Is PPP3CA p.Pro263Leu (c.788C>T) pathogenic?

PPP3CA p.Pro263Leu (c.788C>T) is classified Uncertain significance in PPP3CA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-02). AlphaMissense: likely benign (0.2688); Very rare (popmax 0.00134%, afr); Associated with developmental and epileptic encephalopathy 91.

What condition is associated with PPP3CA p.Pro263Leu (c.788C>T)?

PPP3CA p.Pro263Leu (c.788C>T) is associated with developmental and epileptic encephalopathy 91, arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ClinVar).

How common is PPP3CA p.Pro263Leu (c.788C>T) in the general population?

PPP3CA p.Pro263Leu (c.788C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PPP3CA p.Pro263Leu (c.788C>T)?

AlphaMissense predicts likely benign (score 0.2688) — an in-silico prediction, not a clinical call.

PPP3CA p.Pro263Leu

c.788C>T · VCV3393059

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2688 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

developmental and epileptic encephalopathy 91

Computational evidence

Protein change
AlphaMissense	0.2688	likely benign
REVEL	0.35	indeterminate
SaProt	LLR -14.61	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 170 kb · p 4.9e-41 · regional, not allelic
Overall
CADD	29.2	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 0.00134% African / African-American · 1/74,670 alleles

Overall 0.000187% 3/1,608,194 alleles · very rare exomes 2/1,456,056 · genomes 1/152,138 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,670
South Asian	0.00111%	90,190
European (non-Finnish)	8.5e-05%	1,176,782

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: PPP3CA
Protein: p.Pro263Leu
Coding: c.788C>T
MANE Select: NM_000944
Type: single nucleotide variant
Location: chr4:101083258 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 263: the 'catalytic' region; an α-helix

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

Also linked: arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

Similar variants

PPP3CA p.Pro263= Likely benign ★★ same residue
PPP3CA p.Ala447Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PPP3CA p.Arg254Ser 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-pro263leu (accessed [today's date]).

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