Is CACNA1A p.Pro1103= (c.3309C>T) pathogenic?

CACNA1A p.Pro1103= (c.3309C>T) is classified Conflicting classifications of pathogenicity in CACNA1A (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-19). Rare (popmax 0.105%, afr); Associated with developmental and epileptic encephalopathy, 42.

What condition is associated with CACNA1A p.Pro1103= (c.3309C>T)?

CACNA1A p.Pro1103= (c.3309C>T) is associated with developmental and epileptic encephalopathy, 42, episodic ataxia type 2 (ClinVar).

How common is CACNA1A p.Pro1103= (c.3309C>T) in the general population?

CACNA1A p.Pro1103= (c.3309C>T) is rare (popmax 0.105%, afr) (gnomAD).

CACNA1A p.Pro1103=

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.3309C>T · rs374749004 · VCV195472

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.105%, afr)

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 -2.4	GERP -4.9
Overall
CADD	3.149	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.105% African / African-American · 79/74,912 alleles

Filtering AF 0.0867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0798%

Overall 0.0374% 601/1,607,292 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.133%	753
African / African-Americangrpmax	0.105%	948
Remaining individualsnot grpmax-eligible	0.0514%	1,945
European (non-Finnish)	0.0331%	3,025
South Asian	0.0209%	4,777

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1103=
Coding: c.3309C>T
MANE Select: NM_001127222
dbSNP: rs374749004
Type: single nucleotide variant
Location: chr19:13286747 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.34 · 4 PDB
Residue 1103: 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.Pro1103Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CACNA1A p.Pro1103Ser 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-pro1103 (accessed [today's date]).

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