Is AP4E1 p.Ala565Val (c.1694C>T) pathogenic?

AP4E1 p.Ala565Val (c.1694C>T) is classified Conflicting classifications of pathogenicity in AP4E1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0842); Ultra-rare (popmax 0.0825%, eas); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Ala565Val (c.1694C>T)?

AP4E1 p.Ala565Val (c.1694C>T) is associated with Spastic paraplegia, hereditary spastic paraplegia (ClinVar).

How common is AP4E1 p.Ala565Val (c.1694C>T) in the general population?

AP4E1 p.Ala565Val (c.1694C>T) is ultra-rare (popmax 0.0825%, eas) (gnomAD).

What do computational predictors say about AP4E1 p.Ala565Val (c.1694C>T)?

AlphaMissense predicts likely benign (score 0.0842) — an in-silico prediction, not a clinical call.

AP4E1 p.Ala565Val

c.1694C>T · rs142762839 · VCV568340

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0842 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0842	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -4.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	18.72	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 0.0825% East Asian · 37/44,868 alleles

Filtering AF 0.0615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.0216% 349/1,614,132 alleles · ultra-rare exomes 324/1,461,838 · genomes 25/152,294 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0825%	1,213
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.04%	2,500
South Asian	0.0318%	3,141
European (non-Finnish)	0.0202%	4,958
African / African-American	0.012%	8,337
Admixed American	0.00833%	12,004
Finnishnot grpmax-eligible	0.00312%	32,011

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.Ala565Val
Coding: c.1694C>T
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

Also linked: hereditary spastic paraplegia

Similar variants

AP4E1 p.Ala565Glu 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-ala565val (accessed [today's date]).

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