Is PPA2 p.Arg127Cys (c.379C>T) pathogenic?

PPA2 p.Arg127Cys (c.379C>T) is classified Conflicting classifications of pathogenicity in PPA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.0846); Very rare (popmax 0.00804%, afr).

How common is PPA2 p.Arg127Cys (c.379C>T) in the general population?

PPA2 p.Arg127Cys (c.379C>T) is very rare (popmax 0.00804%, afr) (gnomAD).

What do computational predictors say about PPA2 p.Arg127Cys (c.379C>T)?

AlphaMissense predicts likely benign (score 0.0846) — an in-silico prediction, not a clinical call.

PPA2 p.Arg127Cys

c.379C>T · rs372302682 · VCV1189243

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0846 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00804%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0846	likely benign
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -9.81	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	32.0	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 0.00804% African / African-American · 6/74,614 alleles

Filtering AF 0.00351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00319%

Overall 0.00436% 70/1,605,782 alleles · very rare exomes 64/1,453,508 · genomes 6/152,274 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00804%	12,436
Admixed American	0.00684%	14,629
East Asian	0.00678%	14,758
European (non-Finnish)	0.0045%	22,206
Remaining individualsnot grpmax-eligible	0.00322%	31,104
South Asian	0.00225%	44,498

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.Arg127Cys
Coding: c.379C>T
MANE Select: NM_176869
dbSNP: rs372302682
Type: single nucleotide variant
Location: chr4:105446445 (GRCh38)
Gene constraint: LOEUF 1.324 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.39
Residue 127: a UniProt-annotated variant site (in scfi)

Full PPA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPA2 p.Arg127Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
PPA2 p.Arg127His Uncertain significance ★ ⚠ same residue
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-arg127cys (accessed [today's date]).

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