Is USP7 p.Pro257= (c.771T>A) pathogenic?

USP7 p.Pro257= (c.771T>A) is classified Uncertain significance in USP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). Absent from gnomAD v4.1; Associated with Hao-Fountain syndrome due to USP7 mutation.

What condition is associated with USP7 p.Pro257= (c.771T>A)?

USP7 p.Pro257= (c.771T>A) is associated with Hao-Fountain syndrome due to USP7 mutation (ClinVar).

How common is USP7 p.Pro257= (c.771T>A) in the general population?

USP7 p.Pro257= (c.771T>A) is absent from gnomAD v4.1 (gnomAD).

USP7 p.Pro257=

c.771T>A · VCV4076297

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Hao-Fountain syndrome due to USP7 mutation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.18	GERP -4.6, phastCons 0.004
Overall
CADD	4.603	PHRED · no single calibrated threshold — expert panels disagree

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.Pro257=
Coding: c.771T>A
MANE Select: NM_003470
Type: single nucleotide variant
Location: chr16:8917106 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 257: 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

Disease context

Hao-Fountain syndrome due to USP7 mutation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hao-Fountain syndrome (Orphanet):

Onset: Infancy, Neonatal

Similar variants

USP7 p.Pro257Ser Uncertain significance ★ ⚠ same residue
USP7 p.Arg1018Ter Pathogenic/Likely pathogenic ★★ same condition
USP7 p.Arg508Ter Pathogenic ★★ same condition
USP7 p.Arg793Cys Uncertain significance ★★ ⚠ same condition
USP7 c.2919+1G>A Likely pathogenic ★ same condition
USP7 c.3040-1G>A Likely pathogenic ★ same condition
USP7 c.3111+1G>A Pathogenic ★ same condition
USP7 p.Arg1023Ter Likely pathogenic ★ 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-pro257 (accessed [today's date]).

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