Is PPP3CA p.Arg254Ser (c.762G>T) pathogenic?

PPP3CA p.Arg254Ser (c.762G>T) is classified Pathogenic/Likely pathogenic in PPP3CA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-31). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy 91.

What condition is associated with PPP3CA p.Arg254Ser (c.762G>T)?

PPP3CA p.Arg254Ser (c.762G>T) is associated with developmental and epileptic encephalopathy 91 (ClinVar).

How common is PPP3CA p.Arg254Ser (c.762G>T) in the general population?

PPP3CA p.Arg254Ser (c.762G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPP3CA p.Arg254Ser (c.762G>T)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

PPP3CA p.Arg254Ser

c.762G>T · rs1334933549 · VCV1686095

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

developmental and epileptic encephalopathy 91

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic ✓ concordant with ClinVar · top 7% in PPP3CA
REVEL	0.43	indeterminate
SaProt	LLR -15.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -0.8, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 170 kb · p 4.9e-41 · regional, not allelic
Overall
CADD	22.0	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: PPP3CA
Protein: p.Arg254Ser
Coding: c.762G>T
MANE Select: NM_000944
dbSNP: rs1334933549
Type: single nucleotide variant
Location: chr4:101093796 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 254: the 'catalytic' region; a turn

Full PPP3CA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy 91 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPP3CA p.Arg254Gly Likely pathogenic ★ same residue
PPP3CA p.Arg254= Likely benign ★ same residue
PPP3CA p.Ala447Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PPP3CA p.Asp234Glu Pathogenic/Likely pathogenic ★★ same condition
PPP3CA p.Glu282Lys Pathogenic/Likely pathogenic ★★ same condition
PPP3CA p.His92Arg Pathogenic/Likely pathogenic ★★ same condition
PPP3CA c.860+3G>A Uncertain significance ★★ same condition
PPP3CA p.Arg28Gln Uncertain significance ★★ ⚠ 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/ppp3ca-p-arg254ser (accessed [today's date]).

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