Is CACNA1A p.Pro2047= (c.6141G>A) pathogenic?

CACNA1A p.Pro2047= (c.6141G>A) is classified Conflicting classifications of pathogenicity in CACNA1A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-27). Ultra-rare (popmax 0.0156%, eas); Associated with developmental and epileptic encephalopathy, 42.

What condition is associated with CACNA1A p.Pro2047= (c.6141G>A)?

CACNA1A p.Pro2047= (c.6141G>A) is associated with developmental and epileptic encephalopathy, 42, episodic ataxia type 2 (ClinVar).

How common is CACNA1A p.Pro2047= (c.6141G>A) in the general population?

CACNA1A p.Pro2047= (c.6141G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

CACNA1A p.Pro2047=

Q: How is Non-specific early-onset epileptic encephalopathy inherited?

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

c.6141G>A · rs760682283 · VCV597706

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

developmental and epileptic encephalopathy, 42

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 -15	GERP -4
Overall
CADD	0.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,846 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000992% 16/1,612,754 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,407
Admixed American	0.00335%	29,884
Remaining individualsnot grpmax-eligible	0.0016%	62,420
African / African-American	0.00134%	74,880
European (non-Finnish)	0.000424%	235,903

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.Pro2047=
Coding: c.6141G>A
MANE Select: NM_001127222
dbSNP: rs760682283
Type: single nucleotide variant
Location: chr19:13212432 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.34 · 4 PDB
Residue 2047: 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

developmental and epileptic encephalopathy, 42 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: episodic ataxia type 2

For Non-specific early-onset epileptic encephalopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Infancy, Neonatal

Similar variants

CACNA1A p.Pro2047Leu Conflicting classifications of pathogenicity ★ ⚠ 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
CACNA1A c.3989+1G>T 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-pro2047 (accessed [today's date]).

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