Is USP4 p.Asp752His (c.2254G>C) pathogenic?

USP4 p.Asp752His (c.2254G>C) is classified Uncertain significance in USP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-14). AlphaMissense: ambiguous (0.3976); Very rare (popmax 0.00534%, afr).

How common is USP4 p.Asp752His (c.2254G>C) in the general population?

USP4 p.Asp752His (c.2254G>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about USP4 p.Asp752His (c.2254G>C)?

AlphaMissense predicts ambiguous (score 0.3976) — an in-silico prediction, not a clinical call.

USP4 p.Asp752His

c.2254G>C · VCV3467056

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Computational evidence

Protein change
AlphaMissense	0.3976	ambiguous
REVEL	0.388	indeterminate
SaProt	LLR -10.91	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 22 kb · p 0.0037 · regional, not allelic
Overall
CADD	23.8	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 0.00534% African / African-American · 4/74,874 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000496% 8/1,613,644 alleles · very rare exomes 6/1,461,596 · genomes 2/152,048 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,718
East Asian	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	0.00017%	589,925

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.Asp752His
Coding: c.2254G>C
MANE Select: NM_003363
Type: single nucleotide variant
Location: chr3:49284866 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 2 PDB
Residue 752: 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-asp752his (accessed [today's date]).

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