Is PPP3CA p.Leu476= (c.1428A>G) pathogenic?

PPP3CA p.Leu476= (c.1428A>G) is classified Likely benign in PPP3CA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-21). Very rare (popmax 0.00334%, amr); Associated with developmental and epileptic encephalopathy 91.

What condition is associated with PPP3CA p.Leu476= (c.1428A>G)?

PPP3CA p.Leu476= (c.1428A>G) is associated with developmental and epileptic encephalopathy 91, arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ClinVar).

How common is PPP3CA p.Leu476= (c.1428A>G) in the general population?

PPP3CA p.Leu476= (c.1428A>G) is very rare (popmax 0.00334%, amr) (gnomAD).

PPP3CA p.Leu476=

c.1428A>G · rs1196954163 · VCV1617376

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

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 0.66	GERP -4.2, phastCons 1
Overall
CADD	4.567	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,950 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,766 alleles · very rare exomes 2/1,461,586 · genomes 0/152,180 · joint denominator

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.Leu476=
Coding: c.1428A>G
MANE Select: NM_000944
dbSNP: rs1196954163
Type: single nucleotide variant
Location: chr4:101026003 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 476: a UniProt-annotated variant site (in iecee1; results in constitutive phosphatase activity in the absence of calmodulin); a UniProt-annotated variant site (in iecee1); the 'autoinhibitory domain' region; the 'disordered' 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.Leu476Ser 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-leu476 (accessed [today's date]).

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