Is USP7 p.Pro34Arg (c.101C>G) pathogenic?

USP7 p.Pro34Arg (c.101C>G) is classified Uncertain significance in USP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely benign (0.3086); Very rare (popmax 0.000848%, nfe); Associated with Inborn genetic diseases.

What condition is associated with USP7 p.Pro34Arg (c.101C>G)?

USP7 p.Pro34Arg (c.101C>G) is associated with Inborn genetic diseases (ClinVar).

How common is USP7 p.Pro34Arg (c.101C>G) in the general population?

USP7 p.Pro34Arg (c.101C>G) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about USP7 p.Pro34Arg (c.101C>G)?

AlphaMissense predicts likely benign (score 0.3086) — an in-silico prediction, not a clinical call.

USP7 p.Pro34Arg

c.101C>G · rs992972868 · VCV2620948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3086	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -6.73	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 2.2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 40 kb · p 0.22 · regional, not allelic
Overall
CADD	23.6	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 0.000848% European (non-Finnish) · 10/1,178,638 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000621% 10/1,611,166 alleles · very rare exomes 10/1,458,952 · genomes 0/152,214 · 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.Pro34Arg
Coding: c.101C>G
MANE Select: NM_003470
dbSNP: rs992972868
Type: single nucleotide variant
Location: chr16:8930376 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 34: the 'interaction with tspyl5' region; the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USP7 p.Pro34Ser Uncertain significance ★★ ⚠ same residue
USP7 c.611+1G>A Likely pathogenic ★★ same condition
USP7 p.Arg919Trp Uncertain significance ★★ ⚠ same condition
USP7 p.Asp374Asn Uncertain significance ★★ ⚠ same condition
USP7 p.Glu24Val Uncertain significance ★★ ⚠ same condition
USP7 p.His3Tyr Uncertain significance ★★ ⚠ same condition
USP7 p.Ile660Val Uncertain significance ★★ ⚠ same condition
USP7 p.Lys476Arg Uncertain significance ★★ ⚠ same condition

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-pro34arg (accessed [today's date]).

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