Is PPA2 p.Lys136Arg (c.407A>G) pathogenic?

PPA2 p.Lys136Arg (c.407A>G) is classified Uncertain significance in PPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely benign (0.0938); Very rare (popmax 0.00226%, eas).

How common is PPA2 p.Lys136Arg (c.407A>G) in the general population?

PPA2 p.Lys136Arg (c.407A>G) is very rare (popmax 0.00226%, eas) (gnomAD).

What do computational predictors say about PPA2 p.Lys136Arg (c.407A>G)?

AlphaMissense predicts likely benign (score 0.0938) — an in-silico prediction, not a clinical call.

PPA2 p.Lys136Arg

c.407A>G · rs1722387350 · VCV2044130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00226%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0938	likely benign
REVEL	0.404	indeterminate
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	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 tolerated — 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

Grpmax group 0.00226% East Asian · 1/44,328 alleles

Overall 6.23e-05% 1/1,605,404 alleles · very rare exomes 1/1,453,104 · genomes 0/152,300 · 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.Lys136Arg
Coding: c.407A>G
MANE Select: NM_176869
dbSNP: rs1722387350
Type: single nucleotide variant
Location: chr4:105446417 (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

Similar variants

PPA2 p.Arg127Leu Pathogenic/Likely pathogenic ★★ ⚠ same type
PPA2 p.Glu172Lys Pathogenic/Likely pathogenic ★★ same type
PPA2 p.Pro228Leu Pathogenic/Likely pathogenic ★★ ⚠ same type
PPA2 p.Thr159Met Pathogenic/Likely pathogenic ★★ ⚠ same type
PPA2 c.528+1G>T Uncertain significance ★★ same type
PPA2 p.Ala12Val Uncertain significance ★★ ⚠ same type
PPA2 p.Ala130Val Uncertain significance ★★ ⚠ same type
PPA2 p.Ala16Val Uncertain significance ★★ ⚠ same type

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-lys136arg (accessed [today's date]).

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