Is USP8 p.Gln433= (c.1299A>G) pathogenic?

USP8 p.Gln433= (c.1299A>G) is classified Likely benign in USP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-17). Ultra-rare (popmax 0.058%, eas); Associated with hereditary spastic paraplegia.

What condition is associated with USP8 p.Gln433= (c.1299A>G)?

USP8 p.Gln433= (c.1299A>G) is associated with hereditary spastic paraplegia (ClinVar).

How common is USP8 p.Gln433= (c.1299A>G) in the general population?

USP8 p.Gln433= (c.1299A>G) is ultra-rare (popmax 0.058%, eas) (gnomAD).

USP8 p.Gln433=

c.1299A>G · rs373025012 · VCV2782243

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.058%, eas)

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 0.35	GERP -3.8, phastCons 0.004
Overall
CADD	5.786	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.058% East Asian · 26/44,858 alleles

Filtering AF 0.0405% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0347%

Overall 0.00527% 85/1,613,448 alleles · ultra-rare exomes 76/1,461,088 · genomes 9/152,360 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.058%	1,725
Middle Eastern	0.033%	3,030
African / African-American	0.016%	6,253
South Asian	0.00771%	12,967
European (non-Finnish)	0.00314%	31,888
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Gln433=
Coding: c.1299A>G
MANE Select: NM_005154
dbSNP: rs373025012
Type: single nucleotide variant
Location: chr15:50481561 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB
Residue 433: 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-gln433 (accessed [today's date]).

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