Is PPA2 p.Met80Val (c.238A>G) pathogenic?

PPA2 p.Met80Val (c.238A>G) is classified Likely benign in PPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-25). AlphaMissense: likely benign (0.0643); Ultra-rare (popmax 0.0827%, eas).

How common is PPA2 p.Met80Val (c.238A>G) in the general population?

PPA2 p.Met80Val (c.238A>G) is ultra-rare (popmax 0.0827%, eas) (gnomAD).

What do computational predictors say about PPA2 p.Met80Val (c.238A>G)?

AlphaMissense predicts likely benign (score 0.0643) — an in-silico prediction, not a clinical call.

PPA2 p.Met80Val

c.238A>G · rs138556360 · VCV2178790

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0643 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0827%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0643	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -4.52	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 2.1	GERP 0.38, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	13.93	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 0.0827% East Asian · 37/44,750 alleles

Filtering AF 0.0616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0543%

Overall 0.00243% 39/1,607,362 alleles · ultra-rare exomes 34/1,455,034 · genomes 5/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0827%	1,209
Remaining individualsnot grpmax-eligible	0.00161%	62,248
European (non-Finnish)	8.5e-05%	1,176,851

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.Met80Val
Coding: c.238A>G
MANE Select: NM_176869
dbSNP: rs138556360
Type: single nucleotide variant
Location: chr4:105453627 (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-met80val (accessed [today's date]).

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