Is USP7 p.Ala221Val (c.662C>T) pathogenic?

USP7 p.Ala221Val (c.662C>T) is classified Uncertain significance in USP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-13). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1.

How common is USP7 p.Ala221Val (c.662C>T) in the general population?

USP7 p.Ala221Val (c.662C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USP7 p.Ala221Val (c.662C>T)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

USP7 p.Ala221Val

c.662C>T · rs2141207701 · VCV1315948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 6% in USP7
REVEL	0.593	indeterminate
SaProt	LLR -12.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 4,910 bp · p 1.6e-25 · regional, not allelic
Overall
CADD	24.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: USP7
Protein: p.Ala221Val
Coding: c.662C>T
MANE Select: NM_003470
dbSNP: rs2141207701
Type: single nucleotide variant
Location: chr16:8919089 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 221: the usp domain; 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); an α-helix

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

Similar variants

USP7 p.Ala221= Likely benign ★ 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-ala221val (accessed [today's date]).

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