Is AP5Z1 p.Ser710= (c.2130C>A) pathogenic?

AP5Z1 p.Ser710= (c.2130C>A) is classified Likely benign in AP5Z1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-01). Very rare (popmax 0.00408%, nfe); Associated with hereditary spastic paraplegia 48.

What condition is associated with AP5Z1 p.Ser710= (c.2130C>A)?

AP5Z1 p.Ser710= (c.2130C>A) is associated with hereditary spastic paraplegia 48 (ClinVar).

How common is AP5Z1 p.Ser710= (c.2130C>A) in the general population?

AP5Z1 p.Ser710= (c.2130C>A) is very rare (popmax 0.00408%, nfe) (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.Ser710=

c.2130C>A · rs755965893 · VCV2862358

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00408%, nfe)

Conditions

hereditary spastic paraplegia 48

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -3.2
Overall
CADD	1.853	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00408% European (non-Finnish) · 48/1,177,422 alleles

Filtering AF 0.00316% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00324% 52/1,605,966 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00482%	20,743
European (non-Finnish)grpmax	0.00408%	24,530
African / African-American	0.00134%	74,756

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser710=
Coding: c.2130C>A
MANE Select: NM_014855
dbSNP: rs755965893
Type: single nucleotide variant
Location: chr7:4790864 (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-ser710 (accessed [today's date]).

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