PCCA

Chr 13AR

propionyl-CoA carboxylase subunit alpha

NCBI Gene: 5095ENSG00000175198UniProt: P05165

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.[provided by RefSeq, May 2010]

Primary Disease Associations & Inheritance

PropionicacidemiaMIM #606054
AR
UniProtPropionic acidemia type I
785
ClinVar variants
190
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— PCCA
🧬
Gene-Disease Validity (ClinGen)
propionic acidemia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
190 Pathogenic / Likely Pathogenic· 190 VUS of 785 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.91LOEUF
pLI 0.000
Z-score 2.06
OE 0.67 (0.50–0.91)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.19Z-score
OE missense 0.97 (0.90–1.06)
387 obs / 397.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.67 (0.50–0.91)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.90–1.06)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.90
0≤1.21.6
LoF obs/exp: 30 / 44.9Missense obs/exp: 387 / 397.4Syn Z: 0.91

ClinVar Variant Classifications

785 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic92
Likely Pathogenic98
VUS190
Likely Benign394
Benign11
92
Pathogenic
98
Likely Pathogenic
190
VUS
394
Likely Benign
11
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
28
1
63
0
92
Likely Pathogenic
70
4
24
0
98
VUS
0
155
24
11
190
Likely Benign
0
2
215
177
394
Benign
0
1
10
0
11
Total98163336188785

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PCCA · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PCCA-related propionic acidemia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Propionicacidemia

MIM #606054

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PCCA
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Epidemiology of cholangiocarcinoma.
Qurashi M et al.·Eur J Surg Oncol
2025Review
Pathophysiological mechanisms of complications associated with propionic acidemia.
Marchuk H et al.·Pharmacol Ther
2023Review
Clinical treatment of cholangiocarcinoma: an updated comprehensive review.
Elvevi A et al.·Ann Hepatol
2022Review
Targeting cholangiocarcinoma.
Mertens JC et al.·Biochim Biophys Acta Mol Basis Dis
2018Review
Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry.
Izquierdo-Sanchez L et al.·J Hepatol
2022
Silencing PCCA Suppresses CRC Growth and Spread by Modulating EMT and M1 Macrophage Polarization.
Zhang C et al.·Int J Med Sci
2025
Prevalence of propionic acidemia in China.
Zhang Y et al.·Orphanet J Rare Dis
2023Review
Adeno-Associated Virus Gene Therapy Development: Early Planning and Regulatory Considerations to Advance the Platform Vector Gene Therapy Program.
Lomash RM et al.·Hum Gene Ther
2025
Overview of mutations in the PCCA and PCCB genes causing propionic acidemia.
Ugarte M et al.·Hum Mutat
1999Review
Clinical presentation, diagnosis and staging of cholangiocarcinoma.
Forner A et al.·Liver Int
2019Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Dravet SyndromeEpilepsy

Neurodevelopmental Impact of Epilepsy on Autonomic Function in Dravet Syndrome

ACTIVE NOT RECRUITING
NCT05472389Phase NAHospices Civils de LyonStarted 2022-10-14
Video-electroencephalographyBlood Samples

External Resources

Links to major genomics databases and tools