SUCLG1

Chr 2AR

succinate-CoA ligase GDP/ADP-forming subunit alpha

Also known as: GALPHA, MTDPS9, SUCLA1

NCBI Gene: 8802ENSG00000163541UniProt: P53597

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. [provided by RefSeq, Feb 2010]

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria)MIM #245400
AR
396
ClinVar variants
47
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— SUCLG1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
47 Pathogenic / Likely Pathogenic· 142 VUS of 396 total submissions
💊
Clinical Trials
1 active or recruiting trial — 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.
0.88LOEUF
pLI 0.000
Z-score 1.94
OE 0.49 (0.28–0.88)
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.
-0.22Z-score
OE missense 1.04 (0.93–1.18)
199 obs / 190.6 exp
Tolerant

Tolerant to missense variation

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.0.49 (0.28–0.88)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.04 (0.93–1.18)
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.1.02
0≤1.21.6
LoF obs/exp: 8 / 16.5Missense obs/exp: 199 / 190.6Syn Z: -0.13

ClinVar Variant Classifications

396 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35
Likely Pathogenic12
VUS142
Likely Benign150
Benign28
Conflicting20
35
Pathogenic
12
Likely Pathogenic
142
VUS
150
Likely Benign
28
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
4
22
0
35
Likely Pathogenic
4
5
3
0
12
VUS
0
124
15
3
142
Likely Benign
0
3
80
67
150
Benign
0
0
28
0
28
Conflicting
—20
Total1313614870387

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

View in ClinVar →

Protein Context — Lollipop Plot

SUCLG1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SUCLG1-related fatal infantile lactic acidosis

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria)

MIM #245400

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
Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital.
Stenton SL et al.·Ann Neurol
2022Cohort
SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.
Yan W et al.·EMBO J
2024
SUCLG1 mutations and mitochondrial encephalomyopathy: a case study and review of the literature.
Molaei Ramsheh S et al.·Mol Biol Rep
2020Case report
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
Novel compound heterozygous SUCLG1 variants may contribute to mitochondria DNA depletion syndrome-9.
Chen YM et al.·Mol Genet Genomic Med
2022Case report
Biomarker Identification and Risk Prediction Model Development for Differentiated Thyroid Carcinoma Lung Metastasis Based on Primary Lesion Proteomics.
Peng X et al.·Clin Cancer Res
2024Functional
The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein.
Rouzier C et al.·J Med Genet
2010Case report
Clinical, Molecular, and Computational Analysis in two cases with mitochondrial encephalomyopathy associated with SUCLG1 mutation in a consanguineous family.
Maalej M et al.·Biochem Biophys Res Commun
2018Case report
Expanding the phenotypic spectrum of Succinyl-CoA ligase deficiency through functional validation of a new SUCLG1 variant.
Donti TR et al.·Mol Genet Metab
2016Case report
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

External Resources

Links to major genomics databases and tools