Is USP8 p.Phe875Ser (c.2624T>C) pathogenic?

USP8 p.Phe875Ser (c.2624T>C) is classified Uncertain significance in USP8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-13). AlphaMissense: likely pathogenic (0.9978); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia.

What condition is associated with USP8 p.Phe875Ser (c.2624T>C)?

USP8 p.Phe875Ser (c.2624T>C) is associated with hereditary spastic paraplegia (ClinVar).

How common is USP8 p.Phe875Ser (c.2624T>C) in the general population?

USP8 p.Phe875Ser (c.2624T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USP8 p.Phe875Ser (c.2624T>C)?

AlphaMissense predicts likely pathogenic (score 0.9978) — an in-silico prediction, not a clinical call.

USP8 p.Phe875Ser

c.2624T>C · rs2141323193 · VCV1517217

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9978 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.9978	likely pathogenic · top 4% in USP8
REVEL	0.631	indeterminate
SaProt	LLR -10.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 6,369 bp · p 7.7e-17 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: USP8
Protein: p.Phe875Ser
Coding: c.2624T>C
MANE Select: NM_005154
dbSNP: rs2141323193
Type: single nucleotide variant
Location: chr15:50494246 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB
Residue 875: the usp domain; 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.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
USP8 p.Asn764Lys 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-phe875ser (accessed [today's date]).

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