APPL1 p.Phe89=
c.267T>C · rs2528759616 · VCV2705460
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 6.86e-05%)
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 3.5 | GERP 0.69, phastCons 1 |
| Overall | ||
| CADD | 9.981 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
6.86e-05%
Overall
6.86e-05%
1/1,458,632 alleles · very rare
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.Phe89=
- Coding
- c.267T>C
- MANE Select
- NM_012096
- dbSNP
- rs2528759616
- Type
- single nucleotide variant
- Location
- chr3:57238098 (GRCh38)
- Gene constraint
- LOEUF 0.524 · pLI 0.88 (gnomAD)
- Structure
- AlphaFold pLDDT 81.44 · 8 PDB
- Residue 89
- the bar domain; an α-helix; 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-phe89 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown