Is PPA2 p.Gln294Pro (c.881A>C) pathogenic?

PPA2 p.Gln294Pro (c.881A>C) is classified Pathogenic in PPA2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-11-23). AlphaMissense: likely benign (0.1584); Absent from gnomAD v4.1; Associated with sudden cardiac failure, infantile.

What condition is associated with PPA2 p.Gln294Pro (c.881A>C)?

PPA2 p.Gln294Pro (c.881A>C) is associated with sudden cardiac failure, infantile (ClinVar).

How common is PPA2 p.Gln294Pro (c.881A>C) in the general population?

PPA2 p.Gln294Pro (c.881A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPA2 p.Gln294Pro (c.881A>C)?

AlphaMissense predicts likely benign (score 0.1584) — an in-silico prediction, not a clinical call.

PPA2 p.Gln294Pro

c.881A>C · rs1057517678 · VCV372221

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1584 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sudden cardiac failure, infantile

Computational evidence

Protein change
AlphaMissense	0.1584	likely benign ⚠ discordant with ClinVar
REVEL	0.156	moderately benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	15.89	PHRED · no single calibrated threshold — expert panels disagree

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.Gln294Pro
Coding: c.881A>C
MANE Select: NM_176869
dbSNP: rs1057517678
Type: single nucleotide variant
Location: chr4:105386625 (GRCh38)
Gene constraint: LOEUF 1.324 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.39
Residue 294: a UniProt-annotated variant site (in scfi)

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.Gln294Arg Uncertain significance ★ ⚠ same residue
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

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-gln294pro (accessed [today's date]).

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