Is USP5 p.Val583Ala (c.1748T>C) pathogenic?

USP5 p.Val583Ala (c.1748T>C) is classified Uncertain significance in USP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-23). AlphaMissense: likely pathogenic (0.9115); Absent from gnomAD v4.1.

How common is USP5 p.Val583Ala (c.1748T>C) in the general population?

USP5 p.Val583Ala (c.1748T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USP5 p.Val583Ala (c.1748T>C)?

AlphaMissense predicts likely pathogenic (score 0.9115) — an in-silico prediction, not a clinical call.

USP5 p.Val583Ala

c.1748T>C · rs2542425259 · VCV2524013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9115 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9115	likely pathogenic
REVEL	0.306	indeterminate
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 11 kb · p 4e-24 · regional, not allelic
Overall
CADD	25.3	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

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: USP5
Protein: p.Val583Ala
Coding: c.1748T>C
MANE Select: NM_001098536
dbSNP: rs2542425259
Type: single nucleotide variant
Location: chr12:6862544 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 12 PDB
Residue 583: the usp domain

Full USP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP5 p.Leu380= Benign ★★ same type
USP5 p.Leu489= Benign ★★ same type
USP5 p.Pro609= Benign ★★ same type
USP5 p.Val18= Benign ★★ same type
USP5 p.Ala495Thr Uncertain significance ★ ⚠ same type
USP5 p.Ala549Val Uncertain significance ★ ⚠ same type
USP5 p.Ala718Thr Uncertain significance ★ ⚠ same type
USP5 p.Ala780Ser 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/usp5-p-val583ala (accessed [today's date]).

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