Is USP7 p.Arg508Ter (c.1522C>T) pathogenic?

USP7 p.Arg508Ter (c.1522C>T) is classified Pathogenic in USP7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-05). Absent from gnomAD v4.1; Associated with Hao-Fountain syndrome due to USP7 mutation.

What condition is associated with USP7 p.Arg508Ter (c.1522C>T)?

USP7 p.Arg508Ter (c.1522C>T) is associated with Hao-Fountain syndrome due to USP7 mutation (ClinVar).

How common is USP7 p.Arg508Ter (c.1522C>T) in the general population?

USP7 p.Arg508Ter (c.1522C>T) is absent from gnomAD v4.1 (gnomAD).

USP7 p.Arg508Ter

c.1522C>T · rs2061841667 · VCV871804

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

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.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 14 of 31
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	GERP 2.3, phastCons 1
Overall
CADD	47.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Arg508Ter
Coding: c.1522C>T
MANE Select: NM_003470
dbSNP: rs2061841667
Type: single nucleotide variant
Location: chr16:8905238 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 508: an α-helix; 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

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.Arg508Gln Uncertain significance ★ ⚠ same residue
USP7 p.Arg1018Ter Pathogenic/Likely 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
USP7 p.Glu60Ter 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-arg508ter (accessed [today's date]).

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