Is AP5Z1 p.Ser574fs (c.1719del) pathogenic?

AP5Z1 p.Ser574fs (c.1719del) is classified Pathogenic/Likely pathogenic in AP5Z1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-06-15). Very rare (popmax 0.00195%, amr); Associated with hereditary spastic paraplegia 48.

What condition is associated with AP5Z1 p.Ser574fs (c.1719del)?

AP5Z1 p.Ser574fs (c.1719del) is associated with hereditary spastic paraplegia 48 (ClinVar).

How common is AP5Z1 p.Ser574fs (c.1719del) in the general population?

AP5Z1 p.Ser574fs (c.1719del) is very rare (popmax 0.00195%, amr) (gnomAD).

How is Autosomal recessive spastic paraplegia type 48 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

AP5Z1 p.Ser574fs

c.1719del · rs1562413480 · VCV817957

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 0.00195%, amr)

Conditions

hereditary spastic paraplegia 48

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 14 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -10	GERP -3.1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% Admixed American · 1/51,252 alleles

Filtering AF 0.000441% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000321%

Overall 0.000857% 12/1,399,738 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00195%	51,252
Remaining individualsnot grpmax-eligible	0.00166%	60,154
European (non-Finnish)	0.000871%	114,775

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: AP5Z1
Protein: p.Ser574fs
Coding: c.1719del
MANE Select: NM_014855
dbSNP: rs1562413480
Type: Deletion
Location: chr7:4789841 (GRCh38)
Gene constraint: LOEUF 1.641 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.32

Full AP5Z1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 48 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 48 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

AP5Z1 c.970-2_983del Likely pathogenic ★★ same condition
AP5Z1 p.Ala790_Leu791del Uncertain significance ★★ same condition
AP5Z1 p.Arg358_Val366del Uncertain significance ★★ same condition
AP5Z1 p.Pro788_Leu791del Uncertain significance ★★ same condition
AP5Z1 p.Ser737_Ser740del Benign ★★ same condition
AP5Z1 c.1132+1_1132+3del Likely pathogenic ★ same condition
AP5Z1 c.1509_1595+26del Likely pathogenic ★ same condition
AP5Z1 c.1806-6_1818del 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/ap5z1-p-ser574fs (accessed [today's date]).

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