PCCA

Summary

PCCA (propionyl-CoA carboxylase subunit alpha, HGNC:8653) is a protein-coding gene on chromosome 13q32.3, encoding Propionyl-CoA carboxylase alpha chain, mitochondrial (P05165). 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 the alpha subunit of the heterodimeric mitochondrial enzyme Propionyl-CoA carboxylase. PCCA encodes the biotin-binding region of this enzyme. Mutations in either PCCA or PCCB (encoding the beta subunit) lead to an enzyme deficiency resulting in propionic acidemia. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5095 — RefSeq curated summary.

At a glance

• Gene–disease (curated): propionic acidemia (Definitive, ClinGen)
• GWAS associations: 11
• Clinical variants (ClinVar): 1,617 total — 132 pathogenic, 153 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000282

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8653
Approved symbol	PCCA
Name	propionyl-CoA carboxylase subunit alpha
Location	13q32.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000175198
Ensembl biotype	protein_coding
OMIM	232000
Entrez	5095

Gene structure

Transcript identifiers

Ensembl transcripts: 58 — 53 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000376279, ENST00000376285, ENST00000376286, ENST00000413170, ENST00000424527, ENST00000428969, ENST00000443601, ENST00000458283, ENST00000485946, ENST00000621936, ENST00000636366, ENST00000636420, ENST00000636475, ENST00000637358, ENST00000637657, ENST00000647303, ENST00000881624, ENST00000881625, ENST00000881626, ENST00000881627, ENST00000881628, ENST00000881629, ENST00000881630, ENST00000881631, ENST00000881632, ENST00000881633, ENST00000881634, ENST00000881635, ENST00000881636, ENST00000881637, ENST00000881638, ENST00000881639, ENST00000881640, ENST00000881641, ENST00000881642, ENST00000881643, ENST00000881644, ENST00000881645, ENST00000881646, ENST00000881647, ENST00000881648, ENST00000881649, ENST00000881650, ENST00000940849, ENST00000940850, ENST00000940851, ENST00000940852, ENST00000940853, ENST00000940854, ENST00000956819, ENST00000956820, ENST00000956821, ENST00000956822, ENST00000956823, ENST00000956824, ENST00000956825, ENST00000956826, ENST00000956827

RefSeq mRNA: 11 — MANE Select: NM_000282 NM_000282, NM_001127692, NM_001178004, NM_001352605, NM_001352606, NM_001352607, NM_001352608, NM_001352609, NM_001352610, NM_001352611, NM_001352612

CCDS: CCDS45065, CCDS53878, CCDS9496

Canonical transcript exons

ENST00000376285 — 24 exons

Exon	Start	End
ENSE00001593748	100273196	100273346
ENSE00001622034	100515427	100515567
ENSE00001629467	100307192	100307260
ENSE00001638065	100235842	100235878
ENSE00001648714	100527675	100527752
ENSE00001652442	100301460	100301603
ENSE00001665361	100309833	100309908
ENSE00001673087	100257595	100257673
ENSE00001685308	100089093	100089225
ENSE00001696369	100330561	100330671
ENSE00001697964	100102883	100102960
ENSE00001698412	100262729	100262831
ENSE00001713098	100268689	100268783
ENSE00001723053	100111841	100111888
ENSE00001739393	100111993	100112061
ENSE00001758999	100449252	100449305
ENSE00001804646	100302924	100302998
ENSE00001805607	100209332	100209463
ENSE00002284748	100368472	100368574
ENSE00003460333	100154979	100155092
ENSE00003489775	100157287	100157340
ENSE00003724464	100530098	100530435
ENSE00003784437	100425633	100425731
ENSE00003787009	100340157	100340259

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 97.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.3805 / max 119.1715, expressed in 1761 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
135867	11.3805	1761

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.08	gold quality
corpus epididymis	UBERON:0004359	96.87	gold quality
right adrenal gland cortex	UBERON:0035827	96.17	gold quality
right adrenal gland	UBERON:0001233	95.98	gold quality
mucosa of transverse colon	UBERON:0004991	95.70	gold quality
adult mammalian kidney	UBERON:0000082	95.60	gold quality
left adrenal gland	UBERON:0001234	95.60	gold quality
left adrenal gland cortex	UBERON:0035825	95.47	gold quality
adrenal cortex	UBERON:0001235	95.29	gold quality
liver	UBERON:0002107	94.87	gold quality
adrenal gland	UBERON:0002369	94.72	gold quality
calcaneal tendon	UBERON:0003701	94.47	gold quality
renal medulla	UBERON:0000362	94.43	gold quality
metanephros cortex	UBERON:0010533	93.85	gold quality
body of stomach	UBERON:0001161	93.73	gold quality
nephron tubule	UBERON:0001231	93.59	gold quality
kidney	UBERON:0002113	93.56	gold quality
cortex of kidney	UBERON:0001225	93.53	gold quality
transverse colon	UBERON:0001157	93.38	gold quality
right uterine tube	UBERON:0001302	93.25	gold quality
stomach	UBERON:0000945	92.72	gold quality
adrenal tissue	UBERON:0018303	92.60	gold quality
cerebellar hemisphere	UBERON:0002245	92.51	gold quality
cerebellar cortex	UBERON:0002129	92.45	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.17	gold quality
body of pancreas	UBERON:0001150	92.12	gold quality
apex of heart	UBERON:0002098	91.74	gold quality
fundus of stomach	UBERON:0001160	91.71	gold quality
minor salivary gland	UBERON:0001830	91.64	gold quality
rectum	UBERON:0001052	91.52	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-24	yes	3304.86
E-MTAB-6701	yes	1987.25
E-MTAB-6678	yes	10.15
E-ANND-3	yes	6.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1

miRNA regulators (miRDB)

31 targeting PCCA, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-96-5P	99.95	72.80	2140
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-5007-3P	99.51	68.14	1242
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-7702	99.06	65.95	698
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-3136-5P	98.53	67.68	793
HSA-MIR-4439	98.53	67.53	793
HSA-MIR-7114-5P	98.51	67.87	1349
HSA-MIR-1262	98.17	66.52	757
HSA-MIR-4701-3P	98.17	66.25	788
HSA-MIR-6736-5P	98.17	66.43	760
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-5585-5P	97.95	68.80	1024
HSA-MIR-6818-5P	97.50	67.10	1167
HSA-MIR-514A-3P	96.43	67.77	1048
HSA-MIR-514B-3P	96.43	67.77	1048

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 19)

• pathogenicity of 11 mutations by expression studies and correlation of genotype-phenotype in PCCA-deficient propionic acidemia patients. (PMID:12385775)
• Data reported 9 novel PCCA gene mutations and represents an extensive update of the mutational study of propionic acidemia providing important information about the worldwide distribution of PA mutations. (PMID:12559849)
• analysis of propionyl-CoA carboxylase containing pathogenic mutations in the beta subunit (R165W, E168K, and R410W) and one PCCB polymorphism (A497V) and their structural and functional effects (PMID:15890657)
• analysis of PCCA and PCCB mutations in propionic acidemia (PMID:17051315)
• propionyl CoA carboxylase alpha polypeptide intronic variations causing aberrantly spliced messenger RNA is associated with propionic and methylmalonic acidemia. (PMID:17966092)
• This work describes for the first time the high frequency of large genomic deletions in the PCCA gene, which could be due to the characteristics of the PCCA gene structure and its abundance in intronic repetitive elements. (PMID:19157943)
• Activities of propionyl-CoA carboxylase were not significantly different in pancreatic islets of patients with type 2 diabetes from those of the control. (PMID:19296078)
• cryo-electron microscopy (cryo-EM) reconstruction at 15-A resolution (PMID:20725044)
• Thsi study presented that Propionic acidemia(PCCA mutation) associated with visual hallucinations (PMID:22156789)
• Mutation analysis of the PCCA gene identified homozygous c.1284+1G>A in patient 1, c.230G>A (p.R77Q) and c.1855C>T (p.R619X) in patient 2, homozygous c.2125T>C (p.S709P) in patient 3, and only one mutant allele, c.231+1G>T in patient 4. (PMID:24464666)
• Two PCCA mutations, c.229C–>T (p.R77W) and c.1262A–>C (p.Q421P), were identified in a PCCA-deficient patient. (PMID:24863100)
• Ten propionic acidemia mutations were confirmed, including 8 affecting the PCCA gene and 2 affecting the PCCB gene (PMID:25636094)
• 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). The SNP c.937C>T (p.Arg313Ter), was noted in 9/36 (25%) alleles in the PCCA gene (PMID:27227689)
• The data indicate that amino acid/nucleotide metabolism-related genes OGDH, PPAT and PCCA acquire somatic mutations in microsatellite instability-high gastric cancers and colorectal cancers and that mutational intratumoral heterogeneity may occur in at least some of these tumors. (PMID:27468871)
• 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)
• A novel small molecule approach for the treatment of propionic and methylmalonic acidemias. (PMID:33741272)
• Differentially expressed genes PCCA, ECHS1, and HADH are potential prognostic biomarkers for gastric cancer. (PMID:33881965)
• Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing. (PMID:33923806)
• The mitochondrial carboxylase PCCA interacts with Listeria monocytogenes phospholipase PlcB to modulate bacterial survival. (PMID:38727222)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcca	ENSDARG00000028982
mus_musculus	Pcca	ENSMUSG00000041650
rattus_norvegicus	Pcca	ENSRNOG00000057042
caenorhabditis_elegans		WBGENE00017864

Paralogs (4): ACACB (ENSG00000076555), MCCC1 (ENSG00000078070), PC (ENSG00000173599), ACACA (ENSG00000278540)

Protein

Protein identifiers

Propionyl-CoA carboxylase alpha chain, mitochondrial — P05165 (reviewed: P05165)

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

All UniProt accessions (12): A0A1B0GTR1, A0A1B0GU58, A0A1B0GUX9, A0A1B0GWA1, A0A1B0GWI4, A0A2R8Y725, P05165, H0Y4B9, H0Y5U0, H0Y798, Q5JTW6, Q5JVH2

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. Interacts (via the biotin carboxylation domain) with SIRT4. Interacts with SIRT3 and SIRT5.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Acetylated. The biotin cofactor is covalently attached to the C-terminal biotinyl-binding domain and is required for the catalytic activity. Biotinylation is catalyzed by HLCS.

Disease relevance. Propionic acidemia type I (PA-1) [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.

Cofactor. Binds 2 magnesium or manganese ions per subunit.

Domain organisation. Consists of an N-terminal biotin carboxylation/carboxylase (BC) domain that catalyzes the transient carboxylation of the biotin covalently attached to the C-terminal biotinyl-binding/biotin carboxyl carrier (BCC) domain.

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

Isoforms (3)

UniProt ID	Names	Canonical?
P05165-1	1	yes
P05165-2	2
P05165-3	3

RefSeq proteins (11): NP_000273, NP_001121164, NP_001171475, NP_001339534, NP_001339535, NP_001339536, NP_001339537, NP_001339538, NP_001339539, NP_001339540, NP_001339541 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000089	Biotin_lipoyl	Domain
IPR001882	Biotin_BS	Binding_site
IPR005479	CPAse_ATP-bd	Domain
IPR005481	BC-like_N	Domain
IPR005482	Biotin_COase_C	Domain
IPR011053	Single_hybrid_motif	Homologous_superfamily
IPR011054	Rudment_hybrid_motif	Homologous_superfamily
IPR011761	ATP-grasp	Domain
IPR011764	Biotin_carboxylation_dom	Domain
IPR013815	ATP_grasp_subdomain_1	Homologous_superfamily
IPR016185	PreATP-grasp_dom_sf	Homologous_superfamily
IPR041265	PCC_BT	Domain
IPR050856	Biotin_carboxylase_complex	Family

Pfam: PF00289, PF00364, PF02785, PF02786, PF18140

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 (125 total): strand 37, sequence variant 20, helix 19, modified residue 18, binding site 13, sequence conflict 7, domain 3, turn 3, splice variant 2, transit peptide 1, chain 1, active site 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
2JKU	X-RAY DIFFRACTION	1.5
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
2CQY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05165-F1	87.56	0.71

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): 349

Ligand- & substrate-binding residues (13): 336; 336; 349; 349; 349; 349; 351; 351; 409; 177; 209–270; 261 …

Post-translational modifications (18): 65, 65, 119, 150, 150, 200, 200, 252, 262, 328, 328, 385, 407, 496, 502, 513, 648, 694

Function

Pathways and Gene Ontology

Reactome pathways

3 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

MSigDB gene sets: 286 (showing top): GOBP_FATTY_ACID_CATABOLIC_PROCESS, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, MODULE_404, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, MARTINEZ_RB1_TARGETS_UP, GOBP_SHORT_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, HOSHIDA_LIVER_CANCER_SUBCLASS_S3

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), lipid metabolic process (GO:0006629), lipid catabolic process (GO:0016042)

GO Molecular Function (9): propionyl-CoA carboxylase activity (GO:0004658), ATP binding (GO:0005524), biotin binding (GO:0009374), enzyme binding (GO:0019899), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874), ligase activity, forming carbon-carbon bonds (GO:0016885)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), catalytic complex (GO:1902494)

Reactome top-level categories

Rollup of top-3 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid metabolic process	2
heterocyclic compound binding	2
cytoplasm	2
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
primary metabolic process	1
catabolic process	1
CoA carboxylase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
vitamin binding	1
monocarboxylic acid binding	1
sulfur compound binding	1
protein binding	1
cation binding	1
nucleoside phosphate binding	1
binding	1
catalytic activity	1
ligase activity	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
cellular anatomical structure	1
protein-containing complex	1

Protein interactions and networks

STRING

1788 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCCA	PCCB	P05166	998
PCCA	HLCS	P50747	923
PCCA	MMUT	P22033	887
PCCA	MCCC2	Q9HCC0	809
PCCA	BTD	P43251	779
PCCA	BCKDHB	P21953	653
PCCA	MCEE	Q96PE7	626
PCCA	MMAB	Q96EY8	619
PCCA	BCKDHA	P12694	615
PCCA	MTR	Q99707	598
PCCA	MCC	P23508	594
PCCA	MMADHC	Q9H3L0	551
PCCA	IVD	P26440	544
PCCA	HMGCL	P35914	533
PCCA	HIBADH	P31937	508

IntAct

73 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
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PCCA	MCC	psi-mi:“MI:0915”(physical association)	0.560
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
ICMT	STXBP3	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
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
PARP2	PCCA	psi-mi:“MI:0557”(adp ribosylation reaction)	0.440
PCCA	PB2	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
PAF1	PGRMC1	psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
	NUDT19	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
FPR1	GPR89A	psi-mi:“MI:0914”(association)	0.350
FAM81A	ZZEF1	psi-mi:“MI:0914”(association)	0.350
ACSM5	CLUH	psi-mi:“MI:0914”(association)	0.350

BioGRID (175): PCCA (Affinity Capture-MS), PCCA (Affinity Capture-MS), PCCA (Affinity Capture-MS), PCCA (Affinity Capture-MS), PCCA (Affinity Capture-MS), PCCB (Co-fractionation), PCCA (Affinity Capture-MS), PCCA (Affinity Capture-MS), PCCA (Affinity Capture-MS), PCCA (Affinity Capture-MS), PCCA (Affinity Capture-MS), PCCA (Two-hybrid), PCCA (Affinity Capture-MS), PCCB (Affinity Capture-MS), PCCA (Affinity Capture-MS)

ESM2 similar proteins: A0A0U2WCB2, A6NK44, A6QLI6, A8XX92, A9NNH7, B9FK36, O42764, P05165, P07997, P08680, P0DTA4, P13196, P13446, P14882, P16635, P22557, P43090, P54889, Q19842, Q28CR0, Q2KIZ3, Q2QMG2, Q42523, Q42777, Q4KLB0, Q4WHU1, Q502D1, Q553V2, Q5I0C3, Q5R557, Q5R7K1, Q5R9R9, Q612F5, Q63147, Q6CDR5, Q6JQN1, Q759G5, Q872T7, Q8K370, Q91ZA3

Diamond homologs: A0A0H3JRU9, A0A4P8DJE6, A2C2S8, A5H0J2, A6ZMR9, B3LM95, B8G187, B9HBA8, B9N843, C0H419, C7GRE4, C8ZF72, D3DJ41, D3DJ42, E9Q4Z2, I3R7G3, O00763, O04983, O17732, O27179, O27939, O30019, O34544, O52058, O93918, P05115, P05165, P06959, P0A509, P0DTA4, P10802, P11154, P11497, P11498, P13187, P14882, P24182, P29337, P32327, P32528

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PCCA	“form complex”	PCC	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1617 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	132
Likely pathogenic	153
Uncertain significance	462
Likely benign	670
Benign	61

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070049	NM_000282.4(PCCA):c.1598_1601del (p.Phe533fs)	Pathogenic
1072653	NM_000282.4(PCCA):c.872C>G (p.Ser291Ter)	Pathogenic
1072772	NM_000282.4(PCCA):c.506dup (p.His169fs)	Pathogenic
1073696	NM_000282.4(PCCA):c.1312G>T (p.Gly438Ter)	Pathogenic
1076458	NC_000013.10:g.(?100953694)(101078005_?)del	Pathogenic
1076459	NC_000013.10:g.(?101020716)(101101569_?)del	Pathogenic
12021	NM_000282.4(PCCA):c.1846-2_1852del	Pathogenic
12023	NM_000282.4(PCCA):c.862A>T (p.Arg288Ter)	Pathogenic
12025	NM_000282.4(PCCA):c.1285-1416A>G	Pathogenic
1301319	NM_000282.4(PCCA):c.1831C>T (p.Gln611Ter)	Pathogenic
1374012	NM_000282.4(PCCA):c.127C>T (p.Gln43Ter)	Pathogenic
1386877	NM_000282.4(PCCA):c.415-2A>G	Pathogenic
1392001	NC_000013.10:g.(?100741259)(100741489_?)del	Pathogenic
1403120	NM_000282.4(PCCA):c.1067_1068insCT (p.Glu357fs)	Pathogenic
1409579	NM_000282.4(PCCA):c.505_506del (p.His169fs)	Pathogenic
1451161	NM_000282.4(PCCA):c.1539del (p.Gly514fs)	Pathogenic
1454832	NC_000013.10:g.(?100992391)(100992533_?)del	Pathogenic
1455330	NM_000282.4(PCCA):c.1477del (p.Arg493fs)	Pathogenic
1456785	NM_000282.4(PCCA):c.217G>T (p.Glu73Ter)	Pathogenic
1457382	NC_000013.10:g.(?100925430)(100925620_?)del	Pathogenic
1459857	NM_000282.4(PCCA):c.1746+1G>A	Pathogenic
1459908	NC_000013.10:g.(?101179909)(101180026_?)del	Pathogenic
1508479	NC_000013.10:g.(?100807223)(100809604_?)del	Pathogenic
1508488	NC_000013.10:g.(?100861576)(100955262_?)del	Pathogenic
1686007	NM_000282.4(PCCA):c.562_573del (p.Glu188_Thr191del)	Pathogenic
1803092	NM_000282.4(PCCA):c.959C>A (p.Ala320Asp)	Pathogenic
195456	NM_000282.4(PCCA):c.1788G>A (p.Trp596Ter)	Pathogenic
1965039	NM_000282.4(PCCA):c.85del (p.Ala29fs)	Pathogenic
1984158	NM_000282.4(PCCA):c.449_450del (p.Lys150fs)	Pathogenic
2030448	NM_000282.4(PCCA):c.1003_1012del (p.Val335fs)	Pathogenic

SpliceAI

7774 predictions. Top by Δscore:

Variant	Effect	Δscore
13:100089224:AGG:A	donor_loss	1.0000
13:100089227:T:G	donor_loss	1.0000
13:100102882:GCAT:G	acceptor_gain	1.0000
13:100111836:TTCA:T	acceptor_loss	1.0000
13:100111838:CAG:C	acceptor_loss	1.0000
13:100111839:A:AG	acceptor_gain	1.0000
13:100111839:A:T	acceptor_loss	1.0000
13:100111840:G:GA	acceptor_gain	1.0000
13:100111840:GA:G	acceptor_gain	1.0000
13:100111840:GAC:G	acceptor_gain	1.0000
13:100111840:GACT:G	acceptor_gain	1.0000
13:100111840:GACTT:G	acceptor_gain	1.0000
13:100111884:GTCGG:G	donor_gain	1.0000
13:100111885:TCGG:T	donor_gain	1.0000
13:100111887:GG:G	donor_gain	1.0000
13:100111888:GG:G	donor_gain	1.0000
13:100111889:G:GG	donor_gain	1.0000
13:100111889:GTGA:G	donor_loss	1.0000
13:100111890:T:A	donor_loss	1.0000
13:100154604:GGCA:G	donor_gain	1.0000
13:100154977:A:AG	acceptor_gain	1.0000
13:100154977:A:T	acceptor_loss	1.0000
13:100154978:G:C	acceptor_loss	1.0000
13:100154978:G:GA	acceptor_gain	1.0000
13:100154978:GGTT:G	acceptor_gain	1.0000
13:100154978:GGTTC:G	acceptor_gain	1.0000
13:100155063:G:GT	donor_gain	1.0000
13:100155088:AAGCT:A	donor_gain	1.0000
13:100155089:AGCT:A	donor_gain	1.0000
13:100155090:GCT:G	donor_gain	1.0000

AlphaMissense

4768 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:100262769:T:C	F253L	1.000
13:100262771:T:A	F253L	1.000
13:100262771:T:G	F253L	1.000
13:100111869:G:T	R71I	0.999
13:100257604:T:A	V216D	0.999
13:100257614:G:C	K219N	0.999
13:100257614:G:T	K219N	0.999
13:100257628:G:A	G224D	0.999
13:100257631:G:A	G225D	0.999
13:100257634:G:A	G226E	0.999
13:100257639:G:C	G228R	0.999
13:100262757:G:C	A249P	0.999
13:100268760:G:C	Q297H	0.999
13:100268760:G:T	Q297H	0.999
13:100301464:A:T	E357V	0.999
13:100301599:C:A	A402D	0.999
13:100330574:T:A	N481K	0.999
13:100330574:T:G	N481K	0.999
13:100527715:A:T	K694I	0.999
13:100111869:G:C	R71T	0.998
13:100111870:A:C	R71S	0.998
13:100111870:A:T	R71S	0.998
13:100112041:A:C	S94R	0.998
13:100112043:T:A	S94R	0.998
13:100112043:T:G	S94R	0.998
13:100157297:G:A	G142D	0.998
13:100157303:G:A	G144E	0.998
13:100235866:G:C	A209P	0.998
13:100257612:A:G	K219E	0.998
13:100257625:G:A	G223D	0.998

dbSNP variants (sampled 300 via entrez): RS1000001989 (13:100190534 A>T), RS1000002152 (13:100307715 A>G), RS1000005249 (13:100351404 C>T), RS1000008841 (13:100501269 T>C), RS1000043530 (13:100152884 A>G), RS1000043706 (13:100448636 A>T), RS1000046318 (13:100521945 A>C,G), RS1000048005 (13:100329802 A>C), RS1000061010 (13:100236971 C>T), RS1000061463 (13:100393798 C>A,G), RS1000062089 (13:100108210 A>G), RS1000063469 (13:100357933 G>GT), RS1000066674 (13:100279781 T>G), RS1000078730 (13:100522264 G>A), RS1000091926 (13:100357894 C>G)

Disease associations

OMIM: gene MIM:232000 | disease phenotypes: MIM:606054, MIM:613811

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), pontocerebellar hypoplasia type 2D (MONDO:0013438)

Orphanet (3): Propionic acidemia (Orphanet:35), Progressive cerebello-cerebral atrophy (Orphanet:247198), Pontocerebellar hypoplasia type 2 (Orphanet:2524)

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

11 associations (top):

Study	Trait	p-value
GCST001858_3	Refractive error	2.000000e-08
GCST003997_25	Myopia	9.000000e-25
GCST006291_111	Spherical equivalent or myopia (age of diagnosis)	4.000000e-17
GCST006291_65	Spherical equivalent or myopia (age of diagnosis)	3.000000e-10
GCST007323_24	Risk-taking tendency (4-domain principal component model)	1.000000e-08
GCST008810_8	Smoking initiation (ever regular vs never regular)	2.000000e-09
GCST008948_3	Chromosomal aberration frequency (chromatid type) in genotoxic compound exposure	5.000000e-06
GCST009220_8	Corpus callosum anterior volume	6.000000e-06
GCST009391_421	Metabolite levels	3.000000e-06
GCST009391_480	Metabolite levels	4.000000e-06
GCST010002_194	Refractive error	2.000000e-76

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0008579	risk-taking behaviour
EFO:0005670	smoking initiation
EFO:0009862	chromatid-type aberration frequency
EFO:0010388	phosphatidylcholine 38:6 measurement
EFO:0010389	phosphatidylcholine 40:6 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D056693	Propionic Acidemia	C16.320.565.100.823; C18.452.648.100.823

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066389 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Carboxylases

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.24	Kd	571.5	nM	CHEMBL3752910
6.22	ED50	595.6	nM	CHEMBL3752910
5.17	Kd	6783	nM	CHEMBL5653589
5.15	ED50	7070	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148944: Binding affinity to human PCCA incubated for 45 mins by Kinobead based pull down assay	kd	0.5715	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148944: Binding affinity to human PCCA incubated for 45 mins by Kinobead based pull down assay	kd	6.7833	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression	6
Aflatoxin B1	affects expression, decreases expression, increases methylation	4
bisphenol A	affects expression, affects methylation, affects cotreatment, increases expression	3
sodium arsenite	affects cotreatment, increases abundance, decreases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Valproic Acid	affects expression, decreases methylation	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases methylation	1
dicrotophos	decreases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
sodium arsenate	decreases expression	1
beta-lapachone	increases expression	1
arsenite	decreases reaction, increases reaction, affects binding	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	affects methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
clothianidin	decreases expression	1
bisphenol B	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651986	Binding	Binding affinity to human PCCA incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

14 cell lines: 7 transformed cell line, 4 cancer cell line, 2 induced pluripotent stem cell, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3YU	WG2625	Finite cell line	Male
CVCL_BT63	GM22010	Transformed cell line	Male
CVCL_BT64	GM22011	Transformed cell line	Female
CVCL_BT65	GM22012	Transformed cell line	Male
CVCL_BU27	GM22208	Transformed cell line	Female
CVCL_BU46	GM22366	Transformed cell line	Female
CVCL_BU75	GM22581	Transformed cell line	Female
CVCL_BV17	GM23221	Transformed cell line	Male
CVCL_E0JS	Ubigene HeLa PCCA KO	Cancer cell line	Female
CVCL_E0UR	Ubigene Hep G2 PCCA KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02426775	PHASE3	COMPLETED	Carglumic Acid in Methylmalonic Acidemia and Propionic Acidemia
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
NCT00645879	PHASE1	COMPLETED	Anaplerotic Therapy in Propionic Acidemia
NCT04836494	PHASE1	TERMINATED	A First in Human, Dose Escalation Study to Evaluate the Safety and Tolerability of BBP-671 in Healthy Volunteers and Patients With Propionic Acidemia or Methylmalonic Acidemia
NCT04159103	PHASE1/PHASE2	RECRUITING	Open-Label Study of mRNA-3927 in Participants With Propionic Acidemia
NCT05130437	PHASE1/PHASE2	RECRUITING	A Study to Assess the Long-term Safety and Clinical Activity of mRNA-3927 in Participants Previously Enrolled in the mRNA-3927-P101 Study
NCT02890342	Not specified	RECRUITING	Natural History, Physiology, Microbiome and Biochemistry Studies of Propionic Acidemia
NCT03159026	Not specified	COMPLETED	Review of Charts From Amish/Mennonite Variant PA Patients
NCT03484767	Not specified	COMPLETED	The MaP Study: Mapping the Patient Journey in MMA and PA
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04176523	Not specified	RECRUITING	Understanding the Long-Term Management of Organic Acidemia Patients With CARBAGLU®: A Mixed Methods Approach
NCT05040178	Not specified	RECRUITING	An Observational Study of Carbaglu® for the Treatment of MMA and PA in Adults and Pediatrics
NCT05330039	Not specified	COMPLETED	Characterization of Intestinal Microbiota in Children With Inborn Errors of Metabolism (IEM)
NCT05438485	Not specified	TERMINATED	Natural History Study of Patients With Methylmalonic Acidemia and Propionic Acidemia
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05769621	Not specified	RECRUITING	A Retrospective Study to Characterize Participants With Propionic Acidemia
NCT06664840	Not specified	NOT_YET_RECRUITING	MyRareDiet A Novel Diet Tracking Tool