Is PCCB p.Pro228fs (c.683del) pathogenic?

PCCB p.Pro228fs (c.683del) is classified Pathogenic/Likely pathogenic in PCCB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-14). Very rare (popmax 0.000255%, nfe); Associated with PCCB-related disorder.

What condition is associated with PCCB p.Pro228fs (c.683del)?

PCCB p.Pro228fs (c.683del) is associated with PCCB-related disorder, propionic acidemia (ClinVar).

How common is PCCB p.Pro228fs (c.683del) in the general population?

PCCB p.Pro228fs (c.683del) is very rare (popmax 0.000255%, nfe) (gnomAD).

PCCB p.Pro228fs

c.683del · rs2108197244 · VCV1410349

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Conditions

PCCB-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.7	GERP 2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,178,612 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,460,298 alleles · very rare

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.Pro228fs
Coding: c.683del
MANE Select: NM_000532
dbSNP: rs2108197244
Type: Deletion
Location: chr3:136293782 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.59 · 24 PDB
Residue 228: the coa carboxyltransferase n-terminal domain; a UniProt-annotated variant site (in pa-2); the 'carboxyltransferase' region; an α-helix

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

Disease context

PCCB-related disorder

Also linked: propionic acidemia

Similar variants

PCCB p.Pro228Leu Pathogenic ★★ same residue
PCCB p.Pro228Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-pro228fs (accessed [today's date]).

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