Is PCCA p.Ala2Pro (c.4G>C) pathogenic?

PCCA p.Ala2Pro (c.4G>C) is classified Uncertain significance in PCCA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-23). AlphaMissense: likely benign (0.181); Very rare (popmax 0.00857%, afr); Associated with Inborn genetic diseases.

What condition is associated with PCCA p.Ala2Pro (c.4G>C)?

PCCA p.Ala2Pro (c.4G>C) is associated with Inborn genetic diseases, propionic acidemia (ClinVar).

How common is PCCA p.Ala2Pro (c.4G>C) in the general population?

PCCA p.Ala2Pro (c.4G>C) is very rare (popmax 0.00857%, afr) (gnomAD).

What do computational predictors say about PCCA p.Ala2Pro (c.4G>C)?

AlphaMissense predicts likely benign (score 0.181) — an in-silico prediction, not a clinical call.

PCCA p.Ala2Pro

c.4G>C · rs760710987 · VCV2184254

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.181 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00857%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.181	likely benign
REVEL	0.519	indeterminate
SaProt	LLR -8.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 441 kb · p 0.59 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00857% African / African-American · 6/70,034 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.000466% 7/1,502,014 alleles · very rare exomes 7/1,349,678 · genomes 0/152,336 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00857%	11,672
Remaining individualsnot grpmax-eligible	0.00173%	57,822

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.Ala2Pro
Coding: c.4G>C
MANE Select: NM_000282
dbSNP: rs760710987
Type: single nucleotide variant
Location: chr13:100089124 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 26 PDB

Full PCCA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: propionic acidemia

Similar variants

PCCA p.Ala2= Likely benign ★ 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
PCCA c.1284+1G>A Pathogenic/Likely pathogenic ★★ same condition
PCCA c.1540+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/pcca-p-ala2pro (accessed [today's date]).

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