Is AP5Z1 p.Ser228= (c.684C>T) pathogenic?

AP5Z1 p.Ser228= (c.684C>T) is classified Conflicting classifications of pathogenicity in AP5Z1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-13). Ultra-rare (popmax 0.0307%, afr); Associated with hereditary spastic paraplegia 48.

What condition is associated with AP5Z1 p.Ser228= (c.684C>T)?

AP5Z1 p.Ser228= (c.684C>T) is associated with hereditary spastic paraplegia 48 (ClinVar).

How common is AP5Z1 p.Ser228= (c.684C>T) in the general population?

AP5Z1 p.Ser228= (c.684C>T) is ultra-rare (popmax 0.0307%, afr) (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.Ser228=

c.684C>T · rs746349613 · VCV701338

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Conditions

hereditary spastic paraplegia 48

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.1	GERP -2.8
Overall
CADD	4.614	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0307% African / African-American · 23/74,802 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.005% 80/1,598,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,252
Remaining individualsnot grpmax-eligible	0.0113%	8,850
European (non-Finnish)	0.00392%	25,521
Admixed American	0.00346%	28,943
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,250
South Asian	0.00113%	88,356

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.Ser228=
Coding: c.684C>T
MANE Select: NM_014855
dbSNP: rs746349613
Type: single nucleotide variant
Location: chr7:4784265 (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 p.Ser228Gly Uncertain significance ★ ⚠ same residue
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

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-ser228 (accessed [today's date]).

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