Is USP8 p.Pro1031= (c.3093G>A) pathogenic?

USP8 p.Pro1031= (c.3093G>A) is classified Likely benign in USP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). Ultra-rare (popmax 0.0387%, afr); Associated with hereditary spastic paraplegia.

What condition is associated with USP8 p.Pro1031= (c.3093G>A)?

USP8 p.Pro1031= (c.3093G>A) is associated with hereditary spastic paraplegia (ClinVar).

How common is USP8 p.Pro1031= (c.3093G>A) in the general population?

USP8 p.Pro1031= (c.3093G>A) is ultra-rare (popmax 0.0387%, afr) (gnomAD).

USP8 p.Pro1031=

c.3093G>A · VCV4707759

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0387%, 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 -10	GERP -4.5
Overall
CADD	0.098	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0387% African / African-American · 29/75,010 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0238%

Overall 0.00236% 38/1,612,958 alleles · ultra-rare exomes 24/1,460,698 · genomes 14/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0387%	2,587
Remaining individualsnot grpmax-eligible	0.0048%	20,813
East Asian	0.00223%	44,854
European (non-Finnish)	0.000424%	235,920

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.Pro1031=
Coding: c.3093G>A
MANE Select: NM_005154
Type: single nucleotide variant
Location: chr15:50498650 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB
Residue 1031: the usp domain

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-pro1031 (accessed [today's date]).

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