Is AP4B1 p.Asn178fs (c.530_531insA) pathogenic?

AP4B1 p.Asn178fs (c.530531insA) is classified Pathogenic in AP4B1 (ClinVar, Single submitter, 2 submitters; last evaluated 2015-11-08). Very rare (popmax 0.000339%, nfe).

How common is AP4B1 p.Asn178fs (c.530_531insA) in the general population?

AP4B1 p.Asn178fs (c.530_531insA) is very rare (popmax 0.000339%, nfe) (gnomAD).

AP4B1 p.Asn178fs

c.530_531insA · rs879255397 · VCV252668

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.24	GERP -2, phastCons 0.98

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,966 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,814 alleles · very rare

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.Asn178fs
Coding: c.530_531insA
MANE Select: NM_001253852
dbSNP: rs879255397
Type: Insertion
Location: chr1:113901322 (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

Similar variants

AP4B1 p.Ala375delinsLeuTer Pathogenic ★ same type
AP4B1 p.Ile371fs Pathogenic ★ same type
AP4B1 p.Glu163delinsValTer Pathogenic/Likely pathogenic same type
AP4B1 p.Lys537fs Likely pathogenic same type

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-asn178fs (accessed [today's date]).

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