244192	NC_000013.10:g.(?48517506)(48575405_?)del	Pathogenic
3252235	NM_003850.3(SUCLA2):c.1106dup (p.Val370fs)	Pathogenic
4293474	NM_003850.3(SUCLA2):c.1210del (p.Val404fs)	Pathogenic
4708672	NM_003850.3(SUCLA2):c.145C>T (p.Gln49Ter)	Pathogenic
4761338	NM_003850.3(SUCLA2):c.1240_1241del (p.Val413_Asp414insTer)	Pathogenic
4766711	NM_003850.3(SUCLA2):c.880_884del (p.Trp294fs)	Pathogenic
4809636	NM_003850.3(SUCLA2):c.148C>T (p.Gln50Ter)	Pathogenic
5975	NM_003850.3(SUCLA2):c.789_802+29delinsATAAA	Pathogenic
5976	NM_003850.3(SUCLA2):c.534+1G>A	Pathogenic
5977	NM_003850.3(SUCLA2):c.352G>A (p.Gly118Arg)	Pathogenic
802962	NM_003850.3(SUCLA2):c.887del (p.Gln296fs)	Pathogenic
1328398	NM_003850.3(SUCLA2):c.1134del (p.Phe378fs)	Likely pathogenic
1332823	NM_003850.3(SUCLA2):c.814G>C (p.Asp272His)	Likely pathogenic
1679201	NM_003850.3(SUCLA2):c.1225C>T (p.Gln409Ter)	Likely pathogenic
1685457	NM_003850.3(SUCLA2):c.91-10A>G	Likely pathogenic
203955	NM_003850.3(SUCLA2):c.479G>A (p.Arg160Gln)	Likely pathogenic
203958	NM_003850.3(SUCLA2):c.955G>C (p.Gly319Arg)	Likely pathogenic
2708944	NM_003850.3(SUCLA2):c.1108-1G>A	Likely pathogenic
312271	NM_003850.3(SUCLA2):c.272-2A>G	Likely pathogenic
3576260	NM_003850.3(SUCLA2):c.1165C>T (p.Gln389Ter)	Likely pathogenic
3767160	NM_003850.3(SUCLA2):c.91-3T>A	Likely pathogenic
586919	NM_003850.3(SUCLA2):c.308C>A (p.Ala103Asp)	Likely pathogenic
817362	NM_003850.3(SUCLA2):c.1267del (p.Ser423fs)	Likely pathogenic
870729	NM_003850.3(SUCLA2):c.766G>T (p.Glu256Ter)	Likely pathogenic
872975	NM_003850.3(SUCLA2):c.997G>T (p.Asp333Tyr)	Likely pathogenic

SpliceAI

2501 predictions. Top by Δscore:

Variant	Effect	Δscore
13:47949478:CTCA:C	donor_loss	1.0000
13:47949479:TCACC:T	donor_loss	1.0000
13:47949480:CA:C	donor_loss	1.0000
13:47949481:A:AC	donor_gain	1.0000
13:47949482:C:CC	donor_gain	1.0000
13:47954135:CTTA:C	donor_loss	1.0000
13:47954136:TTA:T	donor_loss	1.0000
13:47954137:TA:T	donor_loss	1.0000
13:47954138:A:AC	donor_gain	1.0000
13:47954139:C:CC	donor_gain	1.0000
13:47954139:C:CG	donor_loss	1.0000
13:47954278:ATTTA:A	acceptor_gain	1.0000
13:47954279:TTTA:T	acceptor_gain	1.0000
13:47954280:TTA:T	acceptor_gain	1.0000
13:47954280:TTACT:T	acceptor_loss	1.0000
13:47954281:TA:T	acceptor_gain	1.0000
13:47954282:ACTA:A	acceptor_loss	1.0000
13:47954283:C:CC	acceptor_gain	1.0000
13:47954284:T:A	acceptor_loss	1.0000
13:47954285:A:AC	acceptor_gain	1.0000
13:47954285:A:C	acceptor_gain	1.0000
13:47954287:A:C	acceptor_gain	1.0000
13:47954302:T:C	acceptor_gain	1.0000
13:47954391:GGTAC:G	donor_loss	1.0000
13:47954394:A:T	donor_loss	1.0000
13:47954395:C:CT	donor_loss	1.0000
13:47954398:AGG:A	donor_gain	1.0000
13:47954412:T:TA	donor_gain	1.0000
13:47954553:CAATA:C	acceptor_gain	1.0000
13:47954554:AATA:A	acceptor_gain	1.0000

AlphaMissense

3036 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:47948947:G:T	A437D	1.000
13:47949028:C:A	G410V	1.000
13:47949483:C:A	G410C	1.000
13:47949483:C:G	G410R	1.000
13:47949543:C:G	G390R	1.000
13:47949559:A:C	C384W	1.000
13:47949560:C:A	C384F	1.000
13:47949560:C:T	C384Y	1.000
13:47949561:A:G	C384R	1.000
13:47949572:C:T	G380E	1.000
13:47949573:C:G	G380R	1.000
13:47949573:C:T	G380R	1.000
13:47949575:C:A	G379V	1.000
13:47949575:C:T	G379E	1.000
13:47949576:C:G	G379R	1.000
13:47949576:C:T	G379R	1.000
13:47949577:A:C	F378L	1.000
13:47949577:A:T	F378L	1.000
13:47949579:A:G	F378L	1.000
13:47949583:G:C	N376K	1.000
13:47949583:G:T	N376K	1.000
13:47954204:A:T	V348D	1.000
13:47954208:C:G	D347H	1.000
13:47954210:A:G	L346P	1.000
13:47954210:A:T	L346H	1.000
13:47954212:G:C	F345L	1.000
13:47954212:G:T	F345L	1.000
13:47954213:A:G	F345S	1.000
13:47954214:A:G	F345L	1.000
13:47954215:G:C	N344K	1.000

dbSNP variants (sampled 300 via entrez): RS1000025556 (13:47971026 A>C,G), RS1000076894 (13:47981841 A>G), RS1000119817 (13:47971260 A>G), RS1000154970 (13:47983232 C>G), RS1000166536 (13:47986693 G>T), RS1000174369 (13:47994365 C>T), RS1000226472 (13:47987800 G>A), RS1000257562 (13:47988184 G>A), RS1000293463 (13:47983535 G>A,T), RS1000303569 (13:47977570 T>C,G), RS1000341167 (13:47958397 A>T), RS1000372265 (13:47990391 T>C), RS1000387751 (13:47983852 G>A,C), RS1000401170 (13:48000688 G>A), RS1000416218 (13:47951899 C>A,G)

Disease associations

OMIM: gene MIM:603921 | disease phenotypes: MIM:612073

GenCC curated gene-disease

Disease	Classification	Inheritance
Leigh syndrome	Definitive	Autosomal recessive
mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
Leigh syndrome	Definitive	AR

Mondo (2): mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (MONDO:0012791), Leigh syndrome (MONDO:0009723)

Orphanet (1): Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (Orphanet:1933)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000512	Abnormal electroretinogram
HP:0000602	Ophthalmoplegia
HP:0000649	Abnormality of visual evoked potentials
HP:0000708	Atypical behavior
HP:0000737	Irritability
HP:0000762	Decreased nerve conduction velocity
HP:0000975	Hyperhidrosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001332	Dystonia
HP:0001349	Facial diplegia
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001935	Microcytic anemia
HP:0002020	Gastroesophageal reflux
HP:0002059	Cerebral atrophy
HP:0002119	Ventriculomegaly

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001166_5	Aging (time to event)	3.000000e-06
GCST001523_6	Visceral adipose tissue adjusted for BMI	5.000000e-06
GCST001524_34	Visceral adipose tissue/subcutaneous adipose tissue ratio	5.000000e-06
GCST002415_2	Colorectal cancer (diet interaction)	3.000000e-06
GCST006201_2	Thiopurine-induced leukopenia in inflammatory bowel disease	1.000000e-33
GCST006204_1	Thiopurine-induced severe leukopenia in inflammatory bowel disease	1.000000e-08
GCST006205_1	Thiopurine-induced acute severe leukopenia in inflammatory bowel disease	1.000000e-08
GCST006206_5	Thiopurine-induced alopecia in inflammatory bowel disease	4.000000e-29
GCST006207_1	Thiopurine-induced severe alopecia in inflammatory bowel disease	1.000000e-08
GCST007229_1	Thiopurine-induced early leukopenia in Crohn’s disease	5.000000e-94
GCST010916_20	Proportion of activated microglia (inferior temporal cortex)	3.000000e-06
GCST012020_333	Serum metabolite levels	3.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0022597	aging
EFO:0004340	body mass index
EFO:0004767	visceral:subcutaneous adipose tissue ratio
EFO:0008111	diet measurement

MeSH disease descriptors (2)

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
C567624	Mitochondrial Dna Depletion Syndrome, Encephalomyopathic Form, With Methylmalonic Aciduria, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105973 (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: 2,167 (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
CHEMBL2105728	CRENOLANIB	3	2,167

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs186364861	NUDT15, SUCLA2		0.00	2
rs766023281	NUDT15, SUCLA2		0.00	1
rs746071566	NUDT15, SUCLA2	3	4.00	8	azathioprine;mercaptopurine;thioguanine

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.15	Kd	7	nM	CRENOLANIB
5.62	Kd	2393	nM	CHEMBL5653589
5.62	ED50	2393	nM	CHEMBL5653589
5.30	Kd	5028	nM	CHEMBL3752910
5.30	ED50	5028	nM	CHEMBL3752910

PubChem BioAssay actives

3 with measured affinity, of 206 total; 3 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
1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine	1425187: 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	0.0070	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149523: Binding affinity to human SUCLA2 incubated for 45 mins by Kinobead based pull down assay	kd	2.3928	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149523: Binding affinity to human SUCLA2 incubated for 45 mins by Kinobead based pull down assay	kd	5.0283	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
sodium arsenite	decreases expression, increases abundance, increases expression	2
bisphenol S	increases expression, increases methylation	2
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation	2
Arsenic	increases expression, affects methylation, increases abundance	2
Gold	decreases expression	2
Rotenone	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
beta-lapachone	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
bisphenol B	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
picoxystrobin	increases expression	1
MT19c compound	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Catechin	increases expression, affects cotreatment	1
Cisplatin	decreases expression	1
Clozapine	affects cotreatment, decreases expression	1
Cuprizone	affects cotreatment, decreases expression	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
CHEMBL3991900	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

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9TK	Ubigene HEK293 SUCLA2 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