Is PRKCB p.Ala2Pro (c.4G>C) pathogenic?

PRKCB p.Ala2Pro (c.4G>C) is classified Uncertain significance in PRKCB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: likely benign (0.2672); Very rare (popmax 0.0019%, amr).

How common is PRKCB p.Ala2Pro (c.4G>C) in the general population?

PRKCB p.Ala2Pro (c.4G>C) is very rare (popmax 0.0019%, amr) (gnomAD).

What do computational predictors say about PRKCB p.Ala2Pro (c.4G>C)?

AlphaMissense predicts likely benign (score 0.2672) — an in-silico prediction, not a clinical call.

PRKCB p.Ala2Pro

c.4G>C · VCV4144402

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0019%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2672	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -9.21	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 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.50	unconstrained · MANE · 42 bp · p 0.018 · regional, not allelic
Overall
CADD	28.9	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 0.0019% Admixed American · 1/52,578 alleles

Overall 7.11e-05% 1/1,406,844 alleles · very rare

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: PRKCB
Protein: p.Ala2Pro
Coding: c.4G>C
MANE Select: NM_002738
Type: single nucleotide variant
Location: chr16:23836179 (GRCh38)
Gene constraint: LOEUF 0.241 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.95 · 8 PDB
Residue 2: a modified residue (n-acetylalanine)

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

Similar variants

PRKCB c.1395-4A>G Benign ★★ same type
PRKCB p.Ile174= Benign ★★ same type
PRKCB p.Lys29= Benign/Likely benign ★★ same type
PRKCB p.Pro400= Likely benign ★★ same type
PRKCB p.Ala395Thr Uncertain significance ★ ⚠ same type
PRKCB p.Ala539Thr Uncertain significance ★ ⚠ same type
PRKCB p.Ala6Thr Uncertain significance ★ ⚠ same type
PRKCB p.Ala6Val Uncertain significance ★ ⚠ 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/prkcb-p-ala2pro (accessed [today's date]).

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