Is PPP2CA p.Cys266Arg (c.796T>C) pathogenic?

PPP2CA p.Cys266Arg (c.796T>C) is classified Likely pathogenic in PPP2CA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with PPP2CA-related disorder.

What condition is associated with PPP2CA p.Cys266Arg (c.796T>C)?

PPP2CA p.Cys266Arg (c.796T>C) is associated with PPP2CA-related disorder (ClinVar).

How common is PPP2CA p.Cys266Arg (c.796T>C) in the general population?

PPP2CA p.Cys266Arg (c.796T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPP2CA p.Cys266Arg (c.796T>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

PPP2CA p.Cys266Arg

c.796T>C · rs2481046894 · VCV2631335

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PPP2CA-related disorder

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic ✓ concordant with ClinVar · top 8% in PPP2CA
REVEL	0.813	moderately pathogenic-leaning
SaProt	LLR -17.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	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	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

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.Cys266Arg
Coding: c.796T>C
MANE Select: NM_002715
dbSNP: rs2481046894
Type: single nucleotide variant
Location: chr5:134199147 (GRCh38)
Gene constraint: LOEUF 0.315 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.86 · 50 PDB
Residue 266: a UniProt-annotated variant site (in hjs3; may be expressed at very low levels, if any); a UniProt-annotated variant site (in hjs3; loss of phosphatase activity in an in vitro assay; complete loss of interaction with pp2a subunit a ppp2r1a/ppp2r1b; interacts with alpha4/igbp1; loss of interaction with pp2a subunit b components); an α-helix

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

Disease context

PPP2CA-related disorder

Similar variants

PPP2CA p.Arg110His Conflicting classifications of pathogenicity ★ ⚠ same condition
PPP2CA p.Glu192Ala Uncertain significance ★ ⚠ 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-cys266arg (accessed [today's date]).

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