Is AP4B1 p.Ser538fs (c.1612del) pathogenic?

AP4B1 p.Ser538fs (c.1612del) is classified Likely pathogenic in AP4B1 (ClinVar, Single submitter, 1 submitter). Absent from gnomAD; Associated with hereditary spastic paraplegia 47.

What condition is associated with AP4B1 p.Ser538fs (c.1612del)?

AP4B1 p.Ser538fs (c.1612del) is associated with hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Ser538fs (c.1612del) in the general population?

AP4B1 p.Ser538fs (c.1612del) is absent from gnomAD (gnomAD).

AP4B1 p.Ser538fs

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.1612del · rs2526494351 · VCV2627503

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 9 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: AP4B1
Protein: p.Ser538fs
Coding: c.1612del
MANE Select: NM_001253852
dbSNP: rs2526494351
Type: Deletion
Location: chr1:113895937 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.56 · 5 PDB
Residue 538: the 'hinge' region

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.Gln331fs Pathogenic/Likely pathogenic ★★ same condition
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

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-ser538fs (accessed [today's date]).

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