Is USP8 p.Val296Ile (c.886G>A) pathogenic?

USP8 p.Val296Ile (c.886G>A) is classified Uncertain significance in USP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-08). AlphaMissense: likely benign (0.0884); Rare (popmax 0.146%, eas); Associated with hereditary spastic paraplegia.

What condition is associated with USP8 p.Val296Ile (c.886G>A)?

USP8 p.Val296Ile (c.886G>A) is associated with hereditary spastic paraplegia (ClinVar).

How common is USP8 p.Val296Ile (c.886G>A) in the general population?

USP8 p.Val296Ile (c.886G>A) is rare (popmax 0.146%, eas) (gnomAD).

What do computational predictors say about USP8 p.Val296Ile (c.886G>A)?

AlphaMissense predicts likely benign (score 0.0884) — an in-silico prediction, not a clinical call.

USP8 p.Val296Ile

c.886G>A · rs138148339 · VCV970553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0884 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.146%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0884	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -4.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -0.46, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 63 bp · p 0.00012 · regional, not allelic
Overall
CADD	19.64	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.146% East Asian · 65/44,520 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.107%

Overall 0.00487% 78/1,601,574 alleles · rare exomes 64/1,449,314 · genomes 14/152,260 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.146%	685
Remaining individualsnot grpmax-eligible	0.021%	4,772

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.Val296Ile
Coding: c.886G>A
MANE Select: NM_005154
dbSNP: rs138148339
Type: single nucleotide variant
Location: chr15:50476885 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB
Residue 296: the rhodanese domain; a β-strand

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-val296ile (accessed [today's date]).

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