Is PPP1CB p.Phe234Leu (c.700T>C) pathogenic?

PPP1CB p.Phe234Leu (c.700T>C) is classified Uncertain significance in PPP1CB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with PPP1CB p.Phe234Leu (c.700T>C)?

PPP1CB p.Phe234Leu (c.700T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is PPP1CB p.Phe234Leu (c.700T>C) in the general population?

PPP1CB p.Phe234Leu (c.700T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPP1CB p.Phe234Leu (c.700T>C)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

PPP1CB p.Phe234Leu

c.700T>C · VCV4614739

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic
REVEL	0.617	indeterminate
SaProt	LLR -13.47	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 6.2	GERP 2.6, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 41 bp · p 0.13 · regional, not allelic
Overall
CADD	26.5	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.Phe234Leu
Coding: c.700T>C
MANE Select: NM_002709
Type: single nucleotide variant
Location: chr2:28788765 (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

Disease context

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

Similar variants

PPP1CB p.Ala2Val Uncertain significance ★★ ⚠ same condition
PPP1CB p.Leu11Val Uncertain significance ★★ ⚠ same condition
PPP1CB p.Leu6Val 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
PPP1CB p.Ala258= Likely benign ★★ same condition
PPP1CB p.Ala278= 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-phe234leu (accessed [today's date]).

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