Is USP4 p.Arg278Ser (c.834G>C) pathogenic?

USP4 p.Arg278Ser (c.834G>C) is classified Uncertain significance in USP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely benign (0.2335); Ultra-rare (popmax 0.0294%, afr).

How common is USP4 p.Arg278Ser (c.834G>C) in the general population?

USP4 p.Arg278Ser (c.834G>C) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

What do computational predictors say about USP4 p.Arg278Ser (c.834G>C)?

AlphaMissense predicts likely benign (score 0.2335) — an in-silico prediction, not a clinical call.

USP4 p.Arg278Ser

c.834G>C · rs149837279 · VCV2251669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2335 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2335	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -5.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 39 kb · p 0.042 · regional, not allelic
Overall
CADD	19.52	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

Grpmax group 0.0294% African / African-American · 22/74,906 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00236% 38/1,613,140 alleles · ultra-rare exomes 24/1,460,968 · genomes 14/152,172 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,405
Admixed American	0.00667%	14,987
South Asian	0.0011%	91,020
European (non-Finnish)	0.000933%	107,234

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.Arg278Ser
Coding: c.834G>C
MANE Select: NM_003363
dbSNP: rs149837279
Type: single nucleotide variant
Location: chr3:49311516 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 2 PDB
Residue 278: the 'required for usp4 activation by providing conformational flexibility between the dusp and catalytic domains' region

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-arg278ser (accessed [today's date]).

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