Is PPA2 p.Arg84Gln (c.251G>A) pathogenic?

PPA2 p.Arg84Gln (c.251G>A) is classified Benign/Likely benign in PPA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0824); Rare (popmax 0.275%, afr).

How common is PPA2 p.Arg84Gln (c.251G>A) in the general population?

PPA2 p.Arg84Gln (c.251G>A) is rare (popmax 0.275%, afr) (gnomAD).

What do computational predictors say about PPA2 p.Arg84Gln (c.251G>A)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

PPA2 p.Arg84Gln

c.251G>A · rs146135315 · VCV1199086

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.275%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.8	GERP 0.72, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	20.8	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 0.275% African / African-American · 205/74,648 alleles

Filtering AF 0.244% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.232%

Overall 0.0169% 271/1,605,410 alleles · rare exomes 120/1,453,150 · genomes 151/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.275%	364
Admixed American	0.0356%	2,805
Remaining individualsnot grpmax-eligible	0.0209%	4,785
South Asian	0.00675%	14,813
European (non-Finnish)	0.00221%	45,221

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.Arg84Gln
Coding: c.251G>A
MANE Select: NM_176869
dbSNP: rs146135315
Type: single nucleotide variant
Location: chr4:105453614 (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.Arg84Gly Uncertain significance ★ ⚠ same residue
PPA2 p.Arg84Ter Conflicting classifications of pathogenicity ★ same residue
PPA2 p.Arg84= Likely benign ★ same residue
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

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-arg84gln (accessed [today's date]).

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