Is PCCB p.Pro493fs (c.1478del) pathogenic?

PCCB p.Pro493fs (c.1478del) is classified Pathogenic/Likely pathogenic in PCCB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-21). Very rare (popmax 0.00267%, afr); Associated with propionic acidemia.

What condition is associated with PCCB p.Pro493fs (c.1478del)?

PCCB p.Pro493fs (c.1478del) is associated with propionic acidemia (ClinVar).

How common is PCCB p.Pro493fs (c.1478del) in the general population?

PCCB p.Pro493fs (c.1478del) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Propionic acidemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PCCB p.Pro493fs

c.1478del · rs749509618 · VCV1973629

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

propionic acidemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (14 of 15, 22 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,950 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,966 alleles · very rare exomes 1/1,461,738 · genomes 1/152,228 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PCCB
Protein: p.Pro493fs
Coding: c.1478del
MANE Select: NM_000532
dbSNP: rs749509618
Type: Deletion
Location: chr3:136328835 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.59 · 24 PDB
Residue 493: the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region; a β-strand

Full PCCB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

propionic acidemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Propionic acidemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: >1 / 1000 (Canada)

Similar variants

PCCB c.1091-8_1091-3del Pathogenic/Likely pathogenic ★★ same condition
PCCB c.1399-2_1399-1del Pathogenic/Likely pathogenic ★★ same condition
PCCB c.155_183+17del Pathogenic/Likely pathogenic ★★ same condition
PCCB c.187_203del Pathogenic/Likely pathogenic ★★ same condition
PCCB p.Gln124fs Pathogenic/Likely pathogenic ★★ same condition
PCCB p.Ile408fs Pathogenic ★★ same condition
PCCB p.Ile460fs Pathogenic/Likely pathogenic ★★ same condition
PCCB p.Leu173fs Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pccb-p-pro493fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown