AP4E1 p.Ser331=
c.993G>A · VCV3342971
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00483%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.48 | acceptor gain · deltas |
|---|---|---|
| Pangolin | Δ0.27 | loss · gain 0.10 · SpliceAI calls gain · independent |
| Constraint at this position | ||
| Conservation | phyloP -0.19 | GERP -3.7, phastCons 0.006 |
| Overall | ||
| CADD | 16.36 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00483%
European (non-Finnish) · 57/1,179,406 alleles
Filtering AF
0.00378%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00345%
Overall
0.00384%
62/1,612,724 alleles · very rare
exomes 58/1,460,646 · genomes 4/152,078 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00483% | 20,691 |
| Remaining individualsnot grpmax-eligible | 0.00481% | 20,807 |
| East Asian | 0.00223% | 44,794 |
| African / African-American | 0.00134% | 74,856 |
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
- AP4E1
- Protein
- p.Ser331=
- Coding
- c.993G>A
- MANE Select
- NM_007347
- Type
- single nucleotide variant
- Location
- chr15:50941491 (GRCh38)
- Gene constraint
- LOEUF 0.576 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 72.42 · 4 PDB
Similar variants
- AP4E1 p.Ser331Leu Uncertain significance ★★ ⚠ same residue
- AP4E1 p.Arg1105Ter Pathogenic ★★ same type
- AP4E1 p.Arg304Ter Pathogenic/Likely pathogenic ★★ same type
- AP4E1 p.Ala119Ser Uncertain significance ★★ ⚠ same type
- AP4E1 p.Ala45Thr Uncertain significance ★★ ⚠ same type
- AP4E1 p.Ala475Val Uncertain significance ★★ ⚠ same type
- AP4E1 p.Ala65Val Uncertain significance ★★ ⚠ same type
- AP4E1 p.Ala678Val 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/ap4e1-p-ser331 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown