Is AP4E1 p.Ser522Pro (c.1564T>C) pathogenic?

AP4E1 p.Ser522Pro (c.1564T>C) is classified Uncertain significance in AP4E1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.7787); Very rare (popmax 0.000424%, nfe); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Ser522Pro (c.1564T>C)?

AP4E1 p.Ser522Pro (c.1564T>C) is associated with Spastic paraplegia (ClinVar).

How common is AP4E1 p.Ser522Pro (c.1564T>C) in the general population?

AP4E1 p.Ser522Pro (c.1564T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about AP4E1 p.Ser522Pro (c.1564T>C)?

AlphaMissense predicts likely pathogenic (score 0.7787) — an in-silico prediction, not a clinical call.

AP4E1 p.Ser522Pro

c.1564T>C · rs760209129 · VCV2081988

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7787 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.7787	likely pathogenic
REVEL	0.27	benign-leaning
SaProt	LLR -13.86	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	23.7	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

Grpmax group 0.000424% European (non-Finnish) · 5/1,178,914 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,612,112 alleles · very rare exomes 4/1,459,892 · genomes 1/152,220 · joint denominator

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.Ser522Pro
Coding: c.1564T>C
MANE Select: NM_007347
dbSNP: rs760209129
Type: single nucleotide variant
Location: chr15:50958507 (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 p.Ser522= Likely benign ★★ same residue
AP4E1 p.Ser522Phe Uncertain significance ★ ⚠ same residue
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

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-ser522pro (accessed [today's date]).

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