CACNA2D2 p.Ile221=
c.663C>A · rs56287038 · VCV1168147
Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Common
common (popmax 30.7%, afr) — too common for a highly-penetrant pathogenic allele
Conditions
1
early-infantile DEE
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.24 | acceptor gain · deltas |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 3 | GERP -2.8, phastCons 1 |
| Overall | ||
| CADD | 15.98 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
30.7%
African / African-American · 22,975/74,784 alleles
Filtering AF
30.4%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 30.3%
Overall
4.2%
67,660/1,611,958 alleles · common
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 30.7% | 3 |
| Ashkenazi Jewishnot grpmax-eligible | 13.1% | 8 |
| Middle Eastern | 11.7% | 9 |
| Remaining individualsnot grpmax-eligible | 6.03% | 17 |
| Admixed American | 4.48% | 22 |
| South Asian | 4.33% | 23 |
| European (non-Finnish) | 2.49% | 40 |
| Finnishnot grpmax-eligible | 0.549% | 182 |
| Amishnot grpmax-eligible | 0.11% | 912 |
| East Asian | 0.0179% | 5,598 |
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.Ile221=
- Coding
- c.663C>A
- MANE Select
- NM_006030
- dbSNP
- rs56287038
- Type
- single nucleotide variant
- Location
- chr3:50381116 (GRCh38)
- Gene constraint
- LOEUF 0.396 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 81.48
Similar variants
- 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.Arg188Ser Uncertain significance ★★ ⚠ same condition
- CACNA2D2 p.Arg422Cys 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-ile221 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown