Is AP4B1 p.Gln118Ter (c.352C>T) pathogenic?

AP4B1 p.Gln118Ter (c.352C>T) is classified Pathogenic in AP4B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 47.

What condition is associated with AP4B1 p.Gln118Ter (c.352C>T)?

AP4B1 p.Gln118Ter (c.352C>T) is associated with hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Gln118Ter (c.352C>T) in the general population?

AP4B1 p.Gln118Ter (c.352C>T) is absent from gnomAD v4.1 (gnomAD).

AP4B1 p.Gln118Ter

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.352C>T · rs1013939776 · VCV1457254

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary spastic paraplegia 47

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.35	loss · gain 0.02 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AP4B1
Protein: p.Gln118Ter
Coding: c.352C>T
MANE Select: NM_001253852
dbSNP: rs1013939776
Type: single nucleotide variant
Location: chr1:113901872 (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.Gln118Arg Uncertain significance ★ ⚠ same residue
AP4B1 c.114-2A>C Pathogenic ★★ same condition
AP4B1 c.114-2A>G Pathogenic ★★ same condition
AP4B1 p.Arg102Ter Pathogenic ★★ same condition
AP4B1 p.Arg206Ter Pathogenic/Likely pathogenic ★★ same condition
AP4B1 p.Arg353Ter Pathogenic/Likely pathogenic ★★ same condition
AP4B1 p.Arg393Ter Pathogenic ★★ same condition
AP4B1 p.Arg406Ter Pathogenic/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-gln118ter (accessed [today's date]).

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