Is PPA2 p.Met114Val (c.340A>G) pathogenic?

PPA2 p.Met114Val (c.340A>G) is classified Conflicting classifications of pathogenicity in PPA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.1668); Very rare (popmax 0.00269%, afr); Associated with sudden cardiac failure, alcohol-induced.

What condition is associated with PPA2 p.Met114Val (c.340A>G)?

PPA2 p.Met114Val (c.340A>G) is associated with sudden cardiac failure, alcohol-induced, sudden cardiac failure, infantile (ClinVar).

How common is PPA2 p.Met114Val (c.340A>G) in the general population?

PPA2 p.Met114Val (c.340A>G) is very rare (popmax 0.00269%, afr) (gnomAD).

What do computational predictors say about PPA2 p.Met114Val (c.340A>G)?

AlphaMissense predicts likely benign (score 0.1668) — an in-silico prediction, not a clinical call.

PPA2 p.Met114Val

c.340A>G · rs375129675 · VCV1048572

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sudden cardiac failure, alcohol-induced

Computational evidence

Protein change
AlphaMissense	0.1668	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -7.87	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 0.36	GERP -3.8, phastCons 0.001
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	4.148	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 0.00269% African / African-American · 2/74,386 alleles

Filtering AF 0.00069% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00054%

Overall 0.00106% 17/1,603,178 alleles · very rare exomes 14/1,450,994 · genomes 3/152,184 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00269%	37,193
Remaining individualsnot grpmax-eligible	0.00161%	62,058
European (non-Finnish)	0.00119%	84,039

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.Met114Val
Coding: c.340A>G
MANE Select: NM_176869
dbSNP: rs375129675
Type: single nucleotide variant
Location: chr4:105446484 (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, alcohol-induced — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sudden cardiac failure, infantile

Similar variants

PPA2 p.Met114Thr Uncertain significance ★ ⚠ 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
PPA2 c.442-16A>T Benign ★★ same condition
PPA2 p.Arg9= Benign/Likely 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-met114val (accessed [today's date]).

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