Is USP7 p.Pro34Ser (c.100C>T) pathogenic?

USP7 p.Pro34Ser (c.100C>T) is classified Uncertain significance in USP7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.1101); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with USP7 p.Pro34Ser (c.100C>T)?

USP7 p.Pro34Ser (c.100C>T) is associated with Inborn genetic diseases (ClinVar).

How common is USP7 p.Pro34Ser (c.100C>T) in the general population?

USP7 p.Pro34Ser (c.100C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about USP7 p.Pro34Ser (c.100C>T)?

AlphaMissense predicts likely benign (score 0.1101) — an in-silico prediction, not a clinical call.

USP7 p.Pro34Ser

c.100C>T · VCV3467325

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1101	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -5.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	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 0.00134% African / African-American · 1/74,684 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,610,988 alleles · very rare exomes 2/1,458,856 · genomes 2/152,132 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,684
European (non-Finnish)	0.000255%	392,859

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.Pro34Ser
Coding: c.100C>T
MANE Select: NM_003470
Type: single nucleotide variant
Location: chr16:8930377 (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.Pro34Arg 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-pro34ser (accessed [today's date]).

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