Is AP4E1 p.Asp367Val (c.1100A>T) pathogenic?

AP4E1 p.Asp367Val (c.1100A>T) is classified Uncertain significance in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.3942); Very rare (popmax 0.00144%, nfe); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Asp367Val (c.1100A>T)?

AP4E1 p.Asp367Val (c.1100A>T) is associated with Spastic paraplegia (ClinVar).

How common is AP4E1 p.Asp367Val (c.1100A>T) in the general population?

AP4E1 p.Asp367Val (c.1100A>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about AP4E1 p.Asp367Val (c.1100A>T)?

AlphaMissense predicts ambiguous (score 0.3942) — an in-silico prediction, not a clinical call.

AP4E1 p.Asp367Val

c.1100A>T · VCV4763487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.3942	ambiguous
REVEL	0.636	indeterminate
SaProt	LLR -0.43	tolerated
Splicing
SpliceAI	Δ0.34	acceptor gain · deltas
Pangolin	Δ0.41	gain · loss 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	31.0	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 0.00144% European (non-Finnish) · 17/1,179,782 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00105% 17/1,613,626 alleles · very rare

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.Asp367Val
Coding: c.1100A>T
MANE Select: NM_007347
Type: single nucleotide variant
Location: chr15:50941699 (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.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-asp367val (accessed [today's date]).

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