CACNA1D p.Ile448=
c.1344C>T · rs145203578 · VCV504765
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 10 submitters
gnomAD v4.1
Rare
rare (popmax 0.413%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.044 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -4.9 | GERP -5.5 |
| Overall | ||
| CADD | 3.95 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.413%
Middle Eastern · 25/6,058 alleles
Filtering AF
0.287%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.245%
Overall
0.134%
2,162/1,614,168 alleles · rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.413% | 242 |
| Remaining individualsnot grpmax-eligible | 0.194% | 517 |
| European (non-Finnish) | 0.156% | 639 |
| Admixed American | 0.133% | 750 |
| South Asian | 0.0494% | 2,024 |
| African / African-American | 0.032% | 3,126 |
| Finnishnot grpmax-eligible | 0.0265% | 3,767 |
| East Asian | 0.00668% | 14,961 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,608 |
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
- CACNA1D
- Protein
- p.Ile448=
- Coding
- c.1344C>T
- MANE Select
- NM_001128840
- dbSNP
- rs145203578
- Type
- single nucleotide variant
- Location
- chr3:53702764 (GRCh38)
- Gene constraint
- LOEUF 0.253 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 64.60 · 6 PDB
Similar variants
- CACNA1D p.Ile448Thr Uncertain significance ★ ⚠ same residue
- CACNA1D p.Ile448Val Uncertain significance ★ ⚠ same residue
- CACNA1D p.Ser652Leu Pathogenic/Likely pathogenic ★★ same type
- CACNA1D c.1892+3A>G Uncertain significance ★★ same type
- CACNA1D c.2406+3A>G Uncertain significance ★★ same type
- CACNA1D c.2474-1G>A Uncertain significance ★★ same type
- CACNA1D c.2474-2A>C Uncertain significance ★★ same type
- CACNA1D c.2751+2T>C 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/cacna1d-p-ile448 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown