CLYBL

Summary

CLYBL (citramalyl-CoA lyase, HGNC:18355) is a protein-coding gene on chromosome 13q32.3, encoding Citramalyl-CoA lyase, mitochondrial (Q8N0X4). Mitochondrial enzyme required to detoxify vitamin B12-poisoning metabolites.

Enables (S)-citramalyl-CoA lyase activity; magnesium ion binding activity; and malate synthase activity. Involved in protein homotrimerization and regulation of cobalamin metabolic process. Located in mitochondrion.

Source: NCBI Gene 171425 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 78 total — 6 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_206808

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18355
Approved symbol	CLYBL
Name	citramalyl-CoA lyase
Location	13q32.3
Locus type	gene with protein product
Status	Approved
Aliases	CLB
Ensembl gene	ENSG00000125246
Ensembl biotype	protein_coding
OMIM	609686
Entrez	171425

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 28 protein_coding, 2 nonsense_mediated_decay

ENST00000339105, ENST00000376354, ENST00000376355, ENST00000416504, ENST00000419700, ENST00000425186, ENST00000443887, ENST00000689673, ENST00000693071, ENST00000898520, ENST00000898521, ENST00000898522, ENST00000898523, ENST00000898524, ENST00000898525, ENST00000898526, ENST00000898527, ENST00000898528, ENST00000898529, ENST00000898530, ENST00000898531, ENST00000898532, ENST00000898533, ENST00000933045, ENST00000933046, ENST00000933047, ENST00000943588, ENST00000943589, ENST00000943590, ENST00000943591

RefSeq mRNA: 9 — MANE Select: NM_206808 NM_001393355, NM_001393356, NM_001393357, NM_001393358, NM_001393359, NM_001393360, NM_001393361, NM_001393362, NM_206808

CCDS: CCDS32002, CCDS91830

Canonical transcript exons

ENST00000339105 — 9 exons

Exon	Start	End
ENSE00000853942	99870938	99871062
ENSE00001265627	99891318	99891437
ENSE00001470288	99606690	99606757
ENSE00001619974	99858861	99859049
ENSE00001642359	99864818	99864911
ENSE00001647881	99862991	99863092
ENSE00001761435	99772824	99773010
ENSE00001765361	99866240	99866407
ENSE00001925660	99892443	99892570

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 94.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.9420 / max 60.5302, expressed in 1463 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
135837	5.9420	1463

Top tissues by expression

248 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	94.02	gold quality
right lobe of liver	UBERON:0001114	93.43	gold quality
liver	UBERON:0002107	92.05	gold quality
adult mammalian kidney	UBERON:0000082	91.79	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.03	gold quality
mucosa of transverse colon	UBERON:0004991	88.98	gold quality
kidney	UBERON:0002113	88.78	gold quality
gastrocnemius	UBERON:0001388	88.66	gold quality
muscle of leg	UBERON:0001383	88.41	gold quality
rectum	UBERON:0001052	88.32	gold quality
vastus lateralis	UBERON:0001379	87.92	gold quality
metanephros cortex	UBERON:0010533	87.88	gold quality
quadriceps femoris	UBERON:0001377	87.66	gold quality
heart left ventricle	UBERON:0002084	87.65	gold quality
apex of heart	UBERON:0002098	87.38	gold quality
cardiac ventricle	UBERON:0002082	87.29	gold quality
jejunal mucosa	UBERON:0000399	86.96	gold quality
cortex of kidney	UBERON:0001225	86.82	gold quality
right adrenal gland	UBERON:0001233	86.59	gold quality
duodenum	UBERON:0002114	86.45	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.42	gold quality
left adrenal gland	UBERON:0001234	85.77	gold quality
right adrenal gland cortex	UBERON:0035827	85.69	gold quality
ileal mucosa	UBERON:0000331	85.65	gold quality
right atrium auricular region	UBERON:0006631	85.49	gold quality
heart	UBERON:0000948	85.42	gold quality
deltoid	UBERON:0001476	85.36	silver quality
left adrenal gland cortex	UBERON:0035825	85.29	gold quality
skeletal muscle tissue	UBERON:0001134	85.22	gold quality
cardiac atrium	UBERON:0002081	85.16	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): XBP1

Literature-anchored findings (GeneRIF, showing 1)

• Study reports that CLYBL loss leads to a cell-autonomous defect in the mitochondrial B12 metabolism and that itaconyl-CoA is a cofactor-inactivating, substrate-analog inhibitor of the mitochondrial B12-dependent methylmalonyl-CoA mutase (PMID:29056341)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	clybl	ENSDARG00000029729
mus_musculus	Clybl	ENSMUSG00000025545
rattus_norvegicus	Clybl	ENSRNOG00000014075

Protein

Protein identifiers

Citramalyl-CoA lyase, mitochondrial — Q8N0X4 (reviewed: Q8N0X4)

Alternative names: (3S)-malyl-CoA thioesterase, Beta-methylmalate synthase, Citrate lyase subunit beta-like protein, Malate synthase

All UniProt accessions (5): Q8N0X4, Q5JVB9, Q5JVC0, Q5JVC1, Q5JVC2

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial enzyme required to detoxify vitamin B12-poisoning metabolites. Acts as a citramalyl-CoA lyase by converting citramalyl-CoA into acetyl-CoA and pyruvate in the C5-dicarboxylate catabolism pathway, a pathway required to detoxify itaconate, a vitamin B12-poisoning metabolite. Also acts as a malyl-CoA thioesterase to detoxify malyl-CoA, a side product of citric acid cycle enzymes, which is toxic for the vitamin B12-dependent enzyme MMUT. Also acts as a malate synthase in vitro, converting glyoxylate and acetyl-CoA to malate. Also acts as a beta-methylmalate synthase in vitro, by mediating conversion of glyoxylate and propionyl-CoA to beta-methylmalate. Also has very weak citramalate synthase activity in vitro.

Subunit / interactions. Homotrimer.

Subcellular location. Mitochondrion.

Cofactor. Binds 1 Mg(2+) ion per subunit.

Polymorphism. The protein is absent in 2.7% of the human population due to a loss-of-function polymorphism (rs41281112) that changes Arg-259 to a premature stop codon, leading to loss of the protein product. This polymorphism is associated with reduction of circulating vitamin B12. The reduction of circulating vitamin B12 is caused by accumulation of citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate. Itaconate acting as a vitamin B12-poisoning metabolite that inactivates the mitochondrial methylglutaconyl-CoA hydratase (AUH) enzyme.

Similarity. Belongs to the HpcH/HpaI aldolase family. Citrate lyase beta subunit-like subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N0X4-1	1	yes
Q8N0X4-2	2

RefSeq proteins (9): NP_001380284, NP_001380285, NP_001380286, NP_001380287, NP_001380288, NP_001380289, NP_001380290, NP_001380291, NP_996531* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005000	Aldolase/citrate-lyase_domain	Domain
IPR011206	Citrate_lyase_beta/mcl1/mcl2	Family
IPR015813	Pyrv/PenolPyrv_kinase-like_dom	Homologous_superfamily
IPR040186	Citramalyl-CoA_lyase	Family
IPR040442	Pyrv_kinase-like_dom_sf	Homologous_superfamily

Pfam: PF03328

Enzyme classification (BRENDA):

• EC 4.1.3.6 — citrate (pro-3S)-lyase (BRENDA: 29 organisms, 16 substrates, 7 inhibitors, 6 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CITRATE	0.12–0.31	6

Catalyzed reactions (Rhea), 4 shown:

• glyoxylate + acetyl-CoA + H2O = (S)-malate + CoA + H(+) (RHEA:18181)
• (3S)-citramalyl-CoA = pyruvate + acetyl-CoA (RHEA:22612)
• (S)-malyl-CoA + H2O = (S)-malate + CoA + H(+) (RHEA:38291)
• propanoyl-CoA + glyoxylate + H2O = 3-methylmalate + CoA + H(+) (RHEA:47628)

UniProt features (53 total): helix 18, strand 11, modified residue 7, binding site 7, sequence variant 4, transit peptide 1, chain 1, splice variant 1, active site 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5VXC	X-RAY DIFFRACTION	1.87
5VXO	X-RAY DIFFRACTION	2.27
5VXS	X-RAY DIFFRACTION	2.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N0X4-F1	91.00	0.82

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 320

Ligand- & substrate-binding residues (7): 50; 57; 61; 107; 171; 206; 272–273

Post-translational modifications (7): 57, 61, 82, 82, 92, 92, 309

Mutagenesis-validated functional residues (1):

Position	Phenotype
320	abolishes citramalyl-coa lyase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 116 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, DARWICHE_PAPILLOMA_PROGRESSION_RISK, GOBP_PROTEIN_TRIMERIZATION, GOBP_COBALAMIN_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_DETOXIFICATION, GOBP_TETRAPYRROLE_METABOLIC_PROCESS, ATCATGA_MIR433, GOBP_PROTEIN_HOMOOLIGOMERIZATION, GOBP_RESPONSE_TO_TOXIC_SUBSTANCE, YAMAZAKI_TCEB3_TARGETS_DN, chr13q32, GOMF_MAGNESIUM_ION_BINDING, GOMF_ACYL_COA_HYDROLASE_ACTIVITY

GO Biological Process (3): protein homotrimerization (GO:0070207), regulation of cobalamin metabolic process (GO:0106064), positive regulation of cobalamin metabolic process (GO:0106121)

GO Molecular Function (8): magnesium ion binding (GO:0000287), malate synthase activity (GO:0004474), hydrolase activity (GO:0016787), (S)-citramalyl-CoA lyase activity (GO:0047777), catalytic activity (GO:0003824), transferase activity (GO:0016740), lyase activity (GO:0016829), metal ion binding (GO:0046872)

GO Cellular Component (2): mitochondrion (GO:0005739), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	3
cobalamin metabolic process	2
protein homooligomerization	1
protein trimerization	1
regulation of tetrapyrrole metabolic process	1
positive regulation of metabolic process	1
regulation of cobalamin metabolic process	1
metal ion binding	1
acyltransferase activity, acyl groups converted into alkyl on transfer	1
oxo-acid-lyase activity	1
molecular_function	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2133 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLYBL	FN1	P02751	602
CLYBL	GAPDH	P00354	536
CLYBL	AUH	Q13825	519
CLYBL	PPP1R12C	Q9BZL4	509
CLYBL	CS	O75390	497
CLYBL	TM9SF2	Q99805	461
CLYBL	PLG	P00747	424
CLYBL	FH	P07954	419
CLYBL	CD320	Q9NPF0	418
CLYBL	ACO2	Q99798	414
CLYBL	GLRX3	O76003	404
CLYBL	PPFIBP1	Q86W92	394
CLYBL	SMIM21	Q3B7S5	393
CLYBL	ACO1	P21399	380
CLYBL	FUT6	P51993	377

IntAct

8 interactions, top by confidence:

A	B	Type	Score
RNASE9	CLYBL	psi-mi:“MI:0915”(physical association)	0.400
XXYLT1	PRMT3	psi-mi:“MI:0914”(association)	0.350
FAM118B	HNRNPCL1	psi-mi:“MI:0914”(association)	0.350
CD300E	RAP1B	psi-mi:“MI:0914”(association)	0.350
FAM181A	CLYBL	psi-mi:“MI:0914”(association)	0.350
POLL	PGK2	psi-mi:“MI:0914”(association)	0.350
	VWA8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (15): CLYBL (Affinity Capture-Western), CLYBL (Proximity Label-MS), CLYBL (Proximity Label-MS), CLYBL (Affinity Capture-MS), CLYBL (Affinity Capture-MS), CLYBL (Affinity Capture-MS), CLYBL (Affinity Capture-MS), CLYBL (Affinity Capture-MS), CLYBL (Affinity Capture-MS), CLYBL (Proximity Label-MS), CLYBL (Co-fractionation), CLYBL (Co-fractionation), CLYBL (Affinity Capture-MS), CLYBL (Proximity Label-MS), CLYBL (Affinity Capture-Western)

ESM2 similar proteins: A1YER2, A1YFX9, A2T7G9, A6NNS2, B0BN93, B0BNF8, O22718, O35331, O35678, O75911, O77769, O80526, O88876, O95154, P11172, P14755, P15904, P84169, Q06136, Q15738, Q1RMJ5, Q28DS0, Q2KIJ5, Q2QNG7, Q2QZ86, Q3SZM9, Q3T067, Q3ZBE9, Q5E964, Q5I0K3, Q5PPL3, Q5R514, Q5R5C9, Q5RDZ2, Q6AY30, Q6UWP2, Q811X6, Q86WA6, Q8JGT5, Q8K183

Diamond homologs: A3PGR7, A3PN16, A4WNM9, A4WVF5, A9WC35, B6E2X2, B9KLE8, B9KNB6, D3JV05, D5AR83, O53078, P0A9I1, P0A9I2, P17725, P44460, P9WPE0, P9WPE1, Q3J5L6, Q5I0K3, Q8N0X4, Q8R4N0, Q9RUZ0, S5N020

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

78 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	60
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1275753	NC_000013.10:g.99162946_101376965del	Pathogenic
2425688	NC_000013.10:g.(?99336978)(102379160_?)del	Pathogenic
442413	GRCh37/hg19 13q32.3(chr13:99333632-100773336)x1	Pathogenic
443855	GRCh37/hg19 13q32.3-33.1(chr13:100016737-101862895)x1	Pathogenic
57682	GRCh38/hg38 13q32.3-33.1(chr13:99034367-101217397)x1	Pathogenic
830571	NC_000013.11:g.(?99385979)(99986648_?)del	Pathogenic
442644	GRCh37/hg19 13q32.1-33.1(chr13:98158452-101950563)x3	Likely pathogenic

SpliceAI

4118 predictions. Top by Δscore:

Variant	Effect	Δscore
13:99606754:GGCT:G	donor_gain	1.0000
13:99606755:GCTG:G	donor_gain	1.0000
13:99772280:GAT:G	donor_gain	1.0000
13:99772820:GCAG:G	acceptor_loss	1.0000
13:99772821:CAG:C	acceptor_loss	1.0000
13:99772822:A:AG	acceptor_gain	1.0000
13:99772822:AG:A	acceptor_gain	1.0000
13:99772823:G:GT	acceptor_gain	1.0000
13:99772823:GG:G	acceptor_gain	1.0000
13:99772823:GGA:G	acceptor_gain	1.0000
13:99772823:GGAA:G	acceptor_gain	1.0000
13:99772823:GGAAA:G	acceptor_gain	1.0000
13:99773007:AAAG:A	donor_loss	1.0000
13:99773008:AAGG:A	donor_loss	1.0000
13:99773009:AGG:A	donor_loss	1.0000
13:99773010:GG:G	donor_loss	1.0000
13:99773011:GTAAT:G	donor_loss	1.0000
13:99813265:A:G	donor_gain	1.0000
13:99606755:GCT:G	donor_gain	0.9900
13:99606758:G:GG	donor_gain	0.9900
13:99649457:T:G	donor_gain	0.9900
13:99662060:G:T	donor_gain	0.9900
13:99662079:G:GT	donor_gain	0.9900
13:99772286:A:AG	donor_gain	0.9900
13:99772287:G:GG	donor_gain	0.9900
13:99773011:GTA:G	donor_gain	0.9900
13:99813265:A:AG	donor_gain	0.9900
13:99858859:A:AG	acceptor_gain	0.9900
13:99858860:G:GG	acceptor_gain	0.9900
13:99858860:GA:G	acceptor_gain	0.9900

AlphaMissense

2198 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:99772987:G:C	D76H	0.998
13:99871025:T:C	L297P	0.998
13:99772988:A:C	D76A	0.997
13:99772988:A:T	D76V	0.997
13:99772989:T:A	D76E	0.997
13:99772989:T:G	D76E	0.997
13:99864894:A:C	D206A	0.997
13:99864895:C:A	D206E	0.997
13:99864895:C:G	D206E	0.997
13:99866282:G:C	R226P	0.997
13:99772978:G:C	D73H	0.996
13:99772985:A:T	E75V	0.996
13:99863064:A:T	E171V	0.996
13:99864894:A:T	D206V	0.996
13:99870938:G:A	G268D	0.996
13:99870954:C:A	H273Q	0.996
13:99870954:C:G	H273Q	0.996
13:99891324:T:C	F312L	0.996
13:99891326:T:A	F312L	0.996
13:99891326:T:G	F312L	0.996
13:99891369:G:C	A327P	0.996
13:99772988:A:G	D76G	0.995
13:99858932:A:C	R107S	0.995
13:99858932:A:T	R107S	0.995
13:99864894:A:G	D206G	0.995
13:99870942:G:C	K269N	0.995
13:99870942:G:T	K269N	0.995
13:99871015:G:C	A294P	0.995
13:99858931:G:C	R107T	0.994
13:99858966:G:C	D119H	0.994

dbSNP variants (sampled 300 via entrez): RS1000022 (13:99808965 C>T), RS1000022782 (13:99854772 G>A), RS1000026668 (13:99894195 C>A,T), RS1000042738 (13:99768071 C>T), RS1000055201 (13:99847098 G>A), RS1000066233 (13:99811988 C>A), RS1000090271 (13:99774759 G>A), RS1000109349 (13:99687272 A>T), RS1000128759 (13:99900695 C>G,T), RS1000131438 (13:99859367 C>A), RS1000133325 (13:99818446 A>C), RS1000133686 (13:99901439 C>T), RS1000152884 (13:99645558 T>C), RS1000160625 (13:99718389 AC>A), RS1000165353 (13:99774388 G>A,T)

Disease associations

OMIM: gene MIM:609686 | disease phenotypes: MIM:609637

GenCC curated gene-disease

Mondo (2): lobar holoprosencephaly (MONDO:0019756), holoprosencephaly 5 (MONDO:0012322)

Orphanet (2): Lobar holoprosencephaly (Orphanet:93924), Holoprosencephaly (Orphanet:2162)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000281_17	Attention deficit hyperactivity disorder	5.000000e-06
GCST001424_5	Vitamin B12 levels	9.000000e-10
GCST001762_166	Obesity-related traits	5.000000e-06
GCST002357_4	Rheumatoid arthritis (ACPA-negative)	6.000000e-08
GCST004485_57	Survival in pancreatic cancer	8.000000e-06
GCST006979_1037	Heel bone mineral density	3.000000e-13
GCST008810_69	Smoking initiation (ever regular vs never regular)	6.000000e-09
GCST010002_194	Refractive error	2.000000e-76

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004620	vitamin B12 measurement
EFO:0000638	overall survival
EFO:0009270	heel bone mineral density
EFO:0005670	smoking initiation

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566464	Holoprosencephaly 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	9
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	5
Aflatoxin B1	decreases methylation, affects expression, decreases expression	4
sodium arsenite	increases expression, decreases expression, affects cotreatment	2
perfluorooctanoic acid	decreases expression, increases expression	2
Cisplatin	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
lead acetate	affects cotreatment, increases expression	1
trichostatin A	increases expression	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
dorsomorphin	increases expression, affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects methylation, increases abundance	1
Atrazine	increases expression	1
Daunorubicin	affects response to substance	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	decreases expression, affects cotreatment	1
Hydralazine	affects cotreatment, increases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.