Is USP8 p.Pro319fs (c.952_955dup) pathogenic?

USP8 p.Pro319fs (c.952955dup) is classified Uncertain significance in USP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-20). No gnomAD frequency available for this variant; Associated with hereditary spastic paraplegia.

What condition is associated with USP8 p.Pro319fs (c.952_955dup)?

USP8 p.Pro319fs (c.952_955dup) is associated with hereditary spastic paraplegia (ClinVar).

How common is USP8 p.Pro319fs (c.952_955dup) in the general population?

USP8 p.Pro319fs (c.952_955dup) is no gnomAD frequency available for this variant (gnomAD).

USP8 p.Pro319fs

c.952_955dup · rs2541953729 · VCV2031312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 9 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.5	GERP 1.3, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: USP8
Protein: p.Pro319fs
Coding: c.952_955dup
MANE Select: NM_005154
dbSNP: rs2541953729
Type: Duplication
Location: chr15:50476948 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB

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 c.2879_2895+12dup Uncertain significance ★ same condition
USP8 c.2658+21_2658+24dup Likely benign ★ same condition
USP8 c.2896-8dup Benign ★ same condition
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

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-pro319fs (accessed [today's date]).

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