PCCB

Summary

PCCB (propionyl-CoA carboxylase subunit beta, HGNC:8654) is a protein-coding gene on chromosome 3q22.3, encoding Propionyl-CoA carboxylase beta chain, mitochondrial (P05166). This is one of the 2 subunits of the biotin-dependent propionyl-CoA carboxylase (PCC), a mitochondrial enzyme involved in the catabolism of odd chain fatty acids, branched-chain amino acids isoleucine, threonine, methionine, and valine and other metabolites.

The protein encoded by this gene is a subunit of the propionyl-CoA carboxylase (PCC) enzyme, which is involved in the catabolism of propionyl-CoA. PCC is a mitochondrial enzyme that probably acts as a dodecamer of six alpha subunits and six beta subunits. This gene encodes the beta subunit of PCC. Defects in this gene are a cause of propionic acidemia type II (PA-2). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5096 — RefSeq curated summary.

At a glance

• Gene–disease (curated): propionic acidemia (Definitive, ClinGen)
• GWAS associations: 40
• Clinical variants (ClinVar): 1,373 total — 119 pathogenic, 113 likely-pathogenic
• Phenotypes (HPO): 41
• MANE Select transcript: NM_000532

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8654
Approved symbol	PCCB
Name	propionyl-CoA carboxylase subunit beta
Location	3q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000114054
Ensembl biotype	protein_coding
OMIM	232050
Entrez	5096

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 31 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000251654, ENST00000459873, ENST00000462542, ENST00000462637, ENST00000465176, ENST00000465423, ENST00000466072, ENST00000468777, ENST00000469217, ENST00000471595, ENST00000473073, ENST00000474833, ENST00000475214, ENST00000478469, ENST00000482086, ENST00000483687, ENST00000484181, ENST00000490504, ENST00000494742, ENST00000878344, ENST00000878345, ENST00000878346, ENST00000878347, ENST00000878348, ENST00000878349, ENST00000878350, ENST00000878351, ENST00000878352, ENST00000878353, ENST00000878354, ENST00000878355, ENST00000878356, ENST00000878357, ENST00000954229, ENST00000954230, ENST00000954231

RefSeq mRNA: 2 — MANE Select: NM_000532 NM_000532, NM_001178014

CCDS: CCDS3089, CCDS54643

Canonical transcript exons

ENST00000251654 — 15 exons

Exon	Start	End
ENSE00001246501	136250340	136250558
ENSE00001246512	136327155	136327255
ENSE00003484920	136329905	136330169
ENSE00003493195	136293756	136293864
ENSE00003504091	136326803	136326910
ENSE00003515190	136256555	136256623
ENSE00003527100	136260479	136260535
ENSE00003549588	136301030	136301111
ENSE00003557049	136261952	136262065
ENSE00003567364	136297952	136298072
ENSE00003627292	136316941	136317064
ENSE00003628331	136255856	136255975
ENSE00003654094	136327634	136327732
ENSE00003666096	136283837	136283947
ENSE00003692187	136328758	136328857

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 97.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.7739 / max 185.4348, expressed in 1814 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38742	32.3048	1814
38744	0.3212	89
38745	0.1126	44
38743	0.0352	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	97.17	gold quality
right adrenal gland	UBERON:0001233	97.09	gold quality
adrenal tissue	UBERON:0018303	96.43	gold quality
left adrenal gland	UBERON:0001234	96.25	gold quality
left adrenal gland cortex	UBERON:0035825	95.82	gold quality
adrenal cortex	UBERON:0001235	95.73	gold quality
adrenal gland	UBERON:0002369	95.71	gold quality
right lobe of liver	UBERON:0001114	95.57	gold quality
liver	UBERON:0002107	95.56	gold quality
sperm	CL:0000019	93.98	gold quality
rectum	UBERON:0001052	93.96	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.90	gold quality
heart left ventricle	UBERON:0002084	93.77	gold quality
cardiac ventricle	UBERON:0002082	93.71	gold quality
mucosa of transverse colon	UBERON:0004991	93.52	gold quality
islet of Langerhans	UBERON:0000006	93.41	gold quality
right atrium auricular region	UBERON:0006631	93.20	gold quality
triceps brachii	UBERON:0001509	93.19	gold quality
adult mammalian kidney	UBERON:0000082	93.17	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.95	gold quality
male germ cell	CL:0000015	92.93	gold quality
secondary oocyte	CL:0000655	92.89	gold quality
cardiac atrium	UBERON:0002081	92.87	gold quality
endometrium epithelium	UBERON:0004811	92.77	gold quality
heart right ventricle	UBERON:0002080	92.72	gold quality
heart	UBERON:0000948	92.46	gold quality
oocyte	CL:0000023	92.40	gold quality
gastrocnemius	UBERON:0001388	92.01	gold quality
muscle of leg	UBERON:0001383	91.99	gold quality
left testis	UBERON:0004533	91.89	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	10.99
E-ANND-3	yes	8.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting PCCB, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-6728-5P	97.79	66.33	891
HSA-MIR-101-5P	96.84	65.66	649

Literature-anchored findings (GeneRIF, showing 18)

• mutations affect homomeric and heteromeric assembly of Propionyl-CoA Carboxylase (PMID:11749052)
• Structure-function analysis of a range of isolated PCCB subunit mutants has elucidated the complex relationship between genotype and phenotype in propionic acidemia. (PMID:12007220)
• Work showed 15 novel PCCB gene mutations and phenotype-genotype correlations for the prediction of the metabolic outcome and for the implementation of treatments tailored to each PA patient. (PMID:12559849)
• pathogenicity of R67S, R165Q and G112D mutations in PCCB gene in propionic acidemia (PMID:12757933)
• analysis of PCCA and PCCB mutations in propionic acidemia (PMID:17051315)
• cryo-electron microscopy (cryo-EM) reconstruction at 15-A resolution (PMID:20725044)
• The c.-4156_183+3713del mutation is the first known large deletion that affects the PCCB gene functions. (PMID:24863100)
• Ten propionic acidemia mutations were confirmed, including 8 affecting the PCCA gene and 2 affecting the PCCB gene (PMID:25636094)
• we identified seven novel genetic variants: p.Leu549Pro, p.Glu564*, p.Leu641Pro in MUT, p.Tyr206Cys in PCCB, p.His194Arg, p.Val298Met in BCKDHA and p.Glu286_Met290del in BCKDHB gene. In silico and/or eukaryotic expression studies confirmed pathogenic effect of all novel genetic variants (PMID:26830710)
• The majority of patients had mutations in the PCCA gene (18/25). A total of 26 mutations were noted: 20 in the PCCA gene and 6 in PCCB gene. Seventeen mutations were novel (14 in PCCA and 3 in PCCB). (PMID:27227689)
• Recurrent lactic acid elevations were present in six out of the eight patients. Five of the eight patients were diagnosed with Autism Spectrum Disorder, four of them had pathogenic variants in PCCB (PMID:27825584)
• his work represents a large-scale update on pathogenic mutations in the PCCA and PCCB genes causing Propionic acidemia (PA), and confirms previous reports indicating a major causative role of mutation-induced protein destabilization (PMID:30274917)
• Biochemical phenotype and its relationship to treatment in 16 individuals with PCCB c.1606A > G (p.Asn536Asp) variant propionic acidemia. (PMID:33127324)
• Gene diagnosis and pedigree analysis of two Han ethnicity families with propionic acidemia in Fujian. (PMID:33725819)
• Novel variants of the PCCB gene in Chinese patients with propionic acidemia. (PMID:33798502)
• Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing. (PMID:33923806)
• Human forebrain organoid-based multi-omics analyses of PCCB as a schizophrenia associated gene linked to GABAergic pathways. (PMID:37620341)
• A common benign intronic deletion masking a pathogenic deep intronic PCCB variant - genome sequencing and RNA studies to the rescue. (PMID:37776842)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pccb	ENSDARG00000038910
mus_musculus	Pccb	ENSMUSG00000032527
rattus_norvegicus	Pccb	ENSRNOG00000015869
drosophila_melanogaster	CG17177	FBGN0036440
drosophila_melanogaster	CG3349	FBGN0036459
caenorhabditis_elegans		WBGENE00018701

Paralogs (1): MCCC2 (ENSG00000131844)

Protein

Protein identifiers

Propionyl-CoA carboxylase beta chain, mitochondrial — P05166 (reviewed: P05166)

Alternative names: Propanoyl-CoA:carbon dioxide ligase subunit beta

All UniProt accessions (14): P05166, C9JAW3, C9JQS9, C9JVW9, C9JVY9, E7ENC1, E7ETT1, E7ETT4, E7EUY3, E7EX59, E9PDR0, E9PEC3, F8WBI9, H7C5C9

UniProt curated annotations — full annotation on UniProt →

Function. This is one of the 2 subunits of the biotin-dependent propionyl-CoA carboxylase (PCC), a mitochondrial enzyme involved in the catabolism of odd chain fatty acids, branched-chain amino acids isoleucine, threonine, methionine, and valine and other metabolites. Propionyl-CoA carboxylase catalyzes the carboxylation of propionyl-CoA/propanoyl-CoA to D-methylmalonyl-CoA/(S)-methylmalonyl-CoA. Within the holoenzyme, the alpha subunit catalyzes the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain, while the beta subunit then transfers the carboxyl group from carboxylated biotin to propionyl-CoA. Propionyl-CoA carboxylase also significantly acts on butyryl-CoA/butanoyl-CoA, which is converted to ethylmalonyl-CoA/(2S)-ethylmalonyl-CoA at a much lower rate. Other alternative minor substrates include (2E)-butenoyl-CoA/crotonoyl-CoA.

Subunit / interactions. The holoenzyme is a dodecamer composed of 6 PCCA/alpha subunits and 6 PCCB/beta subunits.

Subcellular location. Mitochondrion matrix.

Disease relevance. Propionic acidemia type II (PA-2) [MIM:606054] Life-threatening disease characterized by episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The beta subunit contains the carboxyl transferase (CT) domain.

Pathway. Metabolic intermediate metabolism; propanoyl-CoA degradation; succinyl-CoA from propanoyl-CoA: step 1/3.

Similarity. Belongs to the AccD/PCCB family.

Isoforms (2)

UniProt ID	Names	Canonical?
P05166-1	1	yes
P05166-2	2

RefSeq proteins (2): NP_000523, NP_001171485 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011762	COA_CT_N	Domain
IPR011763	COA_CT_C	Domain
IPR029045	ClpP/crotonase-like_dom_sf	Homologous_superfamily
IPR034733	AcCoA_carboxyl_beta	Domain
IPR051047	AccD/PCCB	Family

Pfam: PF01039

Enzyme classification (BRENDA):

• EC 6.4.1.3 — propionyl-CoA carboxylase (BRENDA: 38 organisms, 40 substrates, 35 inhibitors, 52 Km, 9 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PROPANOYL-COA	0.035–2.6	16
PROPIONYL-COA	0.032–1.3	10
ACETYL-COA	0.05–5	8
BUTYRYL-COA	0.036–0.383	7
HCO3-	0.3–7	4
ATP	0.036–0.08	3
BUTANOYL-COA	1.2–1.5	2
SUCCINYL-COA	1.01	1

Catalyzed reactions (Rhea), 2 shown:

• propanoyl-CoA + hydrogencarbonate + ATP = (S)-methylmalonyl-CoA + ADP + phosphate + H(+) (RHEA:23720)
• butanoyl-CoA + hydrogencarbonate + ATP = (2S)-ethylmalonyl-CoA + ADP + phosphate + H(+) (RHEA:59520)

UniProt features (99 total): sequence variant 31, helix 29, strand 17, modified residue 8, turn 6, domain 2, region of interest 2, transit peptide 1, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
7YBU	ELECTRON MICROSCOPY	2.2
9UHR	ELECTRON MICROSCOPY	2.48
8ZV0	ELECTRON MICROSCOPY	2.6
8ZUY	ELECTRON MICROSCOPY	2.63
8ZUX	ELECTRON MICROSCOPY	2.68
8ZUZ	ELECTRON MICROSCOPY	2.73
9UHS	ELECTRON MICROSCOPY	2.76
8ZV3	ELECTRON MICROSCOPY	2.77
8XL5	ELECTRON MICROSCOPY	2.8
8ZV1	ELECTRON MICROSCOPY	2.8
8ZV6	ELECTRON MICROSCOPY	2.9
9UH2	ELECTRON MICROSCOPY	2.91
8ZV4	ELECTRON MICROSCOPY	2.93
9UH5	ELECTRON MICROSCOPY	2.93
9UHY	ELECTRON MICROSCOPY	2.93
8ZV2	ELECTRON MICROSCOPY	2.94
9UH8	ELECTRON MICROSCOPY	2.98
8XL3	ELECTRON MICROSCOPY	3.02
8ZV5	ELECTRON MICROSCOPY	3.1
9UH6	ELECTRON MICROSCOPY	3.1
9UHB	ELECTRON MICROSCOPY	3.16
8XL4	ELECTRON MICROSCOPY	3.38
9UH1	ELECTRON MICROSCOPY	3.41

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05166-F1	93.59	0.88

Functional residue map

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

Post-translational modifications (8): 474, 474, 489, 489, 71, 99, 99, 248

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-196780	Biotin transport and metabolism
R-HSA-3371599	Defective HLCS causes multiple carboxylase deficiency
R-HSA-71032	Propionyl-CoA catabolism
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 308 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GNF2_RRM1, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, GOBP_SHORT_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GNF2_SMC4L1, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, HSIAO_LIVER_SPECIFIC_GENES, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_13, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, GNF2_FEN1

GO Biological Process (5): fatty acid metabolic process (GO:0006631), branched-chain amino acid metabolic process (GO:0009081), short-chain fatty acid catabolic process (GO:0019626), fatty acid biosynthetic process (GO:0006633), fatty acid catabolic process (GO:0009062)

GO Molecular Function (7): propionyl-CoA carboxylase activity (GO:0004658), ATP binding (GO:0005524), nucleotide binding (GO:0000166), acetyl-CoA carboxylase activity (GO:0003989), protein binding (GO:0005515), carboxyl- or carbamoyltransferase activity (GO:0016743), ligase activity (GO:0016874)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), catalytic complex (GO:1902494), acetyl-CoA carboxylase complex (GO:0009317)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Defects in biotin (Btn) metabolism	1
Mitochondrial Fatty Acid Beta-Oxidation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
fatty acid metabolic process	2
CoA carboxylase activity	2
lipid metabolic process	1
monocarboxylic acid metabolic process	1
amino acid metabolic process	1
carboxylic acid metabolic process	1
fatty acid catabolic process	1
short-chain fatty acid metabolic process	1
lipid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
lipid catabolic process	1
monocarboxylic acid catabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
cellular anatomical structure	1
protein-containing complex	1
catalytic complex	1

Protein interactions and networks

STRING

2780 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCCB	PCCA	P05165	998
PCCB	MMUT	P22033	907
PCCB	MMAB	Q96EY8	691
PCCB	MCEE	Q96PE7	673
PCCB	BCKDHB	P21953	667
PCCB	BCKDHA	P12694	664
PCCB	MTR	Q99707	634
PCCB	MMAA	Q8IVH4	618
PCCB	ACACB	O00763	593
PCCB	HLCS	P50747	593
PCCB	IVD	P26440	570
PCCB	MCCC1	Q96RQ3	560
PCCB	MRPS16	Q9Y3D3	553
PCCB	MMACHC	Q9Y4U1	550
PCCB	ETFA	P13804	550

IntAct

67 interactions, top by confidence:

A	B	Type	Score
IFIT1	IFIT3	psi-mi:“MI:0914”(association)	0.920
PCCA	PCCB	psi-mi:“MI:0407”(direct interaction)	0.770
PCCA	PCCB	psi-mi:“MI:0915”(physical association)	0.770
PCCB	PCCA	psi-mi:“MI:0914”(association)	0.770
OPG044	DDX3X	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PCCB	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
FAM81A	PCCA	psi-mi:“MI:0914”(association)	0.530
EBNA-LP	HAX1	psi-mi:“MI:0914”(association)	0.530
PPP2R2B	DDX3X	psi-mi:“MI:0914”(association)	0.460
INPPL1	BCR/ABL fusion	psi-mi:“MI:0914”(association)	0.460
PCCB	TPR	psi-mi:“MI:0915”(physical association)	0.400
CSNK2B	PCCB	psi-mi:“MI:0915”(physical association)	0.370
PCCB	FXR1	psi-mi:“MI:0915”(physical association)	0.370
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
PCCA	PCCB	psi-mi:“MI:0914”(association)	0.350
PAF1	PGRMC1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
	NUDT19	psi-mi:“MI:0914”(association)	0.350
WHR1	ACACB	psi-mi:“MI:0914”(association)	0.350
CDK17	ACACB	psi-mi:“MI:0914”(association)	0.350
GATA4	PCCA	psi-mi:“MI:0914”(association)	0.350
rep	LETM1	psi-mi:“MI:0914”(association)	0.350
IFIT1	PCCA	psi-mi:“MI:0914”(association)	0.350
TLK2	IGKV1D-13	psi-mi:“MI:0914”(association)	0.350
MALSU1	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (196): PCCB (Affinity Capture-MS), PCCB (Affinity Capture-RNA), PCCB (Affinity Capture-RNA), PCCB (Affinity Capture-MS), LYPLA1 (Co-fractionation), PCCB (Co-fractionation), PCCB (Affinity Capture-MS), PCCB (Affinity Capture-MS), PCCB (Affinity Capture-MS), PCCB (Affinity Capture-MS), PCCB (Affinity Capture-RNA), PCCB (Affinity Capture-MS), PCCB (Affinity Capture-MS), PCCB (Affinity Capture-MS), PCCB (Affinity Capture-MS)

ESM2 similar proteins: A2RCY0, A3CQ50, A6LE74, A8AYV4, B0TXA0, B1I9M1, B1YKB2, B2ILX2, B4U1C2, B5E1P0, B5XHX5, B8I942, B8ZLJ3, B9DVD9, C0M857, C0ME08, C1C5G4, C1CCJ2, C1CIS8, C1CPT7, O31825, O53578, O54028, P05166, P07633, P53002, P54541, P63408, P79384, P9WQH4, P9WQH5, P9WQH6, P9WQH7, Q03M45, Q04M48, Q168G2, Q1J593, Q1JA98, Q1JFE3, Q1JKF0

Diamond homologs: A0PXC5, A0RJJ8, A1BI17, A3N2D4, A4IRQ7, A4W6T0, A5FJY2, A5ITM4, A5UY57, A6QHN5, A6T4Y7, A6U2G7, A7GTP6, A7NIE9, A7X3C8, A7Z7K8, A8FG57, A8Z2L6, A9B536, A9VJR3, A9WBQ9, B0BR78, B0RW82, B1HNE3, B1HX17, B1XKV6, B1ZVD6, B3EFW3, B3H2H3, B4SEP9, B7GGS9, B7HFB5, B7HRP1, B7IK00, B7JRX4, B8G381, B9DN96, B9J0A1, B9LE80, C1EUU5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PCCB	“form complex”	PCC	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1373 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	119
Likely pathogenic	113
Uncertain significance	395
Likely benign	583
Benign	27

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067629	NM_000532.5(PCCB):c.2T>C (p.Met1Thr)	Pathogenic
1072310	NM_000532.5(PCCB):c.105dup (p.Asn36Ter)	Pathogenic
1073244	NM_000532.5(PCCB):c.1214dup (p.Tyr405Ter)	Pathogenic
1075304	NM_000532.5(PCCB):c.600T>A (p.Cys200Ter)	Pathogenic
1076061	NM_000532.5(PCCB):c.737G>T (p.Gly246Val)	Pathogenic
1076081	NM_000532.5(PCCB):c.1361_1364del (p.Ala454fs)	Pathogenic
1076889	NC_000003.11:g.(?136012588)(136035916_?)del	Pathogenic
12012	NM_000532.5(PCCB):c.1299+3_1299+10del	Pathogenic
12014	NM_000532.5(PCCB):c.1173dup (p.Val392fs)	Pathogenic
12015	NM_000532.5(PCCB):c.502G>A (p.Glu168Lys)	Pathogenic
12016	NM_000532.5(PCCB):c.1283C>T (p.Thr428Ile)	Pathogenic
12017	NM_000532.5(PCCB):c.1538_1540dup (p.Ala513_Arg514insPro)	Pathogenic
1323418	NM_000532.5(PCCB):c.430-1G>A	Pathogenic
1323419	NM_000532.5(PCCB):c.1142dup (p.Cys381fs)	Pathogenic
132644	NG_008939.1(PCCB):g.896_8947del	Pathogenic
1390253	NM_000532.5(PCCB):c.174_175delinsTA (p.Gln58_His59delinsHisAsn)	Pathogenic
1397031	NM_000532.5(PCCB):c.180_181delinsTT (p.Lys60_Arg61delinsAsnTer)	Pathogenic
1410349	NM_000532.5(PCCB):c.683del (p.Pro228fs)	Pathogenic
1412366	NM_000532.5(PCCB):c.751_752del (p.Thr251fs)	Pathogenic
1436430	NC_000003.11:g.(?136019862)(136019963_?)del	Pathogenic
1444332	NM_000532.5(PCCB):c.1027_1028dup (p.Phe344fs)	Pathogenic
1450368	NM_000532.5(PCCB):c.1275del (p.Val427fs)	Pathogenic
1451153	NM_000532.5(PCCB):c.1519C>T (p.Gln507Ter)	Pathogenic
1455788	NM_000532.5(PCCB):c.1422del (p.His476fs)	Pathogenic
1456492	NM_000532.5(PCCB):c.1043_1044del (p.Asn348fs)	Pathogenic
1458708	NM_000532.5(PCCB):c.614T>A (p.Val205Asp)	Pathogenic
1458710	NM_000532.5(PCCB):c.991G>T (p.Glu331Ter)	Pathogenic
1459842	NC_000003.11:g.(?135974688)(136003251_?)del	Pathogenic
167423	NM_000532.5(PCCB):c.990dup (p.Glu331Ter)	Pathogenic
1910820	NM_000532.5(PCCB):c.1090_1090+1insTC	Pathogenic

SpliceAI

3027 predictions. Top by Δscore:

Variant	Effect	Δscore
3:136250555:GCGA:G	donor_gain	1.0000
3:136250557:GA:G	donor_gain	1.0000
3:136250559:G:GG	donor_gain	1.0000
3:136250571:GGGCC:G	donor_gain	1.0000
3:136250572:GGCC:G	donor_gain	1.0000
3:136256549:T:A	acceptor_gain	1.0000
3:136256553:A:AG	acceptor_gain	1.0000
3:136256554:G:GA	acceptor_gain	1.0000
3:136260536:G:GG	donor_gain	1.0000
3:136262062:TCTGG:T	donor_loss	1.0000
3:136262063:CTGG:C	donor_loss	1.0000
3:136262065:GGTG:G	donor_loss	1.0000
3:136262066:GTGA:G	donor_loss	1.0000
3:136262067:T:A	donor_loss	1.0000
3:136283831:T:TA	acceptor_gain	1.0000
3:136283832:G:A	acceptor_gain	1.0000
3:136283835:A:AG	acceptor_gain	1.0000
3:136283835:AGAG:A	acceptor_gain	1.0000
3:136283836:G:GG	acceptor_gain	1.0000
3:136283836:GA:G	acceptor_gain	1.0000
3:136283836:GAGG:G	acceptor_gain	1.0000
3:136283945:AAGG:A	donor_loss	1.0000
3:136283946:AGGTA:A	donor_loss	1.0000
3:136283947:GGTAA:G	donor_loss	1.0000
3:136283948:GTAA:G	donor_loss	1.0000
3:136283949:T:G	donor_loss	1.0000
3:136293751:TTCA:T	acceptor_loss	1.0000
3:136293752:TCA:T	acceptor_loss	1.0000
3:136293753:CAGG:C	acceptor_loss	1.0000
3:136293754:A:AG	acceptor_gain	1.0000

AlphaMissense

3534 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:136326901:T:C	F397L	1.000
3:136326903:T:A	F397L	1.000
3:136326903:T:G	F397L	1.000
3:136260482:T:C	F126L	0.999
3:136260484:T:A	F126L	0.999
3:136260484:T:G	F126L	0.999
3:136260495:G:A	G130E	0.999
3:136262016:G:C	R165P	0.999
3:136262019:T:C	I166T	0.999
3:136283885:G:C	G198R	0.999
3:136283893:T:G	C200W	0.999
3:136283895:C:A	A201D	0.999
3:136283897:G:C	G202R	0.999
3:136283898:G:A	G202D	0.999
3:136293763:C:T	S221F	0.999
3:136293771:T:C	F224L	0.999
3:136293773:C:A	F224L	0.999
3:136293773:C:G	F224L	0.999
3:136293781:G:A	G227D	0.999
3:136293832:T:C	L244P	0.999
3:136293835:G:A	G245D	0.999
3:136326902:T:C	F397S	0.999
3:136327641:G:A	G436E	0.999
3:136327697:T:A	W455R	0.999
3:136327697:T:C	W455R	0.999
3:136256618:A:C	S123R	0.998
3:136256620:T:A	S123R	0.998
3:136256620:T:G	S123R	0.998
3:136260479:G:C	D125H	0.998
3:136260498:G:A	G131D	0.998

dbSNP variants (sampled 300 via entrez): RS1000095054 (3:136308642 T>C), RS1000103604 (3:136260825 G>A), RS1000140760 (3:136249327 T>C), RS1000173065 (3:136292921 A>C,G), RS1000243307 (3:136267023 C>A), RS1000316849 (3:136255267 C>T), RS1000342395 (3:136296512 G>A), RS1000347184 (3:136283223 G>A), RS1000382784 (3:136249751 G>A), RS1000398649 (3:136256232 C>A,T), RS1000399581 (3:136296276 C>G), RS1000439675 (3:136267665 T>C), RS1000465662 (3:136289628 CAG>C), RS1000501430 (3:136291894 C>T), RS1000565167 (3:136252048 T>C,G)

Disease associations

OMIM: gene MIM:232050 | disease phenotypes: MIM:606054

GenCC curated gene-disease

Disease	Classification	Inheritance
propionic acidemia	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
propionic acidemia	Definitive	AR

Mondo (2): propionic acidemia (MONDO:0011628), hypertrophic cardiomyopathy (MONDO:0005045)

Orphanet (2): Propionic acidemia (Orphanet:35), Rare hypertrophic cardiomyopathy (Orphanet:217569)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000939	Osteoporosis
HP:0000964	Eczematoid dermatitis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001332	Dystonia
HP:0001508	Failure to thrive
HP:0001638	Cardiomyopathy
HP:0001733	Pancreatitis
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001903	Anemia
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001944	Dehydration
HP:0001987	Hyperammonemia
HP:0001992	Organic aciduria
HP:0002013	Vomiting
HP:0002019	Constipation
HP:0002059	Cerebral atrophy
HP:0002104	Apnea
HP:0002154	Hyperglycinemia
HP:0002240	Hepatomegaly
HP:0002509	Limb hypertonia
HP:0002789	Tachypnea
HP:0003108	Hyperglycinuria

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST000366_2	Fibrinogen	6.000000e-10
GCST000817_166	Height	4.000000e-09
GCST002147_16	Fibrinogen	1.000000e-16
GCST002539_50	Schizophrenia	7.000000e-11
GCST004122_18	Fibrinogen levels	7.000000e-21
GCST004521_157	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004946_94	Schizophrenia	4.000000e-15
GCST005980_15	Total bilirubin levels	2.000000e-16
GCST005998_9	Alanine transaminase levels	4.000000e-08
GCST006624_9	Systolic blood pressure	3.000000e-11
GCST006803_84	Schizophrenia	4.000000e-12
GCST007478_8	Non-word reading	7.000000e-06
GCST008074_116	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-12
GCST008074_142	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	6.000000e-13
GCST008075_119	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-14
GCST008075_38	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	9.000000e-17
GCST008078_48	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	7.000000e-06
GCST008079_75	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-06
GCST008083_111	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-13
GCST008083_160	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	7.000000e-14
GCST008084_189	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	4.000000e-16
GCST008084_3	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-16
GCST008085_158	HDL cholesterol levels in current drinkers	4.000000e-09
GCST008085_186	HDL cholesterol levels in current drinkers	2.000000e-06
GCST008087_117	Triglyceride levels in current drinkers	1.000000e-07
GCST008163_263	Height	9.000000e-07
GCST008163_425	Height	3.000000e-06
GCST009364_9	Triglyceride levels x long total sleep time interaction (2df test)	7.000000e-11
GCST009365_52	LDL cholesterol levels x short total sleep time interaction (2df test)	1.000000e-09
GCST009368_36	HDL cholesterol levels x long total sleep time interaction (2df test)	2.000000e-14

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004570	bilirubin measurement
EFO:0006335	systolic blood pressure
EFO:0005299	non-word reading
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0000195	metabolic syndrome
EFO:0004533	alkaline phosphatase measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D056693	Propionic Acidemia	C16.320.565.100.823; C18.452.648.100.823

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Carboxylases

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	2
sodium arsenite	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Acetaminophen	decreases expression	2
Air Pollutants	increases oxidation, affects expression, affects cotreatment, increases abundance	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Cadmium	increases abundance, increases expression, decreases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Valproic Acid	affects cotreatment, increases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
arsenite	affects binding, increases reaction	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
poly(propyleneimine)	decreases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	increases abundance, affects cotreatment, decreases expression	1
Atrazine	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Hydralazine	affects cotreatment, increases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1

Cellosaurus cell lines

16 cell lines: 11 transformed cell line, 5 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1XD	UAMi004-A-1	Induced pluripotent stem cell	Female
CVCL_A8NI	SDQLCHi043-A	Induced pluripotent stem cell	Male
CVCL_B3DJ	Abcam HEK293T PCCB KO	Transformed cell line	Female
CVCL_BT76	GM22025	Transformed cell line	Male
CVCL_BT79	GM22030	Transformed cell line	Female
CVCL_BU04	GM22112	Transformed cell line	Female
CVCL_BU05	GM22113	Transformed cell line	Female
CVCL_BU08	GM22123	Transformed cell line	Female
CVCL_BU09	GM22124	Transformed cell line	Female
CVCL_BU54	GM22496	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT02426775	PHASE3	COMPLETED	Carglumic Acid in Methylmalonic Acidemia and Propionic Acidemia
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
NCT01341379	PHASE2	WITHDRAWN	Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate
NCT01597440	PHASE2	TERMINATED	Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia
NCT04732429	PHASE2	TERMINATED	Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia
NCT00001631	PHASE2	COMPLETED	Study of Blood Flow in Heart Muscle
NCT00001894	PHASE2	COMPLETED	A Comparison of Two Treatments: Pacemaker and Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy
NCT00001960	PHASE2	COMPLETED	Studying the Effectiveness of Pacemaker Therapy in Children Who Have Thickened Heart Muscle
NCT00011076	PHASE2	COMPLETED	Pirfenidone to Treat Hypertrophic Cardiomyopathy
NCT00035386	PHASE2	COMPLETED	Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: A Pilot Study
NCT00430833	PHASE2	UNKNOWN	CHANCE - Candesartan in Hypertrophic Cardiomyopathy
NCT00500552	PHASE2	COMPLETED	Perhexiline Therapy in Patients With Hypertrophic Cardiomyopathy
NCT01150461	PHASE2	COMPLETED	Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy
NCT01230918	PHASE2	TERMINATED	Study to Develop a Non-invasive Marker for Monitoring Myocardial Fibrosis
NCT01447654	PHASE2	COMPLETED	Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy
NCT01696370	PHASE2	UNKNOWN	Trimetazidine Therapy in Hypertrophic Cardiomyopathy
NCT01912534	PHASE2	COMPLETED	Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
NCT02590809	PHASE2	COMPLETED	Hypertrophic Cardiomyopathy Symptom Release by BX1514M
NCT03496168	PHASE2	COMPLETED	Extension Study of Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in PIONEER