Is USP7 p.His3Arg (c.8A>G) pathogenic?

USP7 p.His3Arg (c.8A>G) is classified Uncertain significance in USP7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-08-17). AlphaMissense: likely benign (0.1336); Very rare (popmax 0.00156%, afr).

How common is USP7 p.His3Arg (c.8A>G) in the general population?

USP7 p.His3Arg (c.8A>G) is very rare (popmax 0.00156%, afr) (gnomAD).

What do computational predictors say about USP7 p.His3Arg (c.8A>G)?

AlphaMissense predicts likely benign (score 0.1336) — an in-silico prediction, not a clinical call.

USP7 p.His3Arg

c.8A>G · rs1272991796 · VCV2581988

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1336 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00156%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1336	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -6.47	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 3.5	GERP -0.37, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 40 kb · p 0.22 · regional, not allelic
Overall
CADD	22.7	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 0.00156% African / African-American · 1/63,970 alleles

Overall 7.53e-05% 1/1,328,300 alleles · very rare exomes 0/1,180,898 · genomes 1/147,402 · 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.His3Arg
Coding: c.8A>G
MANE Select: NM_003470
dbSNP: rs1272991796
Type: single nucleotide variant
Location: chr16:8963278 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 3: the 'interaction with tspyl5' region; the 'disordered' region

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

Similar variants

USP7 p.His3Tyr Uncertain significance ★★ ⚠ same residue
USP7 p.His3Gln Uncertain significance ★ ⚠ 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

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-his3arg (accessed [today's date]).

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