Is USP4 p.Ser744Arg (c.2230A>C) pathogenic?

USP4 p.Ser744Arg (c.2230A>C) is classified Uncertain significance in USP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: ambiguous (0.5297); Very rare (popmax 0.00134%, afr).

How common is USP4 p.Ser744Arg (c.2230A>C) in the general population?

USP4 p.Ser744Arg (c.2230A>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about USP4 p.Ser744Arg (c.2230A>C)?

AlphaMissense predicts ambiguous (score 0.5297) — an in-silico prediction, not a clinical call.

USP4 p.Ser744Arg

c.2230A>C · VCV4197574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5297 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5297	ambiguous
REVEL	0.067	moderately benign-leaning
SaProt	LLR -8.25	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 22 kb · p 0.0037 · regional, not allelic
Overall
CADD	23.1	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 0.00134% African / African-American · 1/74,872 alleles

Overall 6.2e-05% 1/1,613,594 alleles · very rare exomes 0/1,461,562 · genomes 1/152,032 · 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: USP4
Protein: p.Ser744Arg
Coding: c.2230A>C
MANE Select: NM_003363
Type: single nucleotide variant
Location: chr3:49284890 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 2 PDB
Residue 744: 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-ser744arg (accessed [today's date]).

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