Is CACNB4 p.Arg74= (c.222A>T) pathogenic?

CACNB4 p.Arg74= (c.222A>T) is classified Benign/Likely benign in CACNB4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-09-01). Rare (popmax 0.341%, sas); Associated with idiopathic generalized epilepsy.

What condition is associated with CACNB4 p.Arg74= (c.222A>T)?

CACNB4 p.Arg74= (c.222A>T) is associated with idiopathic generalized epilepsy (ClinVar).

How common is CACNB4 p.Arg74= (c.222A>T) in the general population?

CACNB4 p.Arg74= (c.222A>T) is rare (popmax 0.341%, sas) (gnomAD).

CACNB4 p.Arg74=

c.222A>T · rs553682728 · VCV377620

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.341%, sas)

Conditions

idiopathic generalized epilepsy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.3	GERP -2.1, phastCons 0.11
Overall
CADD	9.891	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.341% South Asian · 311/91,084 alleles

Filtering AF 0.31% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.298%

Overall 0.02% 322/1,613,884 alleles · rare exomes 302/1,461,556 · genomes 20/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.341%	293
Remaining individualsnot grpmax-eligible	0.0144%	6,941
European (non-Finnish)	0.00017%	589,887

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: CACNB4
Protein: p.Arg74=
Coding: c.222A>T
MANE Select: NM_000726
dbSNP: rs553682728
Type: single nucleotide variant
Location: chr2:151883296 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.29 · 1 PDB
Residue 74: an α-helix

Full CACNB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

idiopathic generalized epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CACNB4 p.Ala12Ser Uncertain significance ★★ ⚠ same condition
CACNB4 p.Arg437Ter Uncertain significance ★★ same condition
CACNB4 p.Arg453Leu Uncertain significance ★★ ⚠ same condition
CACNB4 p.Arg473Cys Uncertain significance ★★ same condition
CACNB4 p.Arg473His Uncertain significance ★★ ⚠ same condition
CACNB4 p.Arg517Gln Uncertain significance ★★ ⚠ same condition
CACNB4 p.Arg517Ter Uncertain significance ★★ same condition
CACNB4 p.Gln343Glu Uncertain significance ★★ ⚠ 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/cacnb4-p-arg74 (accessed [today's date]).

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