Is AP4B1 p.Glu343Ala (c.1028A>C) pathogenic?

AP4B1 p.Glu343Ala (c.1028A>C) is classified Uncertain significance in AP4B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-17). AlphaMissense: likely benign (0.2671); Ultra-rare (popmax 0.0356%, eas); Associated with Inborn genetic diseases.

What condition is associated with AP4B1 p.Glu343Ala (c.1028A>C)?

AP4B1 p.Glu343Ala (c.1028A>C) is associated with Inborn genetic diseases (ClinVar).

How common is AP4B1 p.Glu343Ala (c.1028A>C) in the general population?

AP4B1 p.Glu343Ala (c.1028A>C) is ultra-rare (popmax 0.0356%, eas) (gnomAD).

What do computational predictors say about AP4B1 p.Glu343Ala (c.1028A>C)?

AlphaMissense predicts likely benign (score 0.2671) — an in-silico prediction, not a clinical call.

AP4B1 p.Glu343Ala

c.1028A>C · rs753057320 · VCV3127541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2671 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2671	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -6.81	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 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 9,649 bp · p 0.84 · regional, not allelic
Overall
CADD	25.4	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 0.0356% East Asian · 16/44,906 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00112% 18/1,614,084 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0356%	2,807
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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: AP4B1
Protein: p.Glu343Ala
Coding: c.1028A>C
MANE Select: NM_001253852
dbSNP: rs753057320
Type: single nucleotide variant
Location: chr1:113899990 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.56 · 5 PDB

Full AP4B1 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

AP4B1 c.114-2A>G Pathogenic ★★ same condition
AP4B1 c.470-6T>G Uncertain significance ★★ same condition
AP4B1 p.Ala361Val Uncertain significance ★★ ⚠ same condition
AP4B1 p.Ala83Pro Uncertain significance ★★ ⚠ same condition
AP4B1 p.Arg130Gln Uncertain significance ★★ ⚠ same condition
AP4B1 p.Arg169His Uncertain significance ★★ ⚠ same condition
AP4B1 p.Arg224Cys Uncertain significance ★★ ⚠ same condition
AP4B1 p.Arg301His 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/ap4b1-p-glu343ala (accessed [today's date]).

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