Is PCCA p.Pro412= (c.1236A>G) pathogenic?

PCCA p.Pro412= (c.1236A>G) is classified Conflicting classifications of pathogenicity in PCCA (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-04). Rare (popmax 0.444%, sas); Associated with propionic acidemia.

What condition is associated with PCCA p.Pro412= (c.1236A>G)?

PCCA p.Pro412= (c.1236A>G) is associated with propionic acidemia (ClinVar).

How common is PCCA p.Pro412= (c.1236A>G) in the general population?

PCCA p.Pro412= (c.1236A>G) is rare (popmax 0.444%, sas) (gnomAD).

How is Propionic acidemia inherited?

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

PCCA p.Pro412=

c.1236A>G · rs41281120 · VCV310847

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.444%, sas)

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 -3.2	GERP -5
Overall
CADD	1.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.444% South Asian · 404/90,932 alleles

Filtering AF 0.409% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.394%

Overall 0.289% 4,641/1,606,096 alleles · rare exomes 4,294/1,453,852 · genomes 347/152,244 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.444%	225
European (non-Finnish)	0.324%	308
Remaining individualsnot grpmax-eligible	0.297%	336
Admixed American	0.252%	397
Middle Eastern	0.165%	605
Ashkenazi Jewishnot grpmax-eligible	0.0576%	1,737
African / African-American	0.0521%	1,919
Finnishnot grpmax-eligible	0.0484%	2,065

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.Pro412=
Coding: c.1236A>G
MANE Select: NM_000282
dbSNP: rs41281120
Type: single nucleotide variant
Location: chr13:100302950 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 26 PDB
Residue 412: the biotin carboxylation domain

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 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
PCCA c.1284+1G>A Pathogenic/Likely pathogenic ★★ same condition
PCCA c.1540+1G>C Pathogenic/Likely pathogenic ★★ same condition
PCCA c.1746+1G>A 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-pro412 (accessed [today's date]).

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