Is PPA2 p.Met94Val (c.280A>G) pathogenic?

PPA2 p.Met94Val (c.280A>G) is classified Pathogenic in PPA2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-11-23). AlphaMissense: likely benign (0.1455); Very rare (popmax 0.000173%, nfe); Associated with sudden cardiac failure, infantile.

What condition is associated with PPA2 p.Met94Val (c.280A>G)?

PPA2 p.Met94Val (c.280A>G) is associated with sudden cardiac failure, infantile (ClinVar).

How common is PPA2 p.Met94Val (c.280A>G) in the general population?

PPA2 p.Met94Val (c.280A>G) is very rare (popmax 0.000173%, nfe) (gnomAD).

What do computational predictors say about PPA2 p.Met94Val (c.280A>G)?

AlphaMissense predicts likely benign (score 0.1455) — an in-silico prediction, not a clinical call.

PPA2 p.Met94Val

c.280A>G · rs1057517679 · VCV372223

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1455 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000173%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sudden cardiac failure, infantile

Computational evidence

Protein change
AlphaMissense	0.1455	likely benign ⚠ discordant with ClinVar
REVEL	0.159	moderately benign-leaning
SaProt	LLR -12.74	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	26.3	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

Grpmax group 0.000173% European (non-Finnish) · 2/1,154,630 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000127% 2/1,577,524 alleles · very rare exomes 2/1,425,268 · genomes 0/152,256 · 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: PPA2
Protein: p.Met94Val
Coding: c.280A>G
MANE Select: NM_176869
dbSNP: rs1057517679
Type: single nucleotide variant
Location: chr4:105449391 (GRCh38)
Gene constraint: LOEUF 1.324 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.39
Residue 94: 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.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-met94val (accessed [today's date]).

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