Is PPP2CA p.Val45Met (c.133G>A) pathogenic?

PPP2CA p.Val45Met (c.133G>A) is classified Likely pathogenic in PPP2CA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-06). AlphaMissense: likely pathogenic (0.9253); Very rare (popmax 8.47e-05%, nfe); Associated with Houge-Janssens syndrome 3.

What condition is associated with PPP2CA p.Val45Met (c.133G>A)?

PPP2CA p.Val45Met (c.133G>A) is associated with Houge-Janssens syndrome 3 (ClinVar).

How common is PPP2CA p.Val45Met (c.133G>A) in the general population?

PPP2CA p.Val45Met (c.133G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PPP2CA p.Val45Met (c.133G>A)?

AlphaMissense predicts likely pathogenic (score 0.9253) — an in-silico prediction, not a clinical call.

PPP2CA p.Val45Met

c.133G>A · rs1393362032 · VCV1676571

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9253 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Houge-Janssens syndrome 3

Computational evidence

Protein change
AlphaMissense	0.9253	likely pathogenic ✓ concordant with ClinVar
REVEL	0.397	indeterminate
SaProt	LLR -12.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	29.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,956 alleles

Overall 6.2e-05% 1/1,613,946 alleles · very rare exomes 0/1,461,734 · genomes 1/152,212 · 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: PPP2CA
Protein: p.Val45Met
Coding: c.133G>A
MANE Select: NM_002715
dbSNP: rs1393362032
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

Houge-Janssens syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPP2CA p.Val45Leu Uncertain significance ★ ⚠ same residue
PPP2CA p.Asp223His Pathogenic/Likely pathogenic ★★ same condition
PPP2CA p.Asp88Gly Pathogenic/Likely pathogenic ★★ same condition
PPP2CA p.Gln122His Likely pathogenic ★★ same condition
PPP2CA p.His191Arg Pathogenic/Likely pathogenic ★★ same condition
PPP2CA p.Tyr127Cys Likely pathogenic ★★ same condition
PPP2CA p.Tyr265Cys Likely pathogenic ★★ same condition
PPP2CA p.Ser171Leu 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/ppp2ca-p-val45met (accessed [today's date]).

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