APPL1 p.Arg339=
c.1015C>A · rs371202748 · VCV2974200
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0323%, afr)
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 0.8 | GERP 0.28, phastCons 1 |
| Overall | ||
| CADD | 7.455 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0323%
African / African-American · 24/74,360 alleles
Filtering AF
0.0222%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0189%
Overall
0.00162%
26/1,600,106 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0323% | 3,098 |
| Middle Eastern | 0.0167% | 5,992 |
| Remaining individualsnot grpmax-eligible | 0.00162% | 61,820 |
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.Arg339=
- Coding
- c.1015C>A
- MANE Select
- NM_012096
- dbSNP
- rs371202748
- Type
- single nucleotide variant
- Location
- chr3:57249511 (GRCh38)
- Gene constraint
- LOEUF 0.524 · pLI 0.88 (gnomAD)
- Structure
- AlphaFold pLDDT 81.44 · 8 PDB
- Residue 339
- the ph domain; the 'required for rab5a binding' region; a β-strand
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-arg339 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown