Is USP8 p.Pro649= (c.1947A>G) pathogenic?

USP8 p.Pro649= (c.1947A>G) is classified Likely benign in USP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). Very rare (popmax 0.0006%, nfe); Associated with hereditary spastic paraplegia.

What condition is associated with USP8 p.Pro649= (c.1947A>G)?

USP8 p.Pro649= (c.1947A>G) is associated with hereditary spastic paraplegia (ClinVar).

How common is USP8 p.Pro649= (c.1947A>G) in the general population?

USP8 p.Pro649= (c.1947A>G) is very rare (popmax 0.0006%, nfe) (gnomAD).

USP8 p.Pro649=

c.1947A>G · rs777660185 · VCV2892017

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0006%, nfe)

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 0.47	GERP -0.96, phastCons 0.8
Overall
CADD	9.385	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0006% European (non-Finnish) · 7/1,166,684 alleles

Filtering AF 0.00025% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00016%

Overall 0.000442% 7/1,584,782 alleles · very rare

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.Pro649=
Coding: c.1947A>G
MANE Select: NM_005154
dbSNP: rs777660185
Type: single nucleotide variant
Location: chr15:50489857 (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 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-pro649 (accessed [today's date]).

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