Is PPP1CB p.Ala2Val (c.5C>T) pathogenic?

PPP1CB p.Ala2Val (c.5C>T) is classified Uncertain significance in PPP1CB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-26). AlphaMissense: likely benign (0.2379); Very rare (popmax 0.00196%, amr); Associated with Cardiovascular phenotype.

What condition is associated with PPP1CB p.Ala2Val (c.5C>T)?

PPP1CB p.Ala2Val (c.5C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is PPP1CB p.Ala2Val (c.5C>T) in the general population?

PPP1CB p.Ala2Val (c.5C>T) is very rare (popmax 0.00196%, amr) (gnomAD).

What do computational predictors say about PPP1CB p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2379) — an in-silico prediction, not a clinical call.

PPP1CB p.Ala2Val

c.5C>T · rs1305465866 · VCV1470541

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2379 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2379	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -9.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 0.63, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 25 kb · p 0.016 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00196% Admixed American · 1/50,920 alleles

Overall 6.45e-05% 1/1,549,330 alleles · very rare exomes 0/1,397,278 · genomes 1/152,052 · 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: PPP1CB
Protein: p.Ala2Val
Coding: c.5C>T
MANE Select: NM_002709
dbSNP: rs1305465866
Type: single nucleotide variant
Location: chr2:28752129 (GRCh38)
Gene constraint: LOEUF 0.247 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.91
Residue 2: a modified residue (n-acetylalanine)

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.Ala2= Likely benign ★ same residue
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
PPP1CB p.Ala258= 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-ala2val (accessed [today's date]).

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