Is USP2 p.Lys320Glu (c.958A>G) pathogenic?

USP2 p.Lys320Glu (c.958A>G) is classified Uncertain significance in USP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-26). AlphaMissense: ambiguous (0.351); Ultra-rare (popmax 0.0234%, amr).

How common is USP2 p.Lys320Glu (c.958A>G) in the general population?

USP2 p.Lys320Glu (c.958A>G) is ultra-rare (popmax 0.0234%, amr) (gnomAD).

What do computational predictors say about USP2 p.Lys320Glu (c.958A>G)?

AlphaMissense predicts ambiguous (score 0.351) — an in-silico prediction, not a clinical call.

USP2 p.Lys320Glu

c.958A>G · rs374783359 · VCV3187247

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.351 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.351	ambiguous
REVEL	0.187	benign-leaning
SaProt	LLR -8.14	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 17 kb · p 0.00016 · regional, not allelic
Overall
CADD	25.2	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 0.0234% Admixed American · 14/59,930 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00775% 125/1,613,476 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0234%	4,281
European (non-Finnish)	0.00924%	10,824
Remaining individualsnot grpmax-eligible	0.0032%	31,232

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: USP2
Protein: p.Lys320Glu
Coding: c.958A>G
MANE Select: NM_004205
dbSNP: rs374783359
Type: single nucleotide variant
Location: chr11:119359334 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.00 · 8 PDB
Residue 320: the usp domain; an α-helix

Full USP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP2 p.Glu93= Benign ★★ same type
USP2 p.Ala15Thr Uncertain significance ★ ⚠ same type
USP2 p.Ala244Thr Uncertain significance ★ ⚠ same type
USP2 p.Arg10His Uncertain significance ★ ⚠ same type
USP2 p.Arg148Trp Uncertain significance ★ ⚠ same type
USP2 p.Arg160Gln Uncertain significance ★ ⚠ same type
USP2 p.Arg168His Uncertain significance ★ ⚠ same type
USP2 p.Arg16Cys 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/usp2-p-lys320glu (accessed [today's date]).

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