Is PPP3CA p.Leu29= (c.87T>A) pathogenic?

PPP3CA p.Leu29= (c.87T>A) is classified Likely benign in PPP3CA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-02). Ultra-rare (popmax 0.0746%, afr); Associated with developmental and epileptic encephalopathy 91.

What condition is associated with PPP3CA p.Leu29= (c.87T>A)?

PPP3CA p.Leu29= (c.87T>A) is associated with developmental and epileptic encephalopathy 91, arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ClinVar).

How common is PPP3CA p.Leu29= (c.87T>A) in the general population?

PPP3CA p.Leu29= (c.87T>A) is ultra-rare (popmax 0.0746%, afr) (gnomAD).

PPP3CA p.Leu29=

c.87T>A · rs200922134 · VCV1628986

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0746%, afr)

Conditions

developmental and epileptic encephalopathy 91

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.25	GERP -5.1, phastCons 0.75
Overall
CADD	6.181	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0746% African / African-American · 56/75,040 alleles

Filtering AF 0.0589% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0533%

Overall 0.00378% 61/1,613,994 alleles · ultra-rare exomes 25/1,461,686 · genomes 36/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0746%	1,340
Remaining individualsnot grpmax-eligible	0.0048%	20,834
Admixed American	0.00333%	29,990

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.Leu29=
Coding: c.87T>A
MANE Select: NM_000944
dbSNP: rs200922134
Type: single nucleotide variant
Location: chr4:101196088 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB

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.Leu29Pro Uncertain significance ★ ⚠ 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-leu29 (accessed [today's date]).

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