Is USP7 p.Ser752Cys (c.2255C>G) pathogenic?

USP7 p.Ser752Cys (c.2255C>G) is classified Uncertain significance in USP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-01). AlphaMissense: likely benign (0.2388); Very rare (popmax 0.000339%, nfe).

How common is USP7 p.Ser752Cys (c.2255C>G) in the general population?

USP7 p.Ser752Cys (c.2255C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about USP7 p.Ser752Cys (c.2255C>G)?

AlphaMissense predicts likely benign (score 0.2388) — an in-silico prediction, not a clinical call.

USP7 p.Ser752Cys

c.2255C>G · rs747014527 · VCV2646185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2388 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2388	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -8.46	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 9.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 6,603 bp · p 1.4e-25 · regional, not allelic
Overall
CADD	27.1	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 0.000339% European (non-Finnish) · 4/1,179,740 alleles

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

Overall 0.000248% 4/1,612,532 alleles · very rare exomes 4/1,460,268 · genomes 0/152,264 · joint denominator

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.Ser752Cys
Coding: c.2255C>G
MANE Select: NM_003470
dbSNP: rs747014527
Type: single nucleotide variant
Location: chr16:8900584 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 752: a β-strand; 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); the 'interaction with icp0/vmw110' region

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

Similar variants

USP7 p.Ser752Phe Uncertain significance ★ ⚠ same residue
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

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-ser752cys (accessed [today's date]).

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