Is AP4E1 p.Ala565Glu (c.1694C>A) pathogenic?

AP4E1 p.Ala565Glu (c.1694C>A) is classified Conflicting classifications of pathogenicity in AP4E1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.1909); Rare (popmax 0.252%, afr); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Ala565Glu (c.1694C>A)?

AP4E1 p.Ala565Glu (c.1694C>A) is associated with Spastic paraplegia (ClinVar).

How common is AP4E1 p.Ala565Glu (c.1694C>A) in the general population?

AP4E1 p.Ala565Glu (c.1694C>A) is rare (popmax 0.252%, afr) (gnomAD).

What do computational predictors say about AP4E1 p.Ala565Glu (c.1694C>A)?

AlphaMissense predicts likely benign (score 0.1909) — an in-silico prediction, not a clinical call.

AP4E1 p.Ala565Glu

c.1694C>A · rs142762839 · VCV434234

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1909 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.252%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1909	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	16.21	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 0.252% African / African-American · 189/75,036 alleles

Filtering AF 0.223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.211%

Overall 0.0125% 201/1,614,132 alleles · rare exomes 88/1,461,838 · genomes 113/152,294 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.252%	397
Admixed American	0.00666%	15,005
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)	0.000339%	295,005

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.Ala565Glu
Coding: c.1694C>A
MANE Select: NM_007347
dbSNP: rs142762839
Type: single nucleotide variant
Location: chr15:50958637 (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.Ala565Val Conflicting classifications of pathogenicity ★ ⚠ same residue
AP4E1 p.Ala565Thr 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-ala565glu (accessed [today's date]).

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