Is PCCB p.Pro228Ala (c.682C>G) pathogenic?

PCCB p.Pro228Ala (c.682C>G) is classified Conflicting classifications of pathogenicity in PCCB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-19). AlphaMissense: likely pathogenic (0.8613); Ultra-rare (popmax 0.0166%, mid); Associated with propionic acidemia.

What condition is associated with PCCB p.Pro228Ala (c.682C>G)?

PCCB p.Pro228Ala (c.682C>G) is associated with propionic acidemia (ClinVar).

How common is PCCB p.Pro228Ala (c.682C>G) in the general population?

PCCB p.Pro228Ala (c.682C>G) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

How is Propionic acidemia inherited?

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

What do computational predictors say about PCCB p.Pro228Ala (c.682C>G)?

AlphaMissense predicts likely pathogenic (score 0.8613) — an in-silico prediction, not a clinical call.

PCCB p.Pro228Ala

c.682C>G · rs1052979420 · VCV1333567

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8613 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

propionic acidemia

Computational evidence

Protein change
AlphaMissense	0.8613	likely pathogenic
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -12.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 80 kb · p 0.017 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,034 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000682% 11/1,612,546 alleles · ultra-rare exomes 11/1,460,398 · genomes 0/152,148 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,034
Remaining individualsnot grpmax-eligible	0.0032%	31,231
European (non-Finnish)	0.000679%	147,335

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.Pro228Ala
Coding: c.682C>G
MANE Select: NM_000532
dbSNP: rs1052979420
Type: single nucleotide variant
Location: chr3:136293783 (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

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 p.Pro228Leu Pathogenic ★★ same residue
PCCB p.Pro228fs Pathogenic/Likely pathogenic ★★ same residue
PCCB c.1199-1G>A Pathogenic/Likely pathogenic ★★ same condition
PCCB c.1199-2A>G Pathogenic ★★ same condition
PCCB c.1398+1G>C Pathogenic/Likely pathogenic ★★ same condition
PCCB c.1398+1G>T Pathogenic/Likely pathogenic ★★ same condition
PCCB c.1498+2T>C Pathogenic ★★ same condition
PCCB c.1499-1G>C Pathogenic/Likely 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-pro228ala (accessed [today's date]).

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