Is PPP2CA p.Asp223Val (c.668A>T) pathogenic?

PPP2CA p.Asp223Val (c.668A>T) is classified Likely pathogenic in PPP2CA (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-15). AlphaMissense: likely pathogenic (0.9878); Absent from gnomAD v4.1; Associated with Houge-Janssens syndrome 3.

What condition is associated with PPP2CA p.Asp223Val (c.668A>T)?

PPP2CA p.Asp223Val (c.668A>T) is associated with Houge-Janssens syndrome 3 (ClinVar).

How common is PPP2CA p.Asp223Val (c.668A>T) in the general population?

PPP2CA p.Asp223Val (c.668A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPP2CA p.Asp223Val (c.668A>T)?

AlphaMissense predicts likely pathogenic (score 0.9878) — an in-silico prediction, not a clinical call.

PPP2CA p.Asp223Val

c.668A>T · rs1580636665 · VCV692146

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9878 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Houge-Janssens syndrome 3

Computational evidence

Protein change
AlphaMissense	0.9878	likely pathogenic ✓ concordant with ClinVar
REVEL	0.713	pathogenic-leaning
SaProt	LLR -15.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, 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.Asp223Val
Coding: c.668A>T
MANE Select: NM_002715
dbSNP: rs1580636665
Type: single nucleotide variant
Location: chr5:134200405 (GRCh38)
Gene constraint: LOEUF 0.315 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.86 · 50 PDB
Residue 223: 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); a UniProt-annotated variant site (in hjs3; decreased phosphatase activity in an in vitro assay; no effect on c-terminal methylation; no effect on the interaction with pp2a subunit a ppp2r1a/ppp2r1b; no effect on interaction with pp2a subunit b components); a UniProt-annotated variant site (in hjs3; no effect on phosphatase activity in an in vitro assay; no effect on the interaction with pp2a subunit a ppp2r1a/ppp2r1b; no effect on 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

Houge-Janssens syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPP2CA p.Asp223His Pathogenic/Likely pathogenic ★★ same residue
PPP2CA p.Asp223Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
PPP2CA p.Asp223Tyr Uncertain significance ★ ⚠ same residue
PPP2CA p.Asp88Gly Pathogenic/Likely pathogenic ★★ same condition
PPP2CA p.Gln122His Likely pathogenic ★★ same condition
PPP2CA p.His191Arg Pathogenic/Likely pathogenic ★★ same condition
PPP2CA p.Tyr127Cys Likely pathogenic ★★ same condition
PPP2CA p.Tyr265Cys Likely pathogenic ★★ same condition

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-asp223val (accessed [today's date]).

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