Is USP7 p.Ser84Leu (c.251C>T) pathogenic?

USP7 p.Ser84Leu (c.251C>T) is classified Uncertain significance in USP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-29). AlphaMissense: likely pathogenic (0.8555); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with USP7 p.Ser84Leu (c.251C>T)?

USP7 p.Ser84Leu (c.251C>T) is associated with Inborn genetic diseases (ClinVar).

How common is USP7 p.Ser84Leu (c.251C>T) in the general population?

USP7 p.Ser84Leu (c.251C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about USP7 p.Ser84Leu (c.251C>T)?

AlphaMissense predicts likely pathogenic (score 0.8555) — an in-silico prediction, not a clinical call.

USP7 p.Ser84Leu

c.251C>T · VCV4197925

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8555 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8555	likely pathogenic
REVEL	0.406	indeterminate
SaProt	LLR -14.24	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.28 · evaluated, not missing
Pangolin	Δ0.24	gain · loss 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 9.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 40 kb · p 0.22 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.2e-05% 1/1,614,186 alleles · very rare exomes 1/1,461,892 · genomes 0/152,294 · 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.Ser84Leu
Coding: c.251C>T
MANE Select: NM_003470
Type: single nucleotide variant
Location: chr16:8923347 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 84: the math domain; the 'interaction with tspyl5' region; the 'interaction with p53/tp53, mdm2 and ebna1' region; the 'necessary for nuclear localization' 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.Ser84Thr Uncertain significance ★ ⚠ same residue
USP7 p.Ser84= Likely benign ★ 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

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-ser84leu (accessed [today's date]).

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