Is USP8 p.Glu488= (c.1464G>A) pathogenic?

USP8 p.Glu488= (c.1464G>A) is classified Benign in USP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-13). Rare (popmax 0.257%, afr); Associated with hereditary spastic paraplegia.

What condition is associated with USP8 p.Glu488= (c.1464G>A)?

USP8 p.Glu488= (c.1464G>A) is associated with hereditary spastic paraplegia (ClinVar).

How common is USP8 p.Glu488= (c.1464G>A) in the general population?

USP8 p.Glu488= (c.1464G>A) is rare (popmax 0.257%, afr) (gnomAD).

USP8 p.Glu488=

c.1464G>A · rs142653887 · VCV705823

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.257%, afr)

Conditions

hereditary spastic paraplegia

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 1.8	GERP -1.9, phastCons 1
Overall
CADD	6.291	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.257% African / African-American · 192/74,592 alleles

Filtering AF 0.228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.216%

Overall 0.0134% 215/1,609,310 alleles · rare exomes 101/1,457,356 · genomes 114/151,954 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.257%	389
Remaining individualsnot grpmax-eligible	0.0161%	6,227
Admixed American	0.0152%	6,574
South Asian	0.00111%	89,770
European (non-Finnish)	0.000255%	392,833

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: USP8
Protein: p.Glu488=
Coding: c.1464G>A
MANE Select: NM_005154
dbSNP: rs142653887
Type: single nucleotide variant
Location: chr15:50481726 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB
Residue 488: the 'disordered' region

Full USP8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

USP8 p.Arg133Trp Uncertain significance ★★ ⚠ same condition
USP8 p.Phe875Ser Uncertain significance ★★ ⚠ same condition
USP8 p.Pro703His Uncertain significance ★★ ⚠ same condition
USP8 c.104+16C>T Benign ★★ same condition
USP8 c.250-8A>C Benign ★★ same condition
USP8 p.Ala348Thr Benign ★★ same condition
USP8 p.Arg483Gln Benign ★★ same condition
USP8 p.Arg763Trp 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/usp8-p-glu488 (accessed [today's date]).

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