SUCLA2

Chr 13AR

succinate-CoA ligase ADP-forming subunit beta

NCBI Gene: 8803ENSG00000136143UniProt: 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 (PubMed:15877282, PubMed:34492704, PubMed:40108300). 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 (By similarity). Also able to act as an ATP-specific itaconyl- and malyl-CoA synthetase (PubMed:40108300)

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria)MIM #612073
AR
560
ClinVar variants
60
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— SUCLA2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
60 Pathogenic / Likely Pathogenic· 188 VUS of 560 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.63LOEUF
pLI 0.002
Z-score 2.97
OE 0.36 (0.22–0.63)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.02Z-score
OE missense 0.82 (0.73–0.92)
206 obs / 251.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.36 (0.22–0.63)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.73–0.92)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 9 / 25.1Missense obs/exp: 206 / 251.6Syn Z: 0.04

ClinVar Variant Classifications

560 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic18
VUS188
Likely Benign173
Benign46
Conflicting19
42
Pathogenic
18
Likely Pathogenic
188
VUS
173
Likely Benign
46
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
36
0
42
Likely Pathogenic
5
5
8
0
18
VUS
1
142
41
4
188
Likely Benign
0
1
95
77
173
Benign
0
0
46
0
46
Conflicting
—19
Total1214822681486

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SUCLA2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria)

MIM #612073

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mitochondrial DNA maintenance defects.
El-Hattab AW et al.·Biochim Biophys Acta Mol Basis Dis
2017Review
Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion.
Matilainen S et al.·Eur J Hum Genet
2015Review
Succinyl-CoA ligase ADP-forming subunit beta promotes stress granule assembly to regulate redox and drive cancer metastasis.
Boese AC et al.·Proc Natl Acad Sci U S A
2023
Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes.
Lancaster MS et al.·J Cachexia Sarcopenia Muscle
2024Functional
[SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome: a case report and review of literature].
Liu Z et al.·Zhonghua Er Ke Za Zhi
2014Review
Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients.
Carrozzo R et al.·J Inherit Metab Dis
2016Cohort
Dystonia and deafness due to SUCLA2 defect; Clinical course and biochemical markers in 16 children.
Morava E et al.·Mitochondrion
2009
Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion syndrome.
Couser NL et al.·Am J Med Genet A
2017Case report
Investigating the safety and efficacy of deoxycytidine/deoxythymidine in mitochondrial DNA depletion disorders: phase 2 open-label trial.
Berrahmoune S et al.·J Neurol
2025Clinical trial
The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders.
Cohen BH et al.·Methods
2010Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Mitochondrial DiseasesMitochondrial EncephalomyopathyMitochondrial Encephalopathy

Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome

RECRUITING
NCT04802707Phase PHASE2Kenneth Myers, MDStarted 2021-10-18
deoxycytidine and deoxythymidine
Parkinson Disease

Impact of C-Mill Rehabilitation on the Gut-Brain Axis in Parkinson's Disease

RECRUITING
NCT07434089Phase NAIRCCS Centro Neurolesi Bonino PulejoStarted 2025-10-20
C-Mill technology treadmill equipped with semi-immersive VRC-Mill treatment without semi-immersive virtual reality (VR)Conventional physiotherapy training
Breast Cancer

Treating Breast Cancer Patients Undergoing Trastuzumab Treatment With Carvedilol to Reduce Incidence of Heart Failure

ACTIVE NOT RECRUITING
NCT03879629Phase PHASE2Mayo ClinicStarted 2019-08-21
Carvedilol

External Resources

Links to major genomics databases and tools