Is AP5Z1 p.Pro717= (c.2151C>T) pathogenic?

AP5Z1 p.Pro717= (c.2151C>T) is classified Conflicting classifications of pathogenicity in AP5Z1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-12-11). Very rare (popmax 0.00452%, eas); Associated with hereditary spastic paraplegia 48.

What condition is associated with AP5Z1 p.Pro717= (c.2151C>T)?

AP5Z1 p.Pro717= (c.2151C>T) is associated with hereditary spastic paraplegia 48 (ClinVar).

How common is AP5Z1 p.Pro717= (c.2151C>T) in the general population?

AP5Z1 p.Pro717= (c.2151C>T) is very rare (popmax 0.00452%, eas) (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.Pro717=

c.2151C>T · rs1781745482 · VCV909110

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00452%, eas)

Conditions

hereditary spastic paraplegia 48

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.25	donor loss · deltas
Pangolin	Δ0.22	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.68	GERP 1.6, phastCons 1
Overall
CADD	17.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00452% East Asian · 2/44,290 alleles

Filtering AF 0.000748% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00028%

Overall 0.000138% 2/1,447,452 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: AP5Z1
Protein: p.Pro717=
Coding: c.2151C>T
MANE Select: NM_014855
dbSNP: rs1781745482
Type: single nucleotide variant
Location: chr7:4790885 (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.1312-2A>G Pathogenic/Likely pathogenic ★★ same condition
AP5Z1 c.1707+1G>A Likely pathogenic ★★ same condition
AP5Z1 c.1806-1G>C Likely pathogenic ★★ same condition
AP5Z1 p.Arg138Ter Pathogenic/Likely pathogenic ★★ same condition
AP5Z1 p.Arg310Ter Pathogenic/Likely pathogenic ★★ same condition
AP5Z1 p.Arg311Ter Pathogenic/Likely pathogenic ★★ same condition
AP5Z1 p.Arg345Ter Pathogenic/Likely pathogenic ★★ same condition
AP5Z1 p.Gln17Ter Pathogenic/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-pro717 (accessed [today's date]).

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