Is PPP2CA p.Glu192Ala (c.575A>C) pathogenic?

PPP2CA p.Glu192Ala (c.575A>C) is classified Uncertain significance in PPP2CA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-07). AlphaMissense: likely pathogenic (0.9613); Absent from gnomAD v4.1; Associated with PPP2CA-related disorder.

What condition is associated with PPP2CA p.Glu192Ala (c.575A>C)?

PPP2CA p.Glu192Ala (c.575A>C) is associated with PPP2CA-related disorder (ClinVar).

How common is PPP2CA p.Glu192Ala (c.575A>C) in the general population?

PPP2CA p.Glu192Ala (c.575A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPP2CA p.Glu192Ala (c.575A>C)?

AlphaMissense predicts likely pathogenic (score 0.9613) — an in-silico prediction, not a clinical call.

PPP2CA p.Glu192Ala

c.575A>C · rs2481049567 · VCV2637191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9613 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PPP2CA-related disorder

Computational evidence

Protein change
AlphaMissense	0.9613	likely pathogenic
REVEL	0.428	indeterminate
SaProt	LLR -12.01	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.14	constrained · MANE · 4,233 bp · p 7.9e-44 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PPP2CA
Protein: p.Glu192Ala
Coding: c.575A>C
MANE Select: NM_002715
dbSNP: rs2481049567
Type: single nucleotide variant
Location: chr5:134200986 (GRCh38)
Gene constraint: LOEUF 0.315 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.86 · 50 PDB
Residue 192: a UniProt-annotated variant site (in hjs3; may be expressed at very low levels, if any); a β-strand

Full PPP2CA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PPP2CA-related disorder

Similar variants

PPP2CA p.Cys266Arg Likely pathogenic ★ same condition
PPP2CA p.Arg110His Conflicting classifications of pathogenicity ★ ⚠ same condition
PPP2CA p.Tyr218Ter Likely pathogenic same condition
PPP2CA p.Ala102Val Likely benign same condition
PPP2CA p.Asp223His Pathogenic/Likely pathogenic ★★ same type
PPP2CA p.Asp88Gly Pathogenic/Likely pathogenic ★★ same type
PPP2CA p.Gln122His Likely pathogenic ★★ same type
PPP2CA p.His191Arg Pathogenic/Likely pathogenic ★★ 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/ppp2ca-p-glu192ala (accessed [today's date]).

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