Is AP4E1 p.Leu284= (c.852A>G) pathogenic?

AP4E1 p.Leu284= (c.852A>G) is classified Conflicting classifications of pathogenicity in AP4E1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-21). Rare (popmax 0.909%, afr); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Leu284= (c.852A>G)?

AP4E1 p.Leu284= (c.852A>G) is associated with Spastic paraplegia, hereditary spastic paraplegia (ClinVar).

How common is AP4E1 p.Leu284= (c.852A>G) in the general population?

AP4E1 p.Leu284= (c.852A>G) is rare (popmax 0.909%, afr) (gnomAD).

AP4E1 p.Leu284=

c.852A>G · rs114575519 · VCV695485

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.909%, afr)

Conditions

Spastic paraplegia

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 2.7	GERP 1.7, phastCons 1
Overall
CADD	7.291	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.909% African / African-American · 682/75,038 alleles

Filtering AF 0.852% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.83%

Overall 0.0553% 893/1,614,128 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.909%	110
Middle Eastern	0.182%	551
Admixed American	0.132%	760
Remaining individualsnot grpmax-eligible	0.0896%	1,116
South Asian	0.00988%	10,120
European (non-Finnish)	0.00466%	21,455
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600

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.Leu284=
Coding: c.852A>G
MANE Select: NM_007347
dbSNP: rs114575519
Type: single nucleotide variant
Location: chr15:50930954 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB

Full AP4E1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia

Similar variants

AP4E1 p.Arg304Ter Pathogenic/Likely pathogenic ★★ same condition
AP4E1 p.Ala119Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Ala45Thr Uncertain significance ★★ ⚠ same condition
AP4E1 p.Ala475Val Uncertain significance ★★ ⚠ same condition
AP4E1 p.Arg646Cys Uncertain significance ★★ same condition
AP4E1 p.Asn1086Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Asn311Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Asp484Val Uncertain significance ★★ ⚠ same condition

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-leu284 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown