Is CACNB4 p.Ser2Phe (c.5C>T) pathogenic?

CACNB4 p.Ser2Phe (c.5C>T) is classified Conflicting classifications of pathogenicity in CACNB4 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2025-11-01). AlphaMissense: likely benign (0.1427); Rare (popmax 0.288%, mid); Associated with episodic ataxia type 5.

What condition is associated with CACNB4 p.Ser2Phe (c.5C>T)?

CACNB4 p.Ser2Phe (c.5C>T) is associated with episodic ataxia type 5, idiopathic generalized epilepsy, epilepsy, idiopathic generalized, susceptibility to, 9 (ClinVar).

How common is CACNB4 p.Ser2Phe (c.5C>T) in the general population?

CACNB4 p.Ser2Phe (c.5C>T) is rare (popmax 0.288%, mid) (gnomAD).

How is Episodic ataxia type 5 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CACNB4 p.Ser2Phe (c.5C>T)?

AlphaMissense predicts likely benign (score 0.1427) — an in-silico prediction, not a clinical call.

CACNB4 p.Ser2Phe

c.5C>T · rs200092211 · VCV193120

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.1427 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.288%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

episodic ataxia type 5

Computational evidence

Protein change
AlphaMissense	0.1427	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.91, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 642 bp · p 0.71 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.288% Middle Eastern · 14/4,854 alleles

Filtering AF 0.174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.143%

Overall 0.0877% 1,344/1,533,242 alleles · rare exomes 1,206/1,381,012 · genomes 138/152,230 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.973%	103
Middle Easterngrpmax	0.288%	347
Admixed American	0.187%	535
Remaining individualsnot grpmax-eligible	0.14%	713
European (non-Finnish)	0.0751%	1,332
South Asian	0.0306%	3,271
African / African-American	0.0126%	7,964
Finnishnot grpmax-eligible	0.00168%	59,692

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser2Phe
Coding: c.5C>T
MANE Select: NM_000726
dbSNP: rs200092211
Type: single nucleotide variant
Location: chr2:152099007 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.29 · 1 PDB
Residue 2: the 'disordered' region

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

Disease context

episodic ataxia type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: idiopathic generalized epilepsy epilepsy, idiopathic generalized, susceptibility to, 9

For Episodic ataxia type 5 (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CACNB4 p.Ala12Ser Uncertain significance ★★ ⚠ same condition
CACNB4 p.Ala290Val 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.Arg506Gln Uncertain significance ★★ ⚠ same condition
CACNB4 p.Arg517Gln 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-ser2phe (accessed [today's date]).

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