Is PCCB p.Arg289Ser (c.865C>A) pathogenic?

PCCB p.Arg289Ser (c.865C>A) is classified Uncertain significance in PCCB (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-24). AlphaMissense: ambiguous (0.3463); Very rare (popmax 8.47e-05%, nfe); Associated with propionic acidemia.

What condition is associated with PCCB p.Arg289Ser (c.865C>A)?

PCCB p.Arg289Ser (c.865C>A) is associated with propionic acidemia (ClinVar).

How common is PCCB p.Arg289Ser (c.865C>A) in the general population?

PCCB p.Arg289Ser (c.865C>A) is very rare (popmax 8.47e-05%, nfe) (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.Arg289Ser (c.865C>A)?

AlphaMissense predicts ambiguous (score 0.3463) — an in-silico prediction, not a clinical call.

PCCB p.Arg289Ser

c.865C>A · rs771935604 · VCV1405390

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3463 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

propionic acidemia

Computational evidence

Protein change
AlphaMissense	0.3463	ambiguous
REVEL	0.521	indeterminate
SaProt	LLR -6.71	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.3	GERP 0.007, phastCons 0.9
Regional constraint	o/e 1.09	unconstrained · MANE · 80 kb · p 0.017 · regional, not allelic
Overall
CADD	19.02	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 8.47e-05% European (non-Finnish) · 1/1,179,990 alleles

Overall 6.84e-05% 1/1,461,816 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.Arg289Ser
Coding: c.865C>A
MANE Select: NM_000532
dbSNP: rs771935604
Type: single nucleotide variant
Location: chr3:136298053 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.59 · 24 PDB
Residue 289: the coa carboxyltransferase n-terminal domain; the 'carboxyltransferase' region

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.Arg289Cys Uncertain significance ★★ ⚠ same residue
PCCB p.Arg289His Uncertain significance ★★ ⚠ same residue
PCCB p.Arg289Pro Uncertain significance ★ ⚠ 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

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-arg289ser (accessed [today's date]).

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