Is USP7 p.Met613Ile (c.1839G>A) pathogenic?

USP7 p.Met613Ile (c.1839G>A) is classified Uncertain significance in USP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-02). AlphaMissense: likely pathogenic (0.6887); Very rare (popmax 8.48e-05%, nfe).

How common is USP7 p.Met613Ile (c.1839G>A) in the general population?

USP7 p.Met613Ile (c.1839G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about USP7 p.Met613Ile (c.1839G>A)?

AlphaMissense predicts likely pathogenic (score 0.6887) — an in-silico prediction, not a clinical call.

USP7 p.Met613Ile

c.1839G>A · rs2549226206 · VCV1810500

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6887 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6887	likely pathogenic
REVEL	0.258	benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 4,289 bp · p 4e-10 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

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) · 1/1,179,664 alleles

Overall 6.2e-05% 1/1,613,246 alleles · very rare exomes 1/1,460,954 · genomes 0/152,292 · 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.Met613Ile
Coding: c.1839G>A
MANE Select: NM_003470
dbSNP: rs2549226206
Type: single nucleotide variant
Location: chr16:8903268 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 613: an α-helix; 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)

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

Similar variants

USP7 p.Met613Thr Uncertain significance ★ ⚠ same residue
USP7 p.Met613Leu 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

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-met613ile (accessed [today's date]).

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