Is USP7 p.Arg968Trp (c.2902C>T) pathogenic?

USP7 p.Arg968Trp (c.2902C>T) is classified Uncertain significance in USP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-07). AlphaMissense: likely pathogenic (0.9737); Very rare (popmax 0.0011%, sas).

How common is USP7 p.Arg968Trp (c.2902C>T) in the general population?

USP7 p.Arg968Trp (c.2902C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about USP7 p.Arg968Trp (c.2902C>T)?

AlphaMissense predicts likely pathogenic (score 0.9737) — an in-silico prediction, not a clinical call.

USP7 p.Arg968Trp

c.2902C>T · rs2061670075 · VCV1719511

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9737	likely pathogenic
REVEL	0.302	indeterminate
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -1.6, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 6,603 bp · p 1.4e-25 · regional, not allelic
Overall
CADD	23.5	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 0.0011% South Asian · 1/90,630 alleles

Overall 0.000124% 2/1,612,980 alleles · very rare exomes 2/1,460,794 · genomes 0/152,186 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,630
European (non-Finnish)	8.48e-05%	1,179,679

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: USP7
Protein: p.Arg968Trp
Coding: c.2902C>T
MANE Select: NM_003470
dbSNP: rs2061670075
Type: single nucleotide variant
Location: chr16:8895659 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 968: a UniProt-annotated variant site (in hafous; when expressed in usp7-deficient cells does not rescue defective endosomal protein recycling and reduced f-actin levels); a UniProt-annotated variant site (in hafous)

Full USP7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP7 c.611+1G>A Likely pathogenic ★★ same type
USP7 p.Arg1018Ter Pathogenic/Likely pathogenic ★★ same type
USP7 p.Arg239Ter Pathogenic ★★ same type
USP7 p.Arg508Ter Pathogenic ★★ same type
USP7 p.Gln866Ter Pathogenic/Likely pathogenic ★★ same type
USP7 c.3039+3A>G Uncertain significance ★★ same type
USP7 c.852-4A>G Uncertain significance ★★ same type
USP7 p.Ala27= 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/usp7-p-arg968trp (accessed [today's date]).

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