Is CACNA2D2 p.Arg35fs (c.97_103dup) pathogenic?

CACNA2D2 p.Arg35fs (c.97103dup) is classified Pathogenic/Likely pathogenic in CACNA2D2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-13). Very rare (popmax 0.000222%, nfe); Associated with early-infantile DEE.

What condition is associated with CACNA2D2 p.Arg35fs (c.97_103dup)?

CACNA2D2 p.Arg35fs (c.97_103dup) is associated with early-infantile DEE, cerebellar atrophy with seizures and variable developmental delay (ClinVar).

How common is CACNA2D2 p.Arg35fs (c.97_103dup) in the general population?

CACNA2D2 p.Arg35fs (c.97_103dup) is very rare (popmax 0.000222%, nfe) (gnomAD).

CACNA2D2 p.Arg35fs

c.97_103dup · rs1451909068 · VCV1070772

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000222%, nfe)

Conditions

early-infantile DEE

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 1 of 38
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.58	GERP -2.2, phastCons 0.93
Overall
CADD	19.76	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	G-rich low complexity · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000222% European (non-Finnish) · 1/450,444 alleles

Overall 0.000665% 1/150,312 alleles · very rare

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: CACNA2D2
Protein: p.Arg35fs
Coding: c.97_103dup
MANE Select: NM_006030
dbSNP: rs1451909068
Type: Duplication
Location: chr3:50503320 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48
Residue 35: the 'disordered' region

Full CACNA2D2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

early-infantile DEE — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebellar atrophy with seizures and variable developmental delay

Similar variants

CACNA2D2 p.Asp139fs Pathogenic ★ same condition
CACNA2D2 p.Gln79fs Pathogenic ★ same condition
CACNA2D2 p.His899fs Pathogenic ★ same condition
CACNA2D2 p.Leu882fs Pathogenic ★ same condition
CACNA2D2 p.Phe891fs Pathogenic ★ same condition
CACNA2D2 c.3099-9dup Conflicting classifications of pathogenicity ★ same condition
CACNA2D2 p.Arg34_Pro40dup Uncertain significance ★ same condition
CACNA2D2 p.Gln1132fs 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/cacna2d2-p-arg35fs (accessed [today's date]).

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