Is AP4M1 p.Val48fs (c.142del) pathogenic?

AP4M1 p.Val48fs (c.142del) is classified Pathogenic/Likely pathogenic in AP4M1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-02). Very rare (popmax 0.00237%, nfe); Associated with hereditary spastic paraplegia 50.

What condition is associated with AP4M1 p.Val48fs (c.142del)?

AP4M1 p.Val48fs (c.142del) is associated with hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Val48fs (c.142del) in the general population?

AP4M1 p.Val48fs (c.142del) is very rare (popmax 0.00237%, nfe) (gnomAD).

AP4M1 p.Val48fs

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.142del · rs764326593 · VCV1697248

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Conditions

hereditary spastic paraplegia 50

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 2 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 2.1, phastCons 1
Overall
CADD	35.0	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

Grpmax group 0.00237% European (non-Finnish) · 28/1,179,914 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00174% 28/1,613,046 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: AP4M1
Protein: p.Val48fs
Coding: c.142del
MANE Select: NM_004722
dbSNP: rs764326593
Type: Deletion
Location: chr7:100101963 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB

Full AP4M1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 50 — 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

AP4M1 p.Lys11fs Pathogenic/Likely pathogenic ★★ same condition
AP4M1 c.52_58+6del Pathogenic ★ same condition
AP4M1 c.58+1_58+2del Likely pathogenic ★ same condition
AP4M1 c.607-2_607-1del Likely pathogenic ★ same condition
AP4M1 p.Arg338fs Pathogenic ★ same condition
AP4M1 p.Asn185fs Pathogenic ★ same condition
AP4M1 p.Asp190fs Pathogenic ★ same condition
AP4M1 p.Asp43fs 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/ap4m1-p-val48fs (accessed [today's date]).

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