Is USP4 p.Leu730Phe (c.2188C>T) pathogenic?

USP4 p.Leu730Phe (c.2188C>T) is classified Uncertain significance in USP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: ambiguous (0.4448); Absent from gnomAD v4.1.

How common is USP4 p.Leu730Phe (c.2188C>T) in the general population?

USP4 p.Leu730Phe (c.2188C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USP4 p.Leu730Phe (c.2188C>T)?

AlphaMissense predicts ambiguous (score 0.4448) — an in-silico prediction, not a clinical call.

USP4 p.Leu730Phe

c.2188C>T · VCV4197578

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4448 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4448	ambiguous
REVEL	0.187	benign-leaning
SaProt	LLR -7.78	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 22 kb · p 0.0037 · regional, not allelic
Overall
CADD	24.7	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: USP4
Protein: p.Leu730Phe
Coding: c.2188C>T
MANE Select: NM_003363
Type: single nucleotide variant
Location: chr3:49286110 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 2 PDB
Residue 730: the 'interacts with dusp and ubiquitin-like 1 domains and is required for usp4 activation' region; the usp domain

Full USP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP4 p.Ile846Val Benign ★★ same type
USP4 p.Pro591= Likely benign ★★ same type
USP4 p.Tyr620Cys Benign ★★ same type
USP4 p.Tyr630Cys Likely benign ★★ ⚠ same type
USP4 p.Ala100Glu Uncertain significance ★ ⚠ same type
USP4 p.Ala100Val Uncertain significance ★ ⚠ same type
USP4 p.Ala177Val Uncertain significance ★ ⚠ same type
USP4 p.Ala205Thr 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/usp4-p-leu730phe (accessed [today's date]).

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