Is PPA2 p.Arg84Ter (c.250C>T) pathogenic?

PPA2 p.Arg84Ter (c.250C>T) is classified Conflicting classifications of pathogenicity in PPA2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-03). Very rare (popmax 0.00224%, eas); Associated with sudden cardiac failure, infantile.

What condition is associated with PPA2 p.Arg84Ter (c.250C>T)?

PPA2 p.Arg84Ter (c.250C>T) is associated with sudden cardiac failure, infantile, sudden cardiac failure, alcohol-induced (ClinVar).

How common is PPA2 p.Arg84Ter (c.250C>T) in the general population?

PPA2 p.Arg84Ter (c.250C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

PPA2 p.Arg84Ter

c.250C>T · rs781655422 · VCV1048582

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Conditions

sudden cardiac failure, infantile

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 12
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 0.74, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,698 alleles

Filtering AF 0.000502% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000367%

Overall 0.000748% 12/1,605,042 alleles · very rare exomes 11/1,452,982 · genomes 1/152,060 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,698
European (non-Finnish)	0.000936%	106,875

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.Arg84Ter
Coding: c.250C>T
MANE Select: NM_176869
dbSNP: rs781655422
Type: single nucleotide variant
Location: chr4:105453615 (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

Also linked: sudden cardiac failure, alcohol-induced

Similar variants

PPA2 p.Arg84Gln Benign/Likely benign ★★ same residue
PPA2 p.Arg84Gly Uncertain significance ★ ⚠ same residue
PPA2 p.Arg84= Likely benign ★ 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

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-arg84ter (accessed [today's date]).

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