Is PPA2 p.Pro167Leu (c.500C>T) pathogenic?

PPA2 p.Pro167Leu (c.500C>T) is classified Likely pathogenic in PPA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-03-01). AlphaMissense: ambiguous (0.4563); Very rare (popmax 0.00558%, sas); Associated with sudden cardiac failure, infantile.

What condition is associated with PPA2 p.Pro167Leu (c.500C>T)?

PPA2 p.Pro167Leu (c.500C>T) is associated with sudden cardiac failure, infantile (ClinVar).

How common is PPA2 p.Pro167Leu (c.500C>T) in the general population?

PPA2 p.Pro167Leu (c.500C>T) is very rare (popmax 0.00558%, sas) (gnomAD).

What do computational predictors say about PPA2 p.Pro167Leu (c.500C>T)?

AlphaMissense predicts ambiguous (score 0.4563) — an in-silico prediction, not a clinical call.

PPA2 p.Pro167Leu

c.500C>T · rs546693824 · VCV372227

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4563 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00558%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

sudden cardiac failure, infantile

Computational evidence

Protein change
AlphaMissense	0.4563	ambiguous
REVEL	0.876	moderately pathogenic-leaning
SaProt	LLR -14.37	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	31.0	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 0.00558% South Asian · 5/89,664 alleles

Filtering AF 0.00213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00138%

Overall 0.000435% 7/1,608,738 alleles · very rare exomes 6/1,456,618 · genomes 1/152,120 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00558%	17,933
Remaining individualsnot grpmax-eligible	0.00321%	31,143

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.Pro167Leu
Coding: c.500C>T
MANE Select: NM_176869
dbSNP: rs546693824
Type: single nucleotide variant
Location: chr4:105437978 (GRCh38)
Gene constraint: LOEUF 1.324 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.39
Residue 167: a UniProt-annotated variant site (in scfi; decreased inorganic diphosphatase activity)

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-pro167leu (accessed [today's date]).

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