Is USP5 p.Leu4Pro (c.11T>C) pathogenic?

USP5 p.Leu4Pro (c.11T>C) is classified Uncertain significance in USP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-26). AlphaMissense: likely benign (0.2155); Absent from gnomAD v4.1.

How common is USP5 p.Leu4Pro (c.11T>C) in the general population?

USP5 p.Leu4Pro (c.11T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USP5 p.Leu4Pro (c.11T>C)?

AlphaMissense predicts likely benign (score 0.2155) — an in-silico prediction, not a clinical call.

USP5 p.Leu4Pro

c.11T>C · rs2542390030 · VCV2273952

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2155 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2155	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -3.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 11 kb · p 4e-24 · regional, not allelic
Overall
CADD	26.5	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

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.Leu4Pro
Coding: c.11T>C
MANE Select: NM_001098536
dbSNP: rs2542390030
Type: single nucleotide variant
Location: chr12:6852190 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 12 PDB
Residue 4: an α-helix

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

Similar variants

USP5 p.Leu4Val Uncertain significance ★ ⚠ same residue
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

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-leu4pro (accessed [today's date]).

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