Is AP4M1 p.Arg441fs (c.1320dup) pathogenic?

AP4M1 p.Arg441fs (c.1320dup) is classified Pathogenic in AP4M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-14). Very rare (popmax 0.00267%, afr); Associated with hereditary spastic paraplegia 50.

What condition is associated with AP4M1 p.Arg441fs (c.1320dup)?

AP4M1 p.Arg441fs (c.1320dup) is associated with hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Arg441fs (c.1320dup) in the general population?

AP4M1 p.Arg441fs (c.1320dup) is very rare (popmax 0.00267%, afr) (gnomAD).

AP4M1 p.Arg441fs

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.1320dup · rs1437455190 · VCV1437494

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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	escapes	premature termination codon in the last exon (15 of 15) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Overall
CADD	33.0	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 0.00267% African / African-American · 2/74,946 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00112% 18/1,613,794 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,473
European (non-Finnish)	0.00136%	73,753

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.Arg441fs
Coding: c.1320dup
MANE Select: NM_004722
dbSNP: rs1437455190
Type: Duplication
Location: chr7:100106839 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB
Residue 441: the mhd domain; a β-strand

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.Arg441Gln Uncertain significance ★ ⚠ same residue
AP4M1 p.Arg441Ter Conflicting classifications of pathogenicity ★ same residue
AP4M1 p.Asn73fs Pathogenic ★★ same condition
TAF6 p.Pro441Leu Uncertain significance ★★ ⚠ same residue
AP4M1 p.Asp288fs Pathogenic ★ same condition
AP4M1 c.974+115dup Uncertain significance ★ same condition
AP4M1 c.147+16_147+22dup Likely benign ★ same condition
AP4M1 c.147+18dup Likely benign ★ 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-arg441fs (accessed [today's date]).

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