Is CACNA2D2 p.Val835fs (c.2503del) pathogenic?

CACNA2D2 p.Val835fs (c.2503del) is classified Pathogenic in CACNA2D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-05). Very rare (popmax 8.47e-05%, nfe); Associated with early-infantile DEE.

What condition is associated with CACNA2D2 p.Val835fs (c.2503del)?

CACNA2D2 p.Val835fs (c.2503del) is associated with early-infantile DEE (ClinVar).

How common is CACNA2D2 p.Val835fs (c.2503del) in the general population?

CACNA2D2 p.Val835fs (c.2503del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CACNA2D2 p.Val835fs

c.2503del · VCV3652194

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, 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 29 of 38
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,004 alleles

Overall 0.000657% 1/152,114 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.Val835fs
Coding: c.2503del
MANE Select: NM_006030
Type: Deletion
Location: chr3:50366917 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48
Residue 835: a disulfide bond

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

Similar variants

CACNA2D2 c.1773+20_1773+21del Benign ★★ same condition
CACNA2D2 c.2144-16_2144-15del Likely benign ★★ same condition
CACNA2D2 c.1626+1_1626+32del Likely pathogenic ★ same condition
CACNA2D2 c.206_206+34del Likely pathogenic ★ same condition
CACNA2D2 p.Ala442fs Pathogenic ★ same condition
CACNA2D2 p.Asn432_Tyr433insTer Pathogenic ★ same condition
CACNA2D2 p.Asn652fs Pathogenic ★ same condition
CACNA2D2 p.Asp291fs 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/cacna2d2-p-val835fs (accessed [today's date]).

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