Is PCCA p.Pro423= (c.1269G>A) pathogenic?

PCCA p.Pro423= (c.1269G>A) is classified Likely benign in PCCA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-17). Very rare (popmax 0.00224%, eas); Associated with propionic acidemia.

What condition is associated with PCCA p.Pro423= (c.1269G>A)?

PCCA p.Pro423= (c.1269G>A) is associated with propionic acidemia (ClinVar).

How common is PCCA p.Pro423= (c.1269G>A) in the general population?

PCCA p.Pro423= (c.1269G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

How is Propionic acidemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PCCA p.Pro423=

c.1269G>A · rs778642206 · VCV1561082

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Conditions

propionic acidemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.17	GERP -5
Overall
CADD	7.136	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,704 alleles

Filtering AF 0.000187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000123%

Overall 0.000441% 7/1,588,580 alleles · very rare exomes 6/1,436,450 · genomes 1/152,130 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,704
European (non-Finnish)	0.000519%	192,827

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: PCCA
Protein: p.Pro423=
Coding: c.1269G>A
MANE Select: NM_000282
dbSNP: rs778642206
Type: single nucleotide variant
Location: chr13:100302983 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 26 PDB
Residue 423: the biotin carboxylation domain; a UniProt-annotated variant site (in pa-1)

Full PCCA 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

PCCA p.Pro423Leu Pathogenic/Likely pathogenic ★★ same residue
PCCA p.Pro423Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
PCCA p.Pro423Gln Uncertain significance ★ ⚠ same residue
PCCA c.105+1G>A Pathogenic ★★ same condition
PCCA c.106-1G>A Likely pathogenic ★★ same condition
PCCA c.1065+1G>A Likely pathogenic ★★ same condition
PCCA c.1209+2T>G Likely pathogenic ★★ same condition
PCCA c.1209+3A>G 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/pcca-p-pro423 (accessed [today's date]).

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