Is USP7 p.Lys472Arg (c.1415A>G) pathogenic?

USP7 p.Lys472Arg (c.1415A>G) is classified Uncertain significance in USP7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-01). AlphaMissense: likely benign (0.0693); Very rare (popmax 8.48e-05%, nfe).

How common is USP7 p.Lys472Arg (c.1415A>G) in the general population?

USP7 p.Lys472Arg (c.1415A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about USP7 p.Lys472Arg (c.1415A>G)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

USP7 p.Lys472Arg

c.1415A>G · rs1386022252 · VCV1708688

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.98	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 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.23	constrained · MANE · 5,479 bp · p 2.3e-19 · regional, not allelic
Overall
CADD	23.2	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 8.48e-05% European (non-Finnish) · 1/1,179,938 alleles

Overall 6.2e-05% 1/1,611,946 alleles · very rare exomes 0/1,459,708 · genomes 1/152,238 · 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.Lys472Arg
Coding: c.1415A>G
MANE Select: NM_003470
dbSNP: rs1386022252
Type: single nucleotide variant
Location: chr16:8906439 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 472: 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)

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

Similar variants

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
USP7 p.Ala27= 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-lys472arg (accessed [today's date]).

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