Is CACNA1B p.Lys894Arg (c.2681A>G) pathogenic?

CACNA1B p.Lys894Arg (c.2681A>G) is classified Uncertain significance in CACNA1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). AlphaMissense: likely benign (0.08); Very rare (popmax 0.000977%, nfe).

How common is CACNA1B p.Lys894Arg (c.2681A>G) in the general population?

CACNA1B p.Lys894Arg (c.2681A>G) is very rare (popmax 0.000977%, nfe) (gnomAD).

What do computational predictors say about CACNA1B p.Lys894Arg (c.2681A>G)?

AlphaMissense predicts likely benign (score 0.08) — an in-silico prediction, not a clinical call.

CACNA1B p.Lys894Arg

c.2681A>G · rs550100275 · VCV3239620

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.08 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000977%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.08	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -4.96	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 4.8	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 34 kb · p 1 · regional, not allelic
Overall
CADD	21.0	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 0.000977% European (non-Finnish) · 10/1,023,024 alleles

Filtering AF 0.000494% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00036%

Overall 0.000777% 10/1,287,494 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: CACNA1B
Protein: p.Lys894Arg
Coding: c.2681A>G
MANE Select: NM_000718
dbSNP: rs550100275
Type: single nucleotide variant
Location: chr9:138023424 (GRCh38)
Gene constraint: LOEUF 0.425 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.66 · 7 PDB
Residue 894: a UniProt-annotated variant site (in nedneh); the 'disordered' region

Full CACNA1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CACNA1B p.Lys894Met Conflicting classifications of pathogenicity ★ same residue
CACNA1B p.Arg2102Ter Pathogenic/Likely pathogenic ★★ same type
CACNA1B p.Ala1161Thr Uncertain significance ★★ ⚠ same type
CACNA1B p.Ala1556Val Uncertain significance ★★ ⚠ same type
CACNA1B p.Ala1999Val Uncertain significance ★★ same type
CACNA1B p.Ala2080Thr Uncertain significance ★★ ⚠ same type
CACNA1B p.Ala2214Thr Uncertain significance ★★ ⚠ same type
CACNA1B p.Ala2237Thr 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/cacna1b-p-lys894arg (accessed [today's date]).

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