Is PCCB p.Ala2Val (c.5C>T) pathogenic?

PCCB p.Ala2Val (c.5C>T) is classified Uncertain significance in PCCB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-15). AlphaMissense: likely benign (0.2444); Ultra-rare (popmax 0.0155%, nfe); Associated with propionic acidemia.

What condition is associated with PCCB p.Ala2Val (c.5C>T)?

PCCB p.Ala2Val (c.5C>T) is associated with propionic acidemia (ClinVar).

How common is PCCB p.Ala2Val (c.5C>T) in the general population?

PCCB p.Ala2Val (c.5C>T) is ultra-rare (popmax 0.0155%, 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.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2444) — an in-silico prediction, not a clinical call.

PCCB p.Ala2Val

c.5C>T · rs748003396 · VCV2169171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2444 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

propionic acidemia

Computational evidence

Protein change
AlphaMissense	0.2444	likely benign
REVEL	0.503	indeterminate
SaProt	LLR -10.29	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 80 kb · p 0.017 · regional, not allelic
Overall
CADD	23.9	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 0.0155% European (non-Finnish) · 176/1,132,974 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.012% 183/1,526,734 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0155%	6,437
Remaining individualsnot grpmax-eligible	0.00681%	14,675
South Asian	0.0025%	39,982
African / African-American	0.00138%	72,588

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_000532
dbSNP: rs748003396
Type: single nucleotide variant
Location: chr3:136250380 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.59 · 24 PDB

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.Ala2Glu Uncertain significance ★ ⚠ same residue
PCCB p.Ala2= Likely benign ★ 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-ala2val (accessed [today's date]).

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