Is PCCB p.Phe391Ser (c.1172T>C) pathogenic?

PCCB p.Phe391Ser (c.1172T>C) is classified Pathogenic/Likely pathogenic in PCCB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-15). AlphaMissense: likely pathogenic (0.9721); Very rare (popmax 8.49e-05%, nfe); Associated with propionic acidemia.

What condition is associated with PCCB p.Phe391Ser (c.1172T>C)?

PCCB p.Phe391Ser (c.1172T>C) is associated with propionic acidemia (ClinVar).

How common is PCCB p.Phe391Ser (c.1172T>C) in the general population?

PCCB p.Phe391Ser (c.1172T>C) is very rare (popmax 8.49e-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.Phe391Ser (c.1172T>C)?

AlphaMissense predicts likely pathogenic (score 0.9721) — an in-silico prediction, not a clinical call.

PCCB p.Phe391Ser

c.1172T>C · rs1189355322 · VCV1942487

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9721 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

propionic acidemia

Computational evidence

Protein change
AlphaMissense	0.9721	likely pathogenic ✓ concordant with ClinVar
REVEL	0.979	strongly pathogenic-leaning
SaProt	LLR -15.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 80 kb · p 0.017 · regional, not allelic
Overall
CADD	31.0	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 8.49e-05% European (non-Finnish) · 1/1,177,720 alleles

Overall 6.85e-05% 1/1,459,364 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.Phe391Ser
Coding: c.1172T>C
MANE Select: NM_000532
dbSNP: rs1189355322
Type: single nucleotide variant
Location: chr3:136326884 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.59 · 24 PDB
Residue 391: 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 p.Phe391Cys Likely pathogenic ★ same residue
PCCB p.Phe391= Likely benign ★ same residue
PCCB p.Phe391fs Pathogenic ★ same residue
PCCB p.Phe391Val 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

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-phe391ser (accessed [today's date]).

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