Is USP28 p.Glu450Asp (c.1350A>T) pathogenic?

USP28 p.Glu450Asp (c.1350A>T) is classified Uncertain significance in USP28 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: likely pathogenic (0.6068); Very rare (popmax 0.000508%, nfe).

How common is USP28 p.Glu450Asp (c.1350A>T) in the general population?

USP28 p.Glu450Asp (c.1350A>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about USP28 p.Glu450Asp (c.1350A>T)?

AlphaMissense predicts likely pathogenic (score 0.6068) — an in-silico prediction, not a clinical call.

USP28 p.Glu450Asp

c.1350A>T · rs776898061 · VCV2546944

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6068	likely pathogenic
REVEL	0.256	benign-leaning
SaProt	LLR -5.86	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.29	GERP -3.4, phastCons 1
Overall
CADD	22.2	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 0.000508% European (non-Finnish) · 6/1,180,016 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,614,168 alleles · very rare exomes 6/1,461,894 · genomes 0/152,274 · joint denominator

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: USP28
Protein: p.Glu450Asp
Coding: c.1350A>T
MANE Select: NM_001346252
dbSNP: rs776898061
Type: single nucleotide variant
Location: chr11:113817771 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.20 · 15 PDB
Residue 450: the usp domain; an α-helix

Full USP28 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP28 p.Asp345Asn Uncertain significance ★★ ⚠ same type
USP28 p.Ala104Thr Uncertain significance ★ ⚠ same type
USP28 p.Ala132Val Uncertain significance ★ ⚠ same type
USP28 p.Ala270Ser Uncertain significance ★ ⚠ same type
USP28 p.Ala739Val Uncertain significance ★ ⚠ same type
USP28 p.Ala83Ser Uncertain significance ★ ⚠ same type
USP28 p.Ala89Thr Uncertain significance ★ ⚠ same type
USP28 p.Ala932Val 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/usp28-p-glu450asp (accessed [today's date]).

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