Is USP4 p.Ile117= (c.351C>T) pathogenic?

USP4 p.Ile117= (c.351C>T) is classified Likely benign in USP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-21). Very rare (popmax 0.00133%, afr).

How common is USP4 p.Ile117= (c.351C>T) in the general population?

USP4 p.Ile117= (c.351C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

USP4 p.Ile117=

c.351C>T · rs375989870 · VCV745973

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.33	donor gain · deltas
Constraint at this position
Conservation	phyloP -0.71	GERP -3.7
Overall
CADD	14.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,918 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000496% 8/1,613,924 alleles · very rare exomes 4/1,461,774 · genomes 4/152,150 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,240
African / African-Americangrpmax	0.00133%	74,918
South Asian	0.0011%	91,076
European (non-Finnish)	0.000339%	294,993

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile117=
Coding: c.351C>T
MANE Select: NM_003363
dbSNP: rs375989870
Type: single nucleotide variant
Location: chr3:49327695 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 2 PDB
Residue 117: the dusp domain; the 'necessary for interaction with sart3' region

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

Similar variants

USP4 p.Ile117Val Uncertain significance ★ ⚠ same residue
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

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-ile117 (accessed [today's date]).

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