Is USP3 p.Ile288Val (c.862A>G) pathogenic?

USP3 p.Ile288Val (c.862A>G) is classified Uncertain significance in USP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-03). AlphaMissense: likely benign (0.058); Ultra-rare (popmax 0.0133%, amr).

How common is USP3 p.Ile288Val (c.862A>G) in the general population?

USP3 p.Ile288Val (c.862A>G) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about USP3 p.Ile288Val (c.862A>G)?

AlphaMissense predicts likely benign (score 0.058) — an in-silico prediction, not a clinical call.

USP3 p.Ile288Val

c.862A>G · VCV3466846

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.058 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.058	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -4.97	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 -0.15	GERP -0.79
Regional constraint	o/e 0.76	unconstrained · MANE · 86 kb · p 7.7e-10 · regional, not allelic
Overall
CADD	5.131	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 0.0133% Admixed American · 8/59,996 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.0103% 166/1,614,082 alleles · ultra-rare exomes 159/1,461,848 · genomes 7/152,234 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,500
European (non-Finnish)	0.0126%	7,920
South Asian	0.00659%	15,181
African / African-American	0.00267%	37,474
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: USP3
Protein: p.Ile288Val
Coding: c.862A>G
MANE Select: NM_006537
Type: single nucleotide variant
Location: chr15:63570533 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.40
Residue 288: the usp domain

Full USP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP3 p.Pro360Thr Benign ★★ same type
USP3 p.Ala306Glu Uncertain significance ★ ⚠ same type
USP3 p.Ala64Thr Uncertain significance ★ ⚠ same type
USP3 p.Arg204Gln Uncertain significance ★ same type
USP3 p.Arg204Trp Uncertain significance ★ ⚠ same type
USP3 p.Arg332Thr Uncertain significance ★ ⚠ same type
USP3 p.Arg33Leu Uncertain significance ★ ⚠ same type
USP3 p.Arg352Cys Uncertain significance ★ ⚠ same type

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/usp3-p-ile288val (accessed [today's date]).

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