Is PPA2 p.Ala253Pro (c.757G>C) pathogenic?

PPA2 p.Ala253Pro (c.757G>C) is classified Uncertain significance in PPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-22). AlphaMissense: likely pathogenic (0.5649); Absent from gnomAD v4.1; Associated with sudden cardiac failure, infantile.

What condition is associated with PPA2 p.Ala253Pro (c.757G>C)?

PPA2 p.Ala253Pro (c.757G>C) is associated with sudden cardiac failure, infantile (ClinVar).

How common is PPA2 p.Ala253Pro (c.757G>C) in the general population?

PPA2 p.Ala253Pro (c.757G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPA2 p.Ala253Pro (c.757G>C)?

AlphaMissense predicts likely pathogenic (score 0.5649) — an in-silico prediction, not a clinical call.

PPA2 p.Ala253Pro

c.757G>C · VCV4531916

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5649 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

sudden cardiac failure, infantile

Computational evidence

Protein change
AlphaMissense	0.5649	likely pathogenic
REVEL	0.455	indeterminate
SaProt	LLR -12.95	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PPA2
Protein: p.Ala253Pro
Coding: c.757G>C
MANE Select: NM_176869
Type: single nucleotide variant
Location: chr4:105399063 (GRCh38)
Gene constraint: LOEUF 1.324 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.39

Full PPA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sudden cardiac failure, infantile — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPA2 p.Arg127Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
PPA2 p.Glu172Lys Pathogenic/Likely pathogenic ★★ same condition
PPA2 p.Pro228Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
PPA2 p.Thr159Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
PPA2 p.Ala130Val Uncertain significance ★★ ⚠ same condition
PPA2 c.442-16A>T Benign ★★ same condition
PPA2 p.Arg9= Benign/Likely benign ★★ same condition
PPA2 p.Lys282Asn Benign ★★ 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/ppa2-p-ala253pro (accessed [today's date]).

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