Is PCCA p.Phe409fs (c.1226_1227del) pathogenic?

PCCA p.Phe409fs (c.12261227del) is classified Pathogenic in PCCA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-22). Very rare (popmax 0.00268%, afr); Associated with propionic acidemia.

What condition is associated with PCCA p.Phe409fs (c.1226_1227del)?

PCCA p.Phe409fs (c.1226_1227del) is associated with propionic acidemia (ClinVar).

How common is PCCA p.Phe409fs (c.1226_1227del) in the general population?

PCCA p.Phe409fs (c.1226_1227del) is very rare (popmax 0.00268%, afr) (gnomAD).

How is Propionic acidemia inherited?

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

PCCA p.Phe409fs

c.1226_1227del · rs1329527659 · VCV2052484

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Conditions

propionic acidemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00268% African / African-American · 2/74,640 alleles

Filtering AF 0.000445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000125% 2/1,599,654 alleles · very rare exomes 0/1,447,520 · genomes 2/152,134 · joint denominator

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.Phe409fs
Coding: c.1226_1227del
MANE Select: NM_000282
dbSNP: rs1329527659
Type: Deletion
Location: chr13:100302938 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 26 PDB
Residue 409: a β-strand; a binding site; 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.1899+4_1899+7del Pathogenic/Likely pathogenic ★★ same condition
PCCA p.Ala14fs Pathogenic/Likely pathogenic ★★ same condition
PCCA p.Arg390fs Pathogenic/Likely pathogenic ★★ same condition
PCCA p.Arg493fs Pathogenic ★★ same condition
PCCA p.Asn281fs Pathogenic/Likely pathogenic ★★ same condition
PCCA p.Asp95fs Pathogenic/Likely pathogenic ★★ same condition
PCCA p.Gln23fs Pathogenic ★★ same condition
PCCA p.Glu397fs 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-phe409fs (accessed [today's date]).

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