Is PPA2 p.Pro244Arg (c.731C>G) pathogenic?

PPA2 p.Pro244Arg (c.731C>G) is classified Uncertain significance in PPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: ambiguous (0.4246); Very rare (popmax 0.00803%, afr).

How common is PPA2 p.Pro244Arg (c.731C>G) in the general population?

PPA2 p.Pro244Arg (c.731C>G) is very rare (popmax 0.00803%, afr) (gnomAD).

What do computational predictors say about PPA2 p.Pro244Arg (c.731C>G)?

AlphaMissense predicts ambiguous (score 0.4246) — an in-silico prediction, not a clinical call.

PPA2 p.Pro244Arg

c.731C>G · rs375637385 · VCV1395122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4246 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00803%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4246	ambiguous
REVEL	0.907	moderately pathogenic-leaning
SaProt	LLR -16.02	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.66	donor gain · deltas
Pangolin	Δ0.52	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	35.0	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 0.00803% African / African-American · 6/74,722 alleles

Filtering AF 0.00348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000435% 7/1,610,306 alleles · very rare exomes 2/1,458,294 · genomes 5/152,012 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00803%	12,454
Remaining individualsnot grpmax-eligible	0.0016%	62,396

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.Pro244Arg
Coding: c.731C>G
MANE Select: NM_176869
dbSNP: rs375637385
Type: single nucleotide variant
Location: chr4:105399089 (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-pro244arg (accessed [today's date]).

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