Is AP4B1 p.Gln331fs (c.992_999del) pathogenic?

AP4B1 p.Gln331fs (c.992999del) is classified Pathogenic/Likely pathogenic in AP4B1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-22). Very rare (popmax 0.00246%, nfe); Associated with hereditary spastic paraplegia 47.

What condition is associated with AP4B1 p.Gln331fs (c.992_999del)?

AP4B1 p.Gln331fs (c.992_999del) is associated with hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Gln331fs (c.992_999del) in the general population?

AP4B1 p.Gln331fs (c.992_999del) is very rare (popmax 0.00246%, nfe) (gnomAD).

AP4B1 p.Gln331fs

Q: How is Severe intellectual disability and progressive spastic paraplegia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.992_999del · rs773840258 · VCV2578580

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Conditions

hereditary spastic paraplegia 47

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 5 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 29/1,180,032 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00226% 33/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,836
European (non-Finnish)grpmax	0.00246%	40,691
African / African-American	0.00133%	75,038

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gln331fs
Coding: c.992_999del
MANE Select: NM_001253852
dbSNP: rs773840258
Type: Deletion
Location: chr1:113900019 (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

hereditary spastic paraplegia 47 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe intellectual disability and progressive spastic paraplegia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

AP4B1 p.Thr387fs Pathogenic/Likely pathogenic ★★ same condition
AP4B1 p.Tyr135_Arg137delinsTer Pathogenic ★★ same condition
AP4B1 c.1106_1114+8del Likely pathogenic ★ same condition
AP4B1 p.Ala105fs Pathogenic ★ same condition
AP4B1 p.Arg497fs Pathogenic ★ same condition
AP4B1 p.Cys356fs Likely pathogenic ★ same condition
AP4B1 p.Gly309fs Pathogenic ★ same condition
AP4B1 p.Gly515fs Likely pathogenic ★ 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-gln331fs (accessed [today's date]).

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