Is PCCB p.Pro199Ser (c.595C>T) pathogenic?

PCCB p.Pro199Ser (c.595C>T) is classified Conflicting classifications of pathogenicity in PCCB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.8681); Rare (popmax 0.743%, sas); Associated with propionic acidemia.

What condition is associated with PCCB p.Pro199Ser (c.595C>T)?

PCCB p.Pro199Ser (c.595C>T) is associated with propionic acidemia (ClinVar).

How common is PCCB p.Pro199Ser (c.595C>T) in the general population?

PCCB p.Pro199Ser (c.595C>T) is rare (popmax 0.743%, sas) (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.Pro199Ser (c.595C>T)?

AlphaMissense predicts likely pathogenic (score 0.8681) — an in-silico prediction, not a clinical call.

PCCB p.Pro199Ser

c.595C>T · rs371155999 · VCV343467

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8681 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.743%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

propionic acidemia

Computational evidence

Protein change
AlphaMissense	0.8681	likely pathogenic
REVEL	0.913	moderately pathogenic-leaning
SaProt	LLR -14.75	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 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 80 kb · p 0.017 · regional, not allelic
Overall
CADD	27.4	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 0.743% South Asian · 677/91,070 alleles

Filtering AF 0.697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.678%

Overall 0.0487% 786/1,613,926 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.743%	135
Remaining individualsnot grpmax-eligible	0.0656%	1,524
Middle Eastern	0.0499%	2,005
European (non-Finnish)	0.00542%	18,436
African / African-American	0.00133%	75,014

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.Pro199Ser
Coding: c.595C>T
MANE Select: NM_000532
dbSNP: rs371155999
Type: single nucleotide variant
Location: chr3:136283888 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.59 · 24 PDB
Residue 199: the coa carboxyltransferase n-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.Pro199Leu Uncertain significance ★ ⚠ same residue
PCCB p.Pro199= Likely benign ★ same residue
PCCB p.Pro199Arg 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-pro199ser (accessed [today's date]).

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