Is PPP1CB p.Arg22Pro (c.65G>C) pathogenic?

PPP1CB p.Arg22Pro (c.65G>C) is classified Uncertain significance in PPP1CB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-15). AlphaMissense: likely pathogenic (0.8392); Absent from gnomAD v4.1.

How common is PPP1CB p.Arg22Pro (c.65G>C) in the general population?

PPP1CB p.Arg22Pro (c.65G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPP1CB p.Arg22Pro (c.65G>C)?

AlphaMissense predicts likely pathogenic (score 0.8392) — an in-silico prediction, not a clinical call.

PPP1CB p.Arg22Pro

c.65G>C · VCV3643987

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8392 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8392	likely pathogenic
REVEL	0.325	indeterminate
SaProt	LLR -12.49	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 9.9	GERP 0.029, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 25 kb · p 0.016 · regional, not allelic
Overall
CADD	27.4	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: PPP1CB
Protein: p.Arg22Pro
Coding: c.65G>C
MANE Select: NM_002709
Type: single nucleotide variant
Location: chr2:28776863 (GRCh38)
Gene constraint: LOEUF 0.247 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.91

Full PPP1CB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPP1CB p.Ala56Pro Likely pathogenic ★★★ ⚠ same type
PPP1CB p.Glu183Ala Pathogenic ★★★ ⚠ same type
PPP1CB p.Glu183Val Pathogenic ★★★ same type
PPP1CB p.Glu274Lys Likely pathogenic ★★★ same type
PPP1CB p.Pro49Arg Pathogenic ★★★ same type
PPP1CB c.53-9G>A Benign ★★★ same type
PPP1CB p.Asp9= Benign ★★★ same type
PPP1CB p.Gln67= 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/ppp1cb-p-arg22pro (accessed [today's date]).

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