Is CACNB4 p.Ser3Phe (c.8C>T) pathogenic?

CACNB4 p.Ser3Phe (c.8C>T) is classified Conflicting classifications of pathogenicity in CACNB4 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.115); Rare (popmax 0.184%, mid); Associated with episodic ataxia type 5.

What condition is associated with CACNB4 p.Ser3Phe (c.8C>T)?

CACNB4 p.Ser3Phe (c.8C>T) is associated with episodic ataxia type 5, idiopathic generalized epilepsy (ClinVar).

How common is CACNB4 p.Ser3Phe (c.8C>T) in the general population?

CACNB4 p.Ser3Phe (c.8C>T) is rare (popmax 0.184%, 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.Ser3Phe (c.8C>T)?

AlphaMissense predicts likely benign (score 0.115) — an in-silico prediction, not a clinical call.

CACNB4 p.Ser3Phe

c.8C>T · rs542973906 · VCV204938

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.115 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.184%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

episodic ataxia type 5

Computational evidence

Protein change
AlphaMissense	0.115	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -7.66	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 6.3	GERP 1.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 642 bp · p 0.71 · regional, not allelic
Overall
CADD	22.4	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 0.184% Middle Eastern · 9/4,894 alleles

Filtering AF 0.0959% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0716%

Overall 0.0292% 448/1,535,312 alleles · rare exomes 413/1,383,066 · genomes 35/152,246 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.184%	544
South Asian	0.0451%	2,217
Remaining individualsnot grpmax-eligible	0.0405%	2,470
Ashkenazi Jewishnot grpmax-eligible	0.0361%	2,771
European (non-Finnish)	0.0313%	3,193
Finnishnot grpmax-eligible	0.01%	9,961
African / African-American	0.00417%	23,953
Admixed American	0.00218%	45,944

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.Ser3Phe
Coding: c.8C>T
MANE Select: NM_000726
dbSNP: rs542973906
Type: single nucleotide variant
Location: chr2:152099004 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.29 · 1 PDB
Residue 3: 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

For Episodic ataxia type 5 (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

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.Arg506Gln Uncertain significance ★★ ⚠ same condition
CACNB4 p.Arg517Gln Uncertain significance ★★ ⚠ same condition
CACNB4 p.Arg517Ter 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-ser3phe (accessed [today's date]).

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