Is USP8 p.Pro405Ser (c.1213C>T) pathogenic?

USP8 p.Pro405Ser (c.1213C>T) is classified Uncertain significance in USP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-07). AlphaMissense: ambiguous (0.3537); Very rare (popmax 0.0017%, nfe); Associated with hereditary spastic paraplegia.

What condition is associated with USP8 p.Pro405Ser (c.1213C>T)?

USP8 p.Pro405Ser (c.1213C>T) is associated with hereditary spastic paraplegia (ClinVar).

How common is USP8 p.Pro405Ser (c.1213C>T) in the general population?

USP8 p.Pro405Ser (c.1213C>T) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about USP8 p.Pro405Ser (c.1213C>T)?

AlphaMissense predicts ambiguous (score 0.3537) — an in-silico prediction, not a clinical call.

USP8 p.Pro405Ser

c.1213C>T · rs776747250 · VCV2046621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3537 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.3537	ambiguous
REVEL	0.188	benign-leaning
SaProt	LLR -6.35	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 16 kb · p 0.12 · regional, not allelic
Overall
CADD	24.2	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 0.0017% European (non-Finnish) · 20/1,178,266 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000901%

Overall 0.00124% 20/1,610,550 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.Pro405Ser
Coding: c.1213C>T
MANE Select: NM_005154
dbSNP: rs776747250
Type: single nucleotide variant
Location: chr15:50477494 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB
Residue 405: 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-pro405ser (accessed [today's date]).

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