CLYBL

Chr 13

citramalyl-CoA lyase

Also known as: CLB

NCBI Gene: 171425 ENSG00000125246 UniProt: Q8N0X4

This mitochondrial enzyme detoxifies vitamin B12-poisoning metabolites by acting as a citramalyl-CoA lyase to convert citramalyl-CoA into acetyl-CoA and pyruvate, and functions as a malyl-CoA thioesterase to detoxify toxic malyl-CoA that interferes with vitamin B12-dependent metabolism. Mutations cause autosomal recessive malonic aciduria with developmental delay, seizures, and metabolic decompensation typically presenting in early childhood. The gene shows relaxed evolutionary constraint, suggesting tolerance to some loss-of-function variation.

ResearchSummary from RefSeq, UniProt

Enables several functions, including (S)-citramalyl-CoA lyase activity; magnesium ion binding activity; and malate synthase activity. Involved in protein homotrimerization; regulation of cobalamin metabolic process; and toxic metabolite repair. Is active in mitochondrion. [provided by Alliance of Genome Resources, Jun 2026]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.31

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.31LOEUF

pLI 0.000

Z-score 0.58

OE 0.85 (0.57–1.31)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.08Z-score

OE missense 1.02 (0.90–1.15)

183 obs / 180.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.85 (0.57–1.31)

0≤0.351.4

Missense OE?1.02 (0.90–1.15)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 15 / 17.6Missense obs/exp: 183 / 180.0Syn Z: -0.83

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 91

547 rare PASS variants

Rare truncating (LoF)

1 in 310

137 rare PASS variants

Rare synonymous (reference)

1 in 150

222 rare PASS variants

Rare missense and truncating variants are carried at similar rates in CLYBL; this gene does not show strong loss-of-function constraint by this measure. 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 120	1 in 380
South Asian	~43k	1 in 63	1 in 520
Remaining (unassigned)	~30k	1 in 85	1 in 260
European (Finnish)	~27k	1 in 400	1 in 2,400
Admixed American	~22k	1 in 120	1 in 300
African / African American	~21k	1 in 76	1 in 180
East Asian	~20k	1 in 86	1 in 240
Ashkenazi Jewish	~13k	1 in 750	1 in 600
Middle Eastern	~2,884	1 in 94	1 in 190

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.