Is AP4B1 p.Ala159Val (c.476C>T) pathogenic?

AP4B1 p.Ala159Val (c.476C>T) is classified Uncertain significance in AP4B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.1081); Very rare (popmax 0.008%, afr); Associated with Inborn genetic diseases.

What condition is associated with AP4B1 p.Ala159Val (c.476C>T)?

AP4B1 p.Ala159Val (c.476C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AP4B1 p.Ala159Val (c.476C>T) in the general population?

AP4B1 p.Ala159Val (c.476C>T) is very rare (popmax 0.008%, afr) (gnomAD).

What do computational predictors say about AP4B1 p.Ala159Val (c.476C>T)?

AlphaMissense predicts likely benign (score 0.1081) — an in-silico prediction, not a clinical call.

AP4B1 p.Ala159Val

c.476C>T · rs534678582 · VCV1742946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1081 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.008%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1081	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -7.15	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 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 9,649 bp · p 0.84 · regional, not allelic
Overall
CADD	22.8	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 0.008% African / African-American · 6/74,986 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000558% 9/1,613,920 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.008%	12,498
Finnishnot grpmax-eligible	0.00156%	64,006
European (non-Finnish)	0.00017%	589,939

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.Ala159Val
Coding: c.476C>T
MANE Select: NM_001253852
dbSNP: rs534678582
Type: single nucleotide variant
Location: chr1:113901377 (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-ala159val (accessed [today's date]).

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