Is AP4E1 p.Ile388Val (c.1162A>G) pathogenic?

AP4E1 p.Ile388Val (c.1162A>G) is classified Uncertain significance in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.072); Ultra-rare (popmax 0.0174%, afr); Associated with Inborn genetic diseases.

What condition is associated with AP4E1 p.Ile388Val (c.1162A>G)?

AP4E1 p.Ile388Val (c.1162A>G) is associated with Inborn genetic diseases (ClinVar).

How common is AP4E1 p.Ile388Val (c.1162A>G) in the general population?

AP4E1 p.Ile388Val (c.1162A>G) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about AP4E1 p.Ile388Val (c.1162A>G)?

AlphaMissense predicts likely benign (score 0.072) — an in-silico prediction, not a clinical call.

AP4E1 p.Ile388Val

c.1162A>G · VCV3923293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.072 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.072	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -5.66	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 8.1	GERP 0.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	23.2	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 0.0174% African / African-American · 13/74,916 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00149% 24/1,609,680 alleles · ultra-rare exomes 18/1,457,338 · genomes 6/152,342 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,763
Remaining individualsnot grpmax-eligible	0.00481%	20,785
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,582
Admixed American	0.00167%	59,982
European (non-Finnish)	0.00051%	196,022

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.Ile388Val
Coding: c.1162A>G
MANE Select: NM_007347
Type: single nucleotide variant
Location: chr15:50941761 (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

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AP4E1 p.Gln1093Glu Uncertain significance ★★ ⚠ same condition
AP4E1 p.Gln375Pro Uncertain significance ★★ ⚠ same condition
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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-ile388val (accessed [today's date]).

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