SUCLA2

Chr 13AR

succinate-CoA ligase ADP-forming subunit beta

Also known as: A-BETA, A-SCS, LINC00444, MTDPS5, SCS-betaA

NCBI Gene: 8803 ENSG00000136143 UniProt: Q9P2R7 OMIM: 603921

The protein encodes the ATP-specific beta subunit of succinyl-CoA synthetase, which dimerizes with the alpha subunit to form an essential tricarboxylic acid cycle enzyme that hydrolyzes ATP to convert succinate to succinyl-CoA in the mitochondrial matrix. Biallelic mutations cause mitochondrial DNA depletion syndrome 5, an autosomal recessive encephalomyopathy that may present with or without methylmalonic aciduria. The pathogenic mechanism involves loss of function leading to impaired mitochondrial energy metabolism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.631 OMIM phenotype

Clinical Summary— SUCLA2

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.63LOEUF

pLI 0.002

Z-score 2.97

OE 0.36 (0.22–0.63)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.02Z-score

OE missense 0.82 (0.73–0.92)

206 obs / 251.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.22–0.63)

0≤0.351.4

Missense OE?0.82 (0.73–0.92)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 9 / 25.1Missense obs/exp: 206 / 251.6Syn Z: 0.04

This gene — mechanism propensity

0.6744th %ile

GOF

0.4875th %ile

LOF

0.3453th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.