Is CACNA1H p.Phe409= (c.1227C>T) pathogenic?

CACNA1H p.Phe409= (c.1227C>T) is classified Benign in CACNA1H (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). Very rare (popmax 0.00111%, sas); Associated with idiopathic generalized epilepsy.

What condition is associated with CACNA1H p.Phe409= (c.1227C>T)?

CACNA1H p.Phe409= (c.1227C>T) is associated with idiopathic generalized epilepsy, hyperaldosteronism, familial, type IV (ClinVar).

How common is CACNA1H p.Phe409= (c.1227C>T) in the general population?

CACNA1H p.Phe409= (c.1227C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

CACNA1H p.Phe409=

c.1227C>T · rs369331588 · VCV2952642

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00111%, 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 7.6	GERP 1.6, phastCons 1
Overall
CADD	15.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/89,932 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000207% 3/1,447,308 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	89,932
European (non-Finnish)	0.000171%	585,614

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: CACNA1H
Protein: p.Phe409=
Coding: c.1227C>T
MANE Select: NM_021098
dbSNP: rs369331588
Type: single nucleotide variant
Location: chr16:1201677 (GRCh38)
Gene constraint: LOEUF 1.059 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.35 · 5 PDB
Residue 409: an α-helix

Full CACNA1H 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

Also linked: hyperaldosteronism, familial, type IV

Similar variants

CACNA1H p.Phe409Tyr Uncertain significance ★ ⚠ same residue
CACNA1H p.Phe409Val Uncertain significance ★ ⚠ same residue
CACNA1H c.2451+4C>T Uncertain significance ★★ same condition
CACNA1H c.3154+5G>A Uncertain significance ★★ same condition
CACNA1H c.3744+1G>A Uncertain significance ★★ same condition
CACNA1H c.3969+1G>A Uncertain significance ★★ same condition
CACNA1H c.4038+4C>T Uncertain significance ★★ same condition
CACNA1H c.4038+5C>T 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/cacna1h-p-phe409 (accessed [today's date]).

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