Is PCCB p.Val378Phe (c.1132G>T) pathogenic?

PCCB p.Val378Phe (c.1132G>T) is classified Uncertain significance in PCCB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-19). AlphaMissense: likely pathogenic (0.8941); Absent from gnomAD v4.1; Associated with propionic acidemia.

What condition is associated with PCCB p.Val378Phe (c.1132G>T)?

PCCB p.Val378Phe (c.1132G>T) is associated with propionic acidemia (ClinVar).

How common is PCCB p.Val378Phe (c.1132G>T) in the general population?

PCCB p.Val378Phe (c.1132G>T) is absent from gnomAD v4.1 (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.Val378Phe (c.1132G>T)?

AlphaMissense predicts likely pathogenic (score 0.8941) — an in-silico prediction, not a clinical call.

PCCB p.Val378Phe

c.1132G>T · rs761529521 · VCV859270

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8941 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

propionic acidemia

Computational evidence

Protein change
AlphaMissense	0.8941	likely pathogenic
REVEL	0.977	strongly pathogenic-leaning
SaProt	LLR -14.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.37	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 9.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 80 kb · p 0.017 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PCCB
Protein: p.Val378Phe
Coding: c.1132G>T
MANE Select: NM_000532
dbSNP: rs761529521
Type: single nucleotide variant
Location: chr3:136326844 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.59 · 24 PDB
Residue 378: the coa carboxyltransferase c-terminal domain; 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.Val378Ile Uncertain significance ★★ ⚠ same residue
PCCB p.Val378Leu Uncertain significance ★ ⚠ same residue
PCCB p.Val378= Likely benign ★ same residue
PCCB p.Val378fs 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

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-val378phe (accessed [today's date]).

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