Is AP4E1 p.Pro1096= (c.3288A>G) pathogenic?

AP4E1 p.Pro1096= (c.3288A>G) is classified Conflicting classifications of pathogenicity in AP4E1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-20). Very rare (popmax 0.00263%, nfe); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Pro1096= (c.3288A>G)?

AP4E1 p.Pro1096= (c.3288A>G) is associated with Spastic paraplegia, hereditary spastic paraplegia (ClinVar).

How common is AP4E1 p.Pro1096= (c.3288A>G) in the general population?

AP4E1 p.Pro1096= (c.3288A>G) is very rare (popmax 0.00263%, nfe) (gnomAD).

AP4E1 p.Pro1096=

c.3288A>G · rs764886183 · VCV700538

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 0.00263%, nfe)

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 -0.66	GERP -3.2
Overall
CADD	6.618	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00263% European (non-Finnish) · 31/1,180,020 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00204% 33/1,614,004 alleles · very rare exomes 31/1,461,860 · genomes 2/152,144 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00263%	38,065
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00134%	74,900

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.Pro1096=
Coding: c.3288A>G
MANE Select: NM_007347
dbSNP: rs764886183
Type: single nucleotide variant
Location: chr15:51002536 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB
Residue 1096: the 'interaction with tepsin' region

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-pro1096 (accessed [today's date]).

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