Is AP4E1 p.Leu1065Pro (c.3194T>C) pathogenic?

AP4E1 p.Leu1065Pro (c.3194T>C) is classified Uncertain significance in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). AlphaMissense: ambiguous (0.4918); Absent from gnomAD v4.1; Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Leu1065Pro (c.3194T>C)?

AP4E1 p.Leu1065Pro (c.3194T>C) is associated with Spastic paraplegia (ClinVar).

How common is AP4E1 p.Leu1065Pro (c.3194T>C) in the general population?

AP4E1 p.Leu1065Pro (c.3194T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AP4E1 p.Leu1065Pro (c.3194T>C)?

AlphaMissense predicts ambiguous (score 0.4918) — an in-silico prediction, not a clinical call.

AP4E1 p.Leu1065Pro

c.3194T>C · rs2140939426 · VCV1492872

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4918 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.4918	ambiguous
REVEL	0.291	indeterminate
SaProt	LLR -7.58	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AP4E1
Protein: p.Leu1065Pro
Coding: c.3194T>C
MANE Select: NM_007347
dbSNP: rs2140939426
Type: single nucleotide variant
Location: chr15:51001124 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB
Residue 1065: 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

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.Asp484Val Uncertain significance ★★ ⚠ same condition
AP4E1 p.Asp938Gly 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-leu1065pro (accessed [today's date]).

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