Is PPP3CA p.Leu196= (c.588G>A) pathogenic?

PPP3CA p.Leu196= (c.588G>A) is classified Benign/Likely benign in PPP3CA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-05-01). Ultra-rare (popmax 0.0689%, nfe); Associated with developmental and epileptic encephalopathy 91.

What condition is associated with PPP3CA p.Leu196= (c.588G>A)?

PPP3CA p.Leu196= (c.588G>A) is associated with developmental and epileptic encephalopathy 91, arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ClinVar).

How common is PPP3CA p.Leu196= (c.588G>A) in the general population?

PPP3CA p.Leu196= (c.588G>A) is ultra-rare (popmax 0.0689%, nfe) (gnomAD).

PPP3CA p.Leu196=

c.588G>A · rs142339019 · VCV1600791

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0689%, nfe)

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 0.4	GERP -2.8, phastCons 0.99
Overall
CADD	9.732	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0689% European (non-Finnish) · 813/1,179,278 alleles

Filtering AF 0.0649% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0634%

Overall 0.0533% 859/1,612,778 alleles · ultra-rare exomes 822/1,460,504 · genomes 37/152,274 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0689%	1,451
Remaining individualsnot grpmax-eligible	0.0448%	2,230
African / African-American	0.0133%	7,495
Finnishnot grpmax-eligible	0.00781%	12,803
Admixed American	0.00334%	29,935
South Asian	0.0011%	90,884

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.Leu196=
Coding: c.588G>A
MANE Select: NM_000944
dbSNP: rs142339019
Type: single nucleotide variant
Location: chr4:101098421 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 196: the 'catalytic' region; a β-strand

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.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
PPP3CA p.Arg28Trp 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-leu196 (accessed [today's date]).

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