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.

GeneReviews 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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria)MIM #612073

Clinical highlights

Gene–disease validity (ClinGen)

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.63

LOEUF

Mechanism· predicted

📖

GeneReview available — SUCLA2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in SUCLA2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 86

559 rare PASS variants

Rare truncating (LoF)

1 in 1,500

79 rare PASS variants

Rare synonymous (reference)

1 in 150

183 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SUCLA2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 3,100
South Asian	~43k	1 in 100	1 in 4,300
Remaining (unassigned)	~30k	1 in 83	1 in 520
European (Finnish)	~27k	1 in 240	1 in 5,300
Admixed American	~22k	1 in 96	1 in 1,100
African / African American	~21k	1 in 140	1 in 2,200
East Asian	~20k	1 in 120	1 in 1,700
Ashkenazi Jewish	~13k	1 in 310	1 in 1,400
Middle Eastern	~2,884	1 in 160	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓