Is CACNA1A p.Pro2223Ser (c.6667C>T) pathogenic?

CACNA1A p.Pro2223Ser (c.6667C>T) is classified Conflicting classifications of pathogenicity in CACNA1A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-24). AlphaMissense: likely benign (0.0623); Ultra-rare (popmax 0.0196%, amr); Associated with Inborn genetic diseases.

What condition is associated with CACNA1A p.Pro2223Ser (c.6667C>T)?

CACNA1A p.Pro2223Ser (c.6667C>T) is associated with Inborn genetic diseases, episodic ataxia type 2, developmental and epileptic encephalopathy, 42 (ClinVar).

How common is CACNA1A p.Pro2223Ser (c.6667C>T) in the general population?

CACNA1A p.Pro2223Ser (c.6667C>T) is ultra-rare (popmax 0.0196%, amr) (gnomAD).

What do computational predictors say about CACNA1A p.Pro2223Ser (c.6667C>T)?

AlphaMissense predicts likely benign (score 0.0623) — an in-silico prediction, not a clinical call.

CACNA1A p.Pro2223Ser

c.6667C>T · rs768221184 · VCV589905

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0623 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0196%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0623	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -6.43	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 1.7	GERP -3.2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 6,952 bp · p 0.039 · regional, not allelic
Overall
CADD	12.94	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 0.0196% Admixed American · 10/50,970 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00809%

Overall 0.000846% 13/1,536,142 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0196%	5,097
Remaining individualsnot grpmax-eligible	0.00334%	29,981
South Asian	0.00119%	84,022

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: CACNA1A
Protein: p.Pro2223Ser
Coding: c.6667C>T
MANE Select: NM_001127222
dbSNP: rs768221184
Type: single nucleotide variant
Location: chr19:13208869 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.34 · 4 PDB
Residue 2223: a UniProt-annotated variant site (in ea2 and sca6); the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: episodic ataxia type 2 developmental and epileptic encephalopathy, 42

Similar variants

CACNA1A p.Pro2223= Likely benign ★ same residue
CACNA1A p.Pro2223del Uncertain significance ★ same residue
CACNA1A c.1082+1G>A Pathogenic ★★ same condition
CACNA1A c.1198+1G>A Pathogenic/Likely pathogenic ★★ same condition
CACNA1A c.2105-2A>G Likely pathogenic ★★ same condition
CACNA1A c.3692+1G>A Pathogenic/Likely pathogenic ★★ same condition
CACNA1A c.3822+1G>A Pathogenic ★★ same condition
CACNA1A c.3989+1G>A 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-pro2223ser (accessed [today's date]).

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