Is AP4E1 p.Leu487Phe (c.1461A>T) pathogenic?

AP4E1 p.Leu487Phe (c.1461A>T) is classified Uncertain significance in AP4E1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-11). AlphaMissense: ambiguous (0.4352); Rare (popmax 0.107%, sas); Associated with Inborn genetic diseases.

What condition is associated with AP4E1 p.Leu487Phe (c.1461A>T)?

AP4E1 p.Leu487Phe (c.1461A>T) is associated with Inborn genetic diseases (ClinVar).

How common is AP4E1 p.Leu487Phe (c.1461A>T) in the general population?

AP4E1 p.Leu487Phe (c.1461A>T) is rare (popmax 0.107%, sas) (gnomAD).

What do computational predictors say about AP4E1 p.Leu487Phe (c.1461A>T)?

AlphaMissense predicts ambiguous (score 0.4352) — an in-silico prediction, not a clinical call.

AP4E1 p.Leu487Phe

c.1461A>T · rs774800945 · VCV1403556

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4352 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4352	ambiguous
REVEL	0.196	benign-leaning
SaProt	LLR -8.78	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -0.66, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	20.6	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 0.107% South Asian · 97/91,076 alleles

Filtering AF 0.0893% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0829%

Overall 0.0062% 100/1,613,330 alleles · rare exomes 97/1,461,074 · genomes 3/152,256 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.107%	939
Remaining individualsnot grpmax-eligible	0.0048%	20,819

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.Leu487Phe
Coding: c.1461A>T
MANE Select: NM_007347
dbSNP: rs774800945
Type: single nucleotide variant
Location: chr15:50950082 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AP4E1 p.Leu487= Likely benign ★★ same residue
AP4E1 p.Ala65Val Uncertain significance ★★ ⚠ same condition
AP4E1 p.Ala678Val Uncertain significance ★★ ⚠ same condition
AP4E1 p.Arg304Gln Uncertain significance ★★ ⚠ same condition
AP4E1 p.Asp218Gly Uncertain significance ★★ ⚠ same condition
AP4E1 p.Gln1093Glu Uncertain significance ★★ ⚠ same condition
AP4E1 p.Gln375Pro Uncertain significance ★★ ⚠ same condition
AP4E1 p.Gln989Arg 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-leu487phe (accessed [today's date]).

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