Is PPP1CB p.Pro323= (c.969G>A) pathogenic?

PPP1CB p.Pro323= (c.969G>A) is classified Likely benign in PPP1CB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0112%, eas); Associated with Cardiovascular phenotype.

What condition is associated with PPP1CB p.Pro323= (c.969G>A)?

PPP1CB p.Pro323= (c.969G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is PPP1CB p.Pro323= (c.969G>A) in the general population?

PPP1CB p.Pro323= (c.969G>A) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

PPP1CB p.Pro323=

c.969G>A · rs373638418 · VCV1767848

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -4, phastCons 1
Overall
CADD	13.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0112% East Asian · 5/44,796 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00112% 18/1,602,766 alleles · ultra-rare exomes 12/1,450,726 · genomes 6/152,040 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0112%	8,959
African / African-American	0.00268%	37,295
South Asian	0.0022%	45,413
Admixed American	0.00167%	59,910
Remaining individualsnot grpmax-eligible	0.00161%	62,114
European (non-Finnish)	0.000598%	167,148

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: PPP1CB
Protein: p.Pro323=
Coding: c.969G>A
MANE Select: NM_002709
dbSNP: rs373638418
Type: single nucleotide variant
Location: chr2:28799288 (GRCh38)
Gene constraint: LOEUF 0.247 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.91
Residue 323: the 'disordered' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPP1CB p.Pro323Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PPP1CB p.Ala2Val Uncertain significance ★★ ⚠ same condition
PPP1CB p.Leu11Val Uncertain significance ★★ ⚠ same condition
PPP1CB p.Leu6Val Uncertain significance ★★ ⚠ same condition
PPP1CB p.Phe234Leu Uncertain significance ★★ ⚠ same condition
PPP1CB p.Ser99Cys Uncertain significance ★★ ⚠ same condition
PPP1CB p.Ala127= Likely benign ★★ same condition
PPP1CB p.Ala228= Likely benign ★★ 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/ppp1cb-p-pro323 (accessed [today's date]).

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