Is CACNB3 p.Phe333Leu (c.997T>C) pathogenic?

CACNB3 p.Phe333Leu (c.997T>C) is classified Uncertain significance in CACNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-16). AlphaMissense: likely pathogenic (0.9989); Very rare (popmax 8.47e-05%, nfe).

How common is CACNB3 p.Phe333Leu (c.997T>C) in the general population?

CACNB3 p.Phe333Leu (c.997T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CACNB3 p.Phe333Leu (c.997T>C)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

CACNB3 p.Phe333Leu

c.997T>C · VCV3826754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic · top 5% in CACNB3
REVEL	0.854	moderately pathogenic-leaning
SaProt	LLR -10.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 8,966 bp · p 1e-09 · regional, not allelic
Overall
CADD	27.1	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.84e-05% 1/1,461,828 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: CACNB3
Protein: p.Phe333Leu
Coding: c.997T>C
MANE Select: NM_000725
Type: single nucleotide variant
Location: chr12:48826980 (GRCh38)
Gene constraint: LOEUF 0.722 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.21 · 16 PDB
Residue 333: the 'mediates interaction with the alpha subunit' region

Full CACNB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CACNB3 p.Ala199Ser Uncertain significance ★ ⚠ same type
CACNB3 p.Ala199Val Uncertain significance ★ ⚠ same type
CACNB3 p.Ala63Val Uncertain significance ★ ⚠ same type
CACNB3 p.Arg107Trp Uncertain significance ★ ⚠ same type
CACNB3 p.Arg123Cys Uncertain significance ★ ⚠ same type
CACNB3 p.Arg123His Uncertain significance ★ ⚠ same type
CACNB3 p.Arg123Ser Uncertain significance ★ ⚠ same type
CACNB3 p.Arg150Gln 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/cacnb3-p-phe333leu (accessed [today's date]).

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