Is AP4E1 p.Ile4Lys (c.11T>A) pathogenic?

AP4E1 p.Ile4Lys (c.11T>A) is classified Uncertain significance in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.743); Very rare (popmax 0.000257%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AP4E1 p.Ile4Lys (c.11T>A)?

AP4E1 p.Ile4Lys (c.11T>A) is associated with Inborn genetic diseases (ClinVar).

How common is AP4E1 p.Ile4Lys (c.11T>A) in the general population?

AP4E1 p.Ile4Lys (c.11T>A) is very rare (popmax 0.000257%, nfe) (gnomAD).

What do computational predictors say about AP4E1 p.Ile4Lys (c.11T>A)?

AlphaMissense predicts likely pathogenic (score 0.743) — an in-silico prediction, not a clinical call.

AP4E1 p.Ile4Lys

c.11T>A · VCV4115774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.743 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000257%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.743	likely pathogenic
REVEL	0.169	moderately benign-leaning
SaProt	LLR -8.25	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	24.7	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 0.000257% European (non-Finnish) · 3/1,168,314 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000189% 3/1,589,060 alleles · very rare exomes 3/1,437,796 · genomes 0/151,264 · 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.Ile4Lys
Coding: c.11T>A
MANE Select: NM_007347
Type: single nucleotide variant
Location: chr15:50908789 (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.Ile4Thr Uncertain significance ★ ⚠ 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-ile4lys (accessed [today's date]).

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