Is PPP2CA p.Val45Leu (c.133G>T) pathogenic?

PPP2CA p.Val45Leu (c.133G>T) is classified Uncertain significance in PPP2CA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.9059); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PPP2CA p.Val45Leu (c.133G>T)?

PPP2CA p.Val45Leu (c.133G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PPP2CA p.Val45Leu (c.133G>T) in the general population?

PPP2CA p.Val45Leu (c.133G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPP2CA p.Val45Leu (c.133G>T)?

AlphaMissense predicts likely pathogenic (score 0.9059) — an in-silico prediction, not a clinical call.

PPP2CA p.Val45Leu

c.133G>T · VCV4143149

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9059 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9059	likely pathogenic
REVEL	0.365	indeterminate
SaProt	LLR -11.75	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 20 kb · p 0.0022 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: PPP2CA
Protein: p.Val45Leu
Coding: c.133G>T
MANE Select: NM_002715
Type: single nucleotide variant
Location: chr5:134206101 (GRCh38)
Gene constraint: LOEUF 0.315 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.86 · 50 PDB
Residue 45: a β-strand

Full PPP2CA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPP2CA p.Val45Met Likely pathogenic ★ same residue
PPP2CA p.Glu297Lys Uncertain significance ★★ ⚠ same condition
PPP2CA p.Ile211Val Uncertain significance ★★ ⚠ same condition
PPP2CA p.Asn271Asp Likely pathogenic ★ same condition
PPP2CA c.486+2T>C Uncertain significance ★ same condition
PPP2CA p.Gln46Arg Uncertain significance ★ same condition
PPP2CA p.Pro190Ser Uncertain significance ★ ⚠ same condition
PPP2CA p.Asp223His 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/ppp2ca-p-val45leu (accessed [today's date]).

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