Is AP4E1 p.Val454fs (c.1358_1359dup) pathogenic?

AP4E1 p.Val454fs (c.13581359dup) is classified Likely pathogenic in AP4E1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-10-01). No gnomAD frequency available for this variant; Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Val454fs (c.1358_1359dup)?

AP4E1 p.Val454fs (c.1358_1359dup) is associated with Spastic paraplegia (ClinVar).

How common is AP4E1 p.Val454fs (c.1358_1359dup) in the general population?

AP4E1 p.Val454fs (c.1358_1359dup) is no gnomAD frequency available for this variant (gnomAD).

AP4E1 p.Val454fs

c.1358_1359dup · rs2140861869 · VCV1344793

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: AP4E1
Protein: p.Val454fs
Coding: c.1358_1359dup
MANE Select: NM_007347
dbSNP: rs2140861869
Type: Duplication
Location: chr15:50949866 (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

Similar variants

AP4E1 c.1851+2_1851+5dup Uncertain significance ★★ same condition
AP4E1 c.1966+3_1966+6dup Benign/Likely benign ★★ same condition
AP4E1 c.222+17dup Likely benign ★ same condition
AP4E1 c.703-7dup Benign ★ same condition
AP4E1 c.942_943+3delinsCC Pathogenic/Likely pathogenic ★★ same condition
AP4E1 p.Arg304Ter Pathogenic/Likely pathogenic ★★ same condition
AP4E1 p.Leu1072fs Pathogenic/Likely pathogenic ★★ same condition
AP4E1 p.Ala119Ser 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-val454fs (accessed [today's date]).

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