Is AP4E1 p.Asp300Val (c.899A>T) pathogenic?

AP4E1 p.Asp300Val (c.899A>T) is classified Uncertain significance in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-10). AlphaMissense: ambiguous (0.4199); Very rare (popmax 0.00655%, nfe); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Asp300Val (c.899A>T)?

AP4E1 p.Asp300Val (c.899A>T) is associated with Spastic paraplegia (ClinVar).

How common is AP4E1 p.Asp300Val (c.899A>T) in the general population?

AP4E1 p.Asp300Val (c.899A>T) is very rare (popmax 0.00655%, nfe) (gnomAD).

What do computational predictors say about AP4E1 p.Asp300Val (c.899A>T)?

AlphaMissense predicts ambiguous (score 0.4199) — an in-silico prediction, not a clinical call.

AP4E1 p.Asp300Val

c.899A>T · rs200153804 · VCV1423786

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00655%, nfe)

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.4199	ambiguous
REVEL	0.391	indeterminate
SaProt	LLR -7.85	tolerated
Splicing
SpliceAI	Δ0.29	donor loss, 44 bp away · masked 0 · deltas
Pangolin	Δ0.21	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	26.1	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 0.00655% European (non-Finnish) · 77/1,175,914 alleles

Filtering AF 0.00532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00491%

Overall 0.00485% 78/1,608,958 alleles · very rare exomes 76/1,456,878 · genomes 2/152,080 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00655%	15,272
Remaining individualsnot grpmax-eligible	0.00161%	62,280

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.Asp300Val
Coding: c.899A>T
MANE Select: NM_007347
dbSNP: rs200153804
Type: single nucleotide variant
Location: chr15:50934653 (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.Asp300= Likely benign ★ 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
AP4E1 p.Asp484Val 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-asp300val (accessed [today's date]).

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