Is PPP3CA p.Ile520Ser (c.1559T>G) pathogenic?

PPP3CA p.Ile520Ser (c.1559T>G) is classified Uncertain significance in PPP3CA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-10). AlphaMissense: likely benign (0.0975); Absent from gnomAD v4.1.

How common is PPP3CA p.Ile520Ser (c.1559T>G) in the general population?

PPP3CA p.Ile520Ser (c.1559T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPP3CA p.Ile520Ser (c.1559T>G)?

AlphaMissense predicts likely benign (score 0.0975) — an in-silico prediction, not a clinical call.

PPP3CA p.Ile520Ser

c.1559T>G · rs753154536 · VCV1356943

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0975	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -4.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.51	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 9.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 88 bp · p 0.82 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PPP3CA
Protein: p.Ile520Ser
Coding: c.1559T>G
MANE Select: NM_000944
dbSNP: rs753154536
Type: single nucleotide variant
Location: chr4:101025872 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 520: 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 'disordered' region

Full PPP3CA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPP3CA p.Ile520Met Uncertain significance ★ ⚠ same residue
PPP3CA c.1340-2A>G Pathogenic/Likely pathogenic ★★ same type
PPP3CA p.Ala447Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
PPP3CA p.Arg254Ser Pathogenic/Likely pathogenic ★★ same type
PPP3CA p.Asp234Glu Pathogenic/Likely pathogenic ★★ same type
PPP3CA p.Glu282Lys Pathogenic/Likely pathogenic ★★ same type
PPP3CA p.Glu456Ter Pathogenic/Likely pathogenic ★★ same type
PPP3CA p.His92Arg Pathogenic/Likely pathogenic ★★ same type

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-ile520ser (accessed [today's date]).

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