Is AP4M1 p.Arg338fs (c.1012del) pathogenic?

AP4M1 p.Arg338fs (c.1012del) is classified Pathogenic in AP4M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-24). Ultra-rare (popmax 0.0165%, mid); Associated with hereditary spastic paraplegia 50.

What condition is associated with AP4M1 p.Arg338fs (c.1012del)?

AP4M1 p.Arg338fs (c.1012del) is associated with hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Arg338fs (c.1012del) in the general population?

AP4M1 p.Arg338fs (c.1012del) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

AP4M1 p.Arg338fs

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.1012del · rs2116668499 · VCV1699331

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 13 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.3	GERP -3.9

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000137% 2/1,461,782 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	8.47e-05%	1,179,993

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.Arg338fs
Coding: c.1012del
MANE Select: NM_004722
dbSNP: rs2116668499
Type: Deletion
Location: chr7:100106278 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB
Residue 338: the mhd domain

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.Arg338Ter Pathogenic/Likely pathogenic ★★ same residue
AP4M1 p.Arg338Gln Uncertain significance ★★ ⚠ same residue
AP4M1 p.Lys11fs Pathogenic/Likely pathogenic ★★ same condition
AP4M1 p.Val48fs 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.Asn185fs 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-arg338fs (accessed [today's date]).

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