Is USP3 p.Val428Ile (c.1282G>A) pathogenic?

USP3 p.Val428Ile (c.1282G>A) is classified Uncertain significance in USP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-21). AlphaMissense: likely benign (0.183); Very rare (popmax 0.00833%, amr).

How common is USP3 p.Val428Ile (c.1282G>A) in the general population?

USP3 p.Val428Ile (c.1282G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about USP3 p.Val428Ile (c.1282G>A)?

AlphaMissense predicts likely benign (score 0.183) — an in-silico prediction, not a clinical call.

USP3 p.Val428Ile

c.1282G>A · rs201397735 · VCV3187365

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.183 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.183	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -9.84	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 10	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 86 kb · p 7.7e-10 · regional, not allelic
Overall
CADD	24.8	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 0.00833% Admixed American · 5/60,030 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.00545% 88/1,614,176 alleles · very rare exomes 77/1,461,848 · genomes 11/152,328 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,006
African / African-American	0.00666%	15,009
South Asian	0.00659%	15,181
European (non-Finnish)	0.00593%	16,857
Remaining individualsnot grpmax-eligible	0.0032%	31,254

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.Val428Ile
Coding: c.1282G>A
MANE Select: NM_006537
dbSNP: rs201397735
Type: single nucleotide variant
Location: chr15:63588768 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.40
Residue 428: 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-val428ile (accessed [today's date]).

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