Is PPP3CA p.Lys466fs (c.1390_1394dup) pathogenic?

PPP3CA p.Lys466fs (c.13901394dup) is classified Uncertain significance in PPP3CA (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-27). Associated with developmental and epileptic encephalopathy 91.

What condition is associated with PPP3CA p.Lys466fs (c.1390_1394dup)?

PPP3CA p.Lys466fs (c.1390_1394dup) is associated with developmental and epileptic encephalopathy 91 (ClinVar).

PPP3CA p.Lys466fs

c.1390_1394dup · VCV4819179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

developmental and epileptic encephalopathy 91

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (14 of 14) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.1	GERP 0.2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: PPP3CA
Protein: p.Lys466fs
Coding: c.1390_1394dup
MANE Select: NM_000944
Type: Duplication
Location: chr4:101026036 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 466: 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

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.Ser438fs Pathogenic/Likely pathogenic ★★ same condition
PPP3CA p.Thr429fs Pathogenic/Likely pathogenic ★★ same condition
PPP3CA p.Ala447fs Pathogenic ★ same condition
PPP3CA p.Gly430fs Pathogenic ★ same condition
PPP3CA p.Ser434fs Pathogenic ★ same condition
PPP3CA p.Ser446fs Pathogenic ★ same condition
PPP3CA p.Thr468fs Likely pathogenic ★ same condition
PPP3CA p.Val420fs Pathogenic ★ 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-lys466fs (accessed [today's date]).

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