Is PPP2R5C p.Trp186Arg (c.556T>C) pathogenic?

PPP2R5C p.Trp186Arg (c.556T>C) is classified Uncertain significance in PPP2R5C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-19). AlphaMissense: likely pathogenic (0.9999); Very rare (popmax 0.00134%, afr); Associated with neurodevelopmental disorder.

What condition is associated with PPP2R5C p.Trp186Arg (c.556T>C)?

PPP2R5C p.Trp186Arg (c.556T>C) is associated with neurodevelopmental disorder (ClinVar).

How common is PPP2R5C p.Trp186Arg (c.556T>C) in the general population?

PPP2R5C p.Trp186Arg (c.556T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PPP2R5C p.Trp186Arg (c.556T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

PPP2R5C p.Trp186Arg

c.556T>C · rs367794601 · VCV3252059

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 4% in PPP2R5C
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -14.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.4, phastCons 1
Overall
CADD	32.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM W131R vs ClinVar W186R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,882 alleles

Overall 6.2e-05% 1/1,612,106 alleles · very rare exomes 0/1,459,912 · genomes 1/152,194 · 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: PPP2R5C
Protein: p.Trp186Arg
Coding: c.556T>C
MANE Select: NM_001352913
dbSNP: rs367794601
Type: single nucleotide variant
Location: chr14:101882257 (GRCh38)
Gene constraint: LOEUF 0.198 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.15 · 22 PDB
Residue 131 UniProt numbering: a UniProt-annotated variant site (in hjs4; likely pathogenic; decreased interaction with ppp2ca and ppp2r1a); an α-helix

Full PPP2R5C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPP2R5C p.Cys104Arg Likely pathogenic ★★ same type
PPP2R5C p.Leu307Ile Uncertain significance ★★ ⚠ same type
PPP2R5C p.Met153Val Uncertain significance ★★ ⚠ same type
PPP2R5C p.Phe110Ser Uncertain significance ★★ ⚠ same type
PPP2R5C p.Pro180Ser Uncertain significance ★★ ⚠ same type
PPP2R5C c.1017+19G>A Benign ★★ same type
PPP2R5C c.1018-4G>C Benign/Likely benign ★★ same type
PPP2R5C c.1491+11A>C Benign/Likely benign ★★ 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/ppp2r5c-p-trp186arg (accessed [today's date]).

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