APPL1 p.Ala394=
c.1182T>C · VCV4740793
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
rare (popmax 0.176%, eas)
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 0.92 | GERP -1.2, phastCons 1 |
| Overall | ||
| CADD | 9.569 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.176%
East Asian · 79/44,882 alleles
Filtering AF
0.145%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.133%
Overall
0.0065%
105/1,614,176 alleles · rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.176% | 568 |
| South Asian | 0.022% | 4,554 |
| Remaining individualsnot grpmax-eligible | 0.008% | 12,502 |
| European (non-Finnish) | 8.47e-05% | 1,180,036 |
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
- APPL1
- Protein
- p.Ala394=
- Coding
- c.1182T>C
- MANE Select
- NM_012096
- Type
- single nucleotide variant
- Location
- chr3:57256986 (GRCh38)
- Gene constraint
- LOEUF 0.524 · pLI 0.88 (gnomAD)
- Structure
- AlphaFold pLDDT 81.44 · 8 PDB
- Residue 394
- the 'required for rab5a binding' region
Similar variants
- APPL1 c.1658+6T>G Uncertain significance ★★ same type
- APPL1 p.Arg275Gln Uncertain significance ★★ ⚠ same type
- APPL1 p.Arg407Ser Uncertain significance ★★ ⚠ same type
- APPL1 p.Arg412Trp Uncertain significance ★★ ⚠ same type
- APPL1 p.Arg478Cys Uncertain significance ★★ ⚠ same type
- APPL1 p.Arg526His Uncertain significance ★★ ⚠ same type
- APPL1 p.Arg633His Uncertain significance ★★ ⚠ same type
- APPL1 p.Arg72Cys 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/appl1-p-ala394 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown