Is USP8 p.Gln136Pro (c.407A>C) pathogenic?

USP8 p.Gln136Pro (c.407A>C) is classified Uncertain significance in USP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: likely benign (0.1658); Very rare (popmax 0.000186%); Associated with hereditary spastic paraplegia.

What condition is associated with USP8 p.Gln136Pro (c.407A>C)?

USP8 p.Gln136Pro (c.407A>C) is associated with hereditary spastic paraplegia (ClinVar).

How common is USP8 p.Gln136Pro (c.407A>C) in the general population?

USP8 p.Gln136Pro (c.407A>C) is very rare (popmax 0.000186%) (gnomAD).

What do computational predictors say about USP8 p.Gln136Pro (c.407A>C)?

AlphaMissense predicts likely benign (score 0.1658) — an in-silico prediction, not a clinical call.

USP8 p.Gln136Pro

c.407A>C · VCV3694151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000186%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1658	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -13.95	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 0.0024 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000186%

Overall 0.000186% 3/1,613,918 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.Gln136Pro
Coding: c.407A>C
MANE Select: NM_005154
Type: single nucleotide variant
Location: chr15:50459071 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB
Residue 136: the 'disordered' region; an α-helix

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-gln136pro (accessed [today's date]).

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