Is AP4E1 p.Arg794Lys (c.2381G>A) pathogenic?

AP4E1 p.Arg794Lys (c.2381G>A) is classified Uncertain significance in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely benign (0.0821); Very rare (popmax 6.24e-05%); Associated with Inborn genetic diseases.

What condition is associated with AP4E1 p.Arg794Lys (c.2381G>A)?

AP4E1 p.Arg794Lys (c.2381G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AP4E1 p.Arg794Lys (c.2381G>A) in the general population?

AP4E1 p.Arg794Lys (c.2381G>A) is very rare (popmax 6.24e-05%) (gnomAD).

What do computational predictors say about AP4E1 p.Arg794Lys (c.2381G>A)?

AlphaMissense predicts likely benign (score 0.0821) — an in-silico prediction, not a clinical call.

AP4E1 p.Arg794Lys

c.2381G>A · VCV3923283

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.24e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0821	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -5.43	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 5.1	GERP 0.49, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	17.01	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.24e-05%

Overall 6.24e-05% 1/1,603,418 alleles · very rare exomes 1/1,451,174 · genomes 0/152,244 · joint denominator

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.Arg794Lys
Coding: c.2381G>A
MANE Select: NM_007347
Type: single nucleotide variant
Location: chr15:50997360 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB
Residue 794: the 'interaction with tepsin' region

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.Arg794Gly 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-arg794lys (accessed [today's date]).

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