Is PCCA p.Val583= (c.1749G>A) pathogenic?

PCCA p.Val583= (c.1749G>A) is classified Likely benign in PCCA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). Very rare (popmax 0.004%, afr); Associated with propionic acidemia.

What condition is associated with PCCA p.Val583= (c.1749G>A)?

PCCA p.Val583= (c.1749G>A) is associated with propionic acidemia (ClinVar).

How common is PCCA p.Val583= (c.1749G>A) in the general population?

PCCA p.Val583= (c.1749G>A) is very rare (popmax 0.004%, afr) (gnomAD).

How is Propionic acidemia inherited?

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

PCCA p.Val583=

c.1749G>A · VCV4697926

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

propionic acidemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.757	pathogenic-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	GERP 0.64, phastCons 1
Overall
CADD	15.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,972 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000435% 7/1,610,244 alleles · very rare exomes 5/1,457,862 · genomes 2/152,382 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,991
East Asian	0.00223%	44,850
European (non-Finnish)	0.000255%	392,157

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.Val583=
Coding: c.1749G>A
MANE Select: NM_000282
Type: single nucleotide variant
Location: chr13:100425635 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 26 PDB
Residue 583: a β-strand

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-val583 (accessed [today's date]).

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