Is USP7 p.Ile660Val (c.1978A>G) pathogenic?

USP7 p.Ile660Val (c.1978A>G) is classified Uncertain significance in USP7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-10). AlphaMissense: likely benign (0.0877); Very rare (popmax 0.00769%, sas); Associated with Inborn genetic diseases.

What condition is associated with USP7 p.Ile660Val (c.1978A>G)?

USP7 p.Ile660Val (c.1978A>G) is associated with Inborn genetic diseases (ClinVar).

How common is USP7 p.Ile660Val (c.1978A>G) in the general population?

USP7 p.Ile660Val (c.1978A>G) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about USP7 p.Ile660Val (c.1978A>G)?

AlphaMissense predicts likely benign (score 0.0877) — an in-silico prediction, not a clinical call.

USP7 p.Ile660Val

c.1978A>G · rs776602318 · VCV1981549

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0877 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0877	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -5.72	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 6.2	GERP 2.5, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 4,289 bp · p 4e-10 · regional, not allelic
Overall
CADD	21.9	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 0.00769% South Asian · 7/91,082 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00161% 26/1,614,098 alleles · very rare exomes 24/1,461,882 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,012
Admixed American	0.00167%	59,998
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00144%	69,415

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.Ile660Val
Coding: c.1978A>G
MANE Select: NM_003470
dbSNP: rs776602318
Type: single nucleotide variant
Location: chr16:8902151 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 660: 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

Disease context

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

Similar variants

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.Lys476Arg Uncertain significance ★★ ⚠ same condition
USP7 p.Pro34Ser Uncertain significance ★★ ⚠ same condition
USP7 p.Thr177Ile 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-ile660val (accessed [today's date]).

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