Propionic acidemia

Summary

Propionic acidemia (MONDO:0011628) is a disease caused by variants in PCCA and PCCB, with 6 cohort genes and 19 clinical trials. Top therapeutic interventions include carglumic acid, citric acid, and glutamine.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal genes: PCCA (GenCC Definitive), PCCB (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 2,716
• Phenotypes (HPO): 11
• Clinical trials: 19

Clinical features

Epidemiology

Prevalence records

9 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	1.5	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.2	Europe	Validated
Point prevalence	<1 / 1 000 000	0.0278	China	Validated
Prevalence at birth	>1 / 1000	100	Canada	Validated
Prevalence at birth	1-9 / 1 000 000	0.6	Italy	Validated
Prevalence at birth	1-9 / 100 000	4	Germany	Validated
Prevalence at birth	1-5 / 10 000	33	Saudi Arabia	Validated
Prevalence at birth	1-9 / 100 000	5.7	Japan	Validated
Prevalence at birth	1-9 / 100 000	1.23	Korea, Republic of	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0001943	Hypoglycemia	Very frequent (80-99%)
HP:0001987	Hyperammonemia	Very frequent (80-99%)
HP:0001992	Organic aciduria	Very frequent (80-99%)
HP:0002019	Constipation	Very frequent (80-99%)
HP:0003353	Propionyl-CoA carboxylase deficiency	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0010978	Abnormality of immune system physiology	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	propionic acidemia
Mondo ID	MONDO:0011628
MeSH	D056693
OMIM	606054
Orphanet	35
DOID	DOID:14701
ICD-10-CM	E71.121
NCIT	C85030
SNOMED CT	69080001
UMLS	C0268579
MedGen	75694
GARD	0000467
NORD	714
Is cancer (heuristic)	no

Also known as: GLYCINEMIA, ketotic · ketotic hyperglycinemia · prop · propionic acidemia · propionic aciduria · Propionicacidemia · propionyl-CoA carboxylase deficiency

Data availability: 2,716 ClinVar variants · 13 GenCC gene-disease records · 36 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › classic organic aciduria › propionic acidemia

Related subtypes (14): beta-ketothiolase deficiency, 3-hydroxyisobutyric aciduria, isovaleric acidemia, 3-hydroxy-3-methylglutaric aciduria, 3-hydroxyisobutyryl-CoA hydrolase deficiency, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, 2-methylbutyryl-CoA dehydrogenase deficiency, isobutyryl-CoA dehydrogenase deficiency, combined malonic and methylmalonic acidemia, multiple carboxylase deficiency, methylmalonic aciduria and homocystinuria, vitamin B12-responsive methylmalonic acidemia, 3-methylglutaconic aciduria, 3-methylcrotonyl-CoA carboxylase deficiency

Subtypes (2): PCCA-related propionic acidemia, PCCB-related propionic acidemia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

247 likely benign, 226 uncertain significance, 54 pathogenic, 29 likely pathogenic, 23 pathogenic/likely pathogenic, 15 conflicting classifications of pathogenicity, 4 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1454834	NC_000013.10:g.(?101167671)(101182701_?)del	GGACT	Pathogenic	criteria provided, single submitter
1459911	NC_000013.10:g.(?101179909)(101182420_?)del	GGACT	Pathogenic	criteria provided, single submitter
1066791	NM_000282.4(PCCA):c.183+1G>A	PCCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070049	NM_000282.4(PCCA):c.1598_1601del (p.Phe533fs)	PCCA	Pathogenic	criteria provided, multiple submitters, no conflicts
1071149	NM_000282.4(PCCA):c.1189G>T (p.Glu397Ter)	PCCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072653	NM_000282.4(PCCA):c.872C>G (p.Ser291Ter)	PCCA	Pathogenic	criteria provided, single submitter
1072772	NM_000282.4(PCCA):c.506dup (p.His169fs)	PCCA	Pathogenic	criteria provided, single submitter
1073696	NM_000282.4(PCCA):c.1312G>T (p.Gly438Ter)	PCCA	Pathogenic	criteria provided, single submitter
1074143	NM_000282.4(PCCA):c.1561G>T (p.Glu521Ter)	PCCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076458	NC_000013.10:g.(?100953694)(101078005_?)del	PCCA	Pathogenic	criteria provided, single submitter
1076459	NC_000013.10:g.(?101020716)(101101569_?)del	PCCA	Pathogenic	criteria provided, single submitter
12021	NM_000282.4(PCCA):c.1846-2_1852del	PCCA	Pathogenic	no assertion criteria provided
12023	NM_000282.4(PCCA):c.862A>T (p.Arg288Ter)	PCCA	Pathogenic	no assertion criteria provided
12024	NM_000282.4(PCCA):c.1118T>A (p.Met373Lys)	PCCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12025	NM_000282.4(PCCA):c.1285-1416A>G	PCCA	Pathogenic	no assertion criteria provided
1301319	NM_000282.4(PCCA):c.1831C>T (p.Gln611Ter)	PCCA	Pathogenic	criteria provided, multiple submitters, no conflicts
1324851	NM_000282.4(PCCA):c.284del (p.Asp95fs)	PCCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1358281	NM_000282.4(PCCA):c.600+1G>A	PCCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1374012	NM_000282.4(PCCA):c.127C>T (p.Gln43Ter)	PCCA	Pathogenic	criteria provided, single submitter
1386877	NM_000282.4(PCCA):c.415-2A>G	PCCA	Pathogenic	criteria provided, multiple submitters, no conflicts
1392001	NC_000013.10:g.(?100741259)(100741489_?)del	PCCA	Pathogenic	criteria provided, single submitter
1396166	NM_000282.4(PCCA):c.1716dup (p.Val573fs)	PCCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1403120	NM_000282.4(PCCA):c.1067_1068insCT (p.Glu357fs)	PCCA	Pathogenic	criteria provided, single submitter
1409579	NM_000282.4(PCCA):c.505_506del (p.His169fs)	PCCA	Pathogenic	criteria provided, single submitter
1414656	NM_000282.4(PCCA):c.1456C>T (p.Arg486Ter)	PCCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1416645	NM_000282.4(PCCA):c.672dup (p.Gly225fs)	PCCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451161	NM_000282.4(PCCA):c.1539del (p.Gly514fs)	PCCA	Pathogenic	criteria provided, single submitter
1454832	NC_000013.10:g.(?100992391)(100992533_?)del	PCCA	Pathogenic	criteria provided, single submitter
1455330	NM_000282.4(PCCA):c.1477del (p.Arg493fs)	PCCA	Pathogenic	criteria provided, multiple submitters, no conflicts
1456785	NM_000282.4(PCCA):c.217G>T (p.Glu73Ter)	PCCA	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PCCA	Definitive	Autosomal recessive	propionic acidemia	6
PCCB	Definitive	Autosomal recessive	propionic acidemia	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCCA	Orphanet:35	Propionic acidemia
PCCB	Orphanet:35	Propionic acidemia
UQCRFS1	Orphanet:1460	Isolated complex III deficiency
PAH	Orphanet:2209	Maternal phenylketonuria syndrome
PAH	Orphanet:293284	Tetrahydrobiopterin-responsive phenylketonuria
PAH	Orphanet:708895	Tetrahydrobiopterin-unresponsive phenylketonuria

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PCCA	HGNC:8653	ENSG00000175198	P05165	Propionyl-CoA carboxylase alpha chain, mitochondrial	gencc,clinvar
PCCB	HGNC:8654	ENSG00000114054	P05166	Propionyl-CoA carboxylase beta chain, mitochondrial	gencc,clinvar
UQCRFS1	HGNC:12587	ENSG00000169021	P47985	Cytochrome b-c1 complex subunit Rieske, mitochondrial	clinvar
BIVM	HGNC:16034	ENSG00000134897	Q86UB2	Basic immunoglobulin-like variable motif-containing protein	clinvar
GGACT	HGNC:25100	ENSG00000134864	Q9BVM4	Gamma-glutamylaminecyclotransferase	clinvar
PAH	HGNC:8582	ENSG00000171759	P00439	Phenylalanine-4-hydroxylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCCA	Propionyl-CoA carboxylase alpha chain, mitochondrial	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…
PCCB	Propionyl-CoA carboxylase beta chain, mitochondrial	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…
UQCRFS1	Cytochrome b-c1 complex subunit Rieske, mitochondrial	Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation.
GGACT	Gamma-glutamylaminecyclotransferase	Contributes to degradation of proteins cross-linked by transglutaminases by degrading the cross-link between a lysine and a glutamic acid residue.
PAH	Phenylalanine-4-hydroxylase	Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	4	8.0×	0.001
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCCA	Enzyme (other)	yes	6.4.1.3	Biotin_lipoyl, Biotin_BS, CPAse_ATP-bd
PCCB	Enzyme (other)	yes	6.4.1.3	COA_CT_N, COA_CT_C, ClpP/crotonase-like_dom_sf
UQCRFS1	Other/Unknown	no		Rieske_TM, Rieske_Fe-S_prot_C, Ubiquinol_cyt_c_Rdtase_Fe-S-su
BIVM	Other/Unknown	no
GGACT	Enzyme (other)	yes	4.3.2.8	AIG2-like_dom, GGCT-like, GGCT-like_sf
PAH	Enzyme (other)	yes	1.14.16.1	ArAA_hydroxylase, ACT_dom, Phe-4-hydroxylase_tetra

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right adrenal gland cortex	2
right lobe of liver	2
corpus epididymis	1
adrenal tissue	1
right adrenal gland	1
gastrocnemius	1
heart left ventricle	1
mucosa of transverse colon	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
tibialis anterior	1
kidney epithelium	1
oocyte	1
secondary oocyte	1
gall bladder	1
liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCCA	289	ubiquitous	marker	right lobe of liver, corpus epididymis, right adrenal gland cortex
PCCB	286	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, adrenal tissue
UQCRFS1	134	ubiquitous	marker	gastrocnemius, heart left ventricle, mucosa of transverse colon
BIVM	257	tissue_specific	marker	left ventricle myocardium, tibialis anterior, cardiac muscle of right atrium
GGACT	175	ubiquitous	yes	secondary oocyte, oocyte, kidney epithelium
PAH	175	broad	marker	right lobe of liver, liver, gall bladder

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UQCRFS1	4,001
PCCB	3,043
PCCA	2,036
BIVM	2,003
PAH	1,953
GGACT	229

Intra-cohort edges

A	B	Sources
PCCA	PCCB	biogrid_interaction, intact, string_interaction
PCCA	UQCRFS1	intact

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PCCA	P05165	25
PCCB	P05166	23
PAH	P00439	20
UQCRFS1	P47985	5
GGACT	Q9BVM4	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BIVM	Q86UB2	66.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 6 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Propionyl-CoA catabolism	2	1142.0×	7e-06	PCCA, PCCB
Defective HLCS causes multiple carboxylase deficiency	2	815.7×	8e-06	PCCA, PCCB
Biotin transport and metabolism	2	519.1×	1e-05	PCCA, PCCB
Phenylketonuria	1	2855.0×	7e-04	PAH
Phenylalanine metabolism	1	475.8×	0.003	PAH
Complex III assembly	1	109.8×	0.012	UQCRFS1
Mitochondrial protein degradation	1	28.6×	0.040	PCCB
Respiratory electron transport	1	23.8×	0.041	UQCRFS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
branched-chain amino acid metabolic process	2	2246.9×	1e-06	PCCA, PCCB
short-chain fatty acid catabolic process	2	2246.9×	1e-06	PCCA, PCCB
L-tyrosine biosynthetic process	1	3370.4×	5e-04	PAH
amino acid biosynthetic process	1	3370.4×	5e-04	PAH
modified amino acid catabolic process	1	3370.4×	5e-04	GGACT
fatty acid metabolic process	2	77.5×	5e-04	PCCA, PCCB
catecholamine biosynthetic process	1	1123.5×	0.001	PAH
L-phenylalanine catabolic process	1	421.3×	0.003	PAH
mitochondrial electron transport, ubiquinol to cytochrome c	1	259.3×	0.005	UQCRFS1
mitochondrial respiratory chain complex III assembly	1	240.7×	0.005	UQCRFS1
respiratory electron transport chain	1	168.5×	0.006	UQCRFS1

Therapeutics

Drugs indicated for this disease

1 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Carglumic Acid	Approved (phase 4)

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 2 of 6 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PCCA	0	0
PCCB	0	0
UQCRFS1	0	0
BIVM	0	0
GGACT	0	0
PAH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PAH	4	Binding:4
PCCA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PCCA	6.4.1.3	propionyl-CoA carboxylase
PCCB	6.4.1.3	propionyl-CoA carboxylase
GGACT	4.3.2.8, 4.3.2.9	gamma-glutamylamine cyclotransferase, gamma-glutamylcyclotransferase
PAH	1.14.16.1	phenylalanine 4-monooxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	4	PCCA, PCCB, GGACT, PAH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	UQCRFS1, BIVM

Undrugged target profiles

6 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PCCA	1	—
PCCB	0	—
UQCRFS1	0	—
BIVM	0	—
GGACT	0	—
PAH	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 19.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE2	3
PHASE1/PHASE2	2
PHASE1	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02426775	PHASE3	COMPLETED	Carglumic Acid in Methylmalonic Acidemia and Propionic 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
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
NCT02890342	Not specified	RECRUITING	Natural History, Physiology, Microbiome and Biochemistry Studies of Propionic Acidemia
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
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
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
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

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CARGLUMIC ACID	4	3
CITRIC ACID	4	1
GLUTAMINE	4	1
CHEMBL1891960	0	3