Is USP8 p.Arg322Ter (c.964C>T) pathogenic?

USP8 p.Arg322Ter (c.964C>T) is classified Uncertain significance in USP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-26). Very rare (popmax 0.00134%, afr); Associated with USP8-related disorder.

What condition is associated with USP8 p.Arg322Ter (c.964C>T)?

USP8 p.Arg322Ter (c.964C>T) is associated with USP8-related disorder (ClinVar).

How common is USP8 p.Arg322Ter (c.964C>T) in the general population?

USP8 p.Arg322Ter (c.964C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

USP8 p.Arg322Ter

c.964C>T · rs574030216 · VCV2629055

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

USP8-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 9 of 20
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.42	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.9	GERP 2.1, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,650 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000275% 4/1,454,780 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,444
African / African-Americangrpmax	0.00134%	74,650
European (non-Finnish)	0.00017%	589,338

Ashkenazi Jewish 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: USP8
Protein: p.Arg322Ter
Coding: c.964C>T
MANE Select: NM_005154
dbSNP: rs574030216
Type: single nucleotide variant
Location: chr15:50476963 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB

Full USP8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

USP8-related disorder

Similar variants

USP8 p.Arg322Gln Uncertain significance ★ ⚠ same residue
USP8 p.Ala225Thr Uncertain significance ⚠ same condition
USP8 p.Arg133Trp Uncertain significance ★★ ⚠ same type
USP8 p.Phe875Ser Uncertain significance ★★ ⚠ same type
USP8 p.Pro703His Uncertain significance ★★ ⚠ same type
USP8 c.104+16C>T Benign ★★ same type
USP8 c.250-8A>C Benign ★★ same type
USP8 c.-58G>C Benign ★★ 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/usp8-p-arg322ter (accessed [today's date]).

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