Is CACNA1A p.Ser615Arg (c.1845C>A) pathogenic?

CACNA1A p.Ser615Arg (c.1845C>A) is classified Likely pathogenic in CACNA1A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-06). AlphaMissense: likely pathogenic (0.9984); Absent from gnomAD v4.1; Associated with CACNA1A-related disorder.

What condition is associated with CACNA1A p.Ser615Arg (c.1845C>A)?

CACNA1A p.Ser615Arg (c.1845C>A) is associated with CACNA1A-related disorder (ClinVar).

How common is CACNA1A p.Ser615Arg (c.1845C>A) in the general population?

CACNA1A p.Ser615Arg (c.1845C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CACNA1A p.Ser615Arg (c.1845C>A)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

CACNA1A p.Ser615Arg

c.1845C>A · VCV3345391

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CACNA1A-related disorder

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic ✓ concordant with ClinVar · top 6% in CACNA1A
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -13.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.45	GERP -5.5, phastCons 0.98
Regional constraint	o/e 0.37	unconstrained · MANE · 13 kb · p 3.3e-26 · regional, not allelic
Overall
CADD	21.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CACNA1A
Protein: p.Ser615Arg
Coding: c.1845C>A
MANE Select: NM_001127222
Type: single nucleotide variant
Location: chr19:13308188 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.34 · 4 PDB
Residue 615: an α-helix

Full CACNA1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CACNA1A-related disorder

Similar variants

CACNA1A p.Ser615Asn Conflicting classifications of pathogenicity ★ same residue
CACNA1A c.3989+1G>A Pathogenic ★★ same condition
CACNA1A c.978+1G>A Pathogenic/Likely pathogenic ★★ same condition
CACNA1A p.Arg1277Ter Pathogenic ★★ same condition
CACNA1A p.Arg1345Gln Pathogenic ★★ same condition
CACNA1A p.Arg1348Trp Pathogenic/Likely pathogenic ★★ same condition
CACNA1A p.Arg1351Gln Pathogenic/Likely pathogenic ★★ same condition
CACNA1A p.Arg1351Leu Likely pathogenic ★★ 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/cacna1a-p-ser615arg (accessed [today's date]).

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