CACNA2D4 p.Ala331=
c.993G>A · rs775365422 · VCV1414039
Uncertain significance
Multiple submitters
Classification
Uncertain significance
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0275%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.90 | donor loss at this position · masked 0 · deltas |
|---|---|---|
| Pangolin | Δ0.75 | loss · gain 0.01 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 0.08 | GERP -2.8, phastCons 0.91 |
| Overall | ||
| CADD | 19.07 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0275%
South Asian · 25/91,056 alleles
Filtering AF
0.019%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0163%
Overall
0.00229%
37/1,612,414 alleles · ultra-rare
exomes 34/1,460,348 · genomes 3/152,066 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0275% | 3,642 |
| African / African-American | 0.00401% | 24,938 |
| East Asian | 0.00223% | 44,884 |
| Admixed American | 0.00167% | 59,994 |
| Finnishnot grpmax-eligible | 0.00156% | 63,992 |
| European (non-Finnish) | 0.000509% | 196,448 |
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
- CACNA2D4
- Protein
- p.Ala331=
- Coding
- c.993G>A
- MANE Select
- NM_172364
- dbSNP
- rs775365422
- Type
- single nucleotide variant
- Location
- chr12:1886223 (GRCh38)
- Gene constraint
- LOEUF 1.175 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 81.69
- Residue 331
- the vwfa domain
Similar variants
- CACNA2D4 p.Ala331Val Uncertain significance ★ ⚠ same residue
- CACNA2D4 c.1272+1G>C Uncertain significance ★★ same type
- CACNA2D4 c.1644+5G>A Uncertain significance ★★ same type
- CACNA2D4 c.1719+4G>A Uncertain significance ★★ same type
- CACNA2D4 c.1940+5G>A Uncertain significance ★★ same type
- CACNA2D4 c.2055-1G>A Uncertain significance ★★ same type
- CACNA2D4 c.2055-3C>T Uncertain significance ★★ same type
- CACNA2D4 c.2342+5G>T Uncertain significance ★★ same type
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/cacna2d4-p-ala331 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown