Is PPA2 p.Arg100Gln (c.299G>A) pathogenic?

PPA2 p.Arg100Gln (c.299G>A) is classified Uncertain significance in PPA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-12). AlphaMissense: ambiguous (0.3948); Ultra-rare (popmax 0.0381%, afr).

How common is PPA2 p.Arg100Gln (c.299G>A) in the general population?

PPA2 p.Arg100Gln (c.299G>A) is ultra-rare (popmax 0.0381%, afr) (gnomAD).

What do computational predictors say about PPA2 p.Arg100Gln (c.299G>A)?

AlphaMissense predicts ambiguous (score 0.3948) — an in-silico prediction, not a clinical call.

PPA2 p.Arg100Gln

c.299G>A · rs144503235 · VCV1315555

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3948 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0381%, afr)

Computational evidence

Protein change
AlphaMissense	0.3948	ambiguous
REVEL	0.527	indeterminate
SaProt	LLR -10.32	damaging
Splicing
SpliceAI	Δ0.20	acceptor loss, 31 bp away · masked 0 · deltas
Pangolin	Δ0.21	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	33.0	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 0.0381% African / African-American · 28/73,456 alleles

Filtering AF 0.027% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00235% 37/1,573,798 alleles · ultra-rare exomes 16/1,422,272 · genomes 21/151,526 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0381%	2,623
East Asian	0.00226%	44,240
European (non-Finnish)	0.000695%	143,893

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.Arg100Gln
Coding: c.299G>A
MANE Select: NM_176869
dbSNP: rs144503235
Type: single nucleotide variant
Location: chr4:105449372 (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.Arg100Trp Uncertain significance ★★ ⚠ 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
PPA2 p.Ala12Val Uncertain significance ★★ ⚠ same type
PPA2 p.Ala130Val 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-arg100gln (accessed [today's date]).

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