Is CACNA2D2 p.Pro1131= (c.3393G>A) pathogenic?

CACNA2D2 p.Pro1131= (c.3393G>A) is classified Benign/Likely benign in CACNA2D2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Low-frequency (popmax 1.73%, afr); Associated with early-infantile DEE.

What condition is associated with CACNA2D2 p.Pro1131= (c.3393G>A)?

CACNA2D2 p.Pro1131= (c.3393G>A) is associated with early-infantile DEE, cerebellar atrophy with seizures and variable developmental delay (ClinVar).

How common is CACNA2D2 p.Pro1131= (c.3393G>A) in the general population?

CACNA2D2 p.Pro1131= (c.3393G>A) is low-frequency (popmax 1.73%, afr) (gnomAD).

CACNA2D2 p.Pro1131=

c.3393G>A · rs145772306 · VCV240278

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.73%, afr)

Conditions

early-infantile DEE

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 -2.9	GERP -4.2
Overall
CADD	4.777	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.73% African / African-American · 1,258/72,830 alleles

Filtering AF 1.65% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.62%

Overall 0.0989% 1,527/1,544,338 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.73%	58
Middle Eastern	0.236%	423
Admixed American	0.197%	509
Remaining individualsnot grpmax-eligible	0.132%	755
South Asian	0.00832%	12,014
European (non-Finnish)	0.00647%	15,464

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.Pro1131=
Coding: c.3393G>A
MANE Select: NM_006030
dbSNP: rs145772306
Type: single nucleotide variant
Location: chr3:50364705 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48

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.Pro1131Leu Uncertain significance ★ ⚠ same residue
CACNA2D2 c.2234+1G>A Likely pathogenic ★★ same condition
CACNA2D2 p.Gln519Ter Pathogenic/Likely pathogenic ★★ same condition
CACNA2D2 c.1907+3A>C Uncertain significance ★★ same condition
CACNA2D2 c.785-3C>T Uncertain significance ★★ same condition
CACNA2D2 p.Ala1096Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Arg1039Lys 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-pro1131 (accessed [today's date]).

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