Is USP7 p.Arg77Cys (c.229C>T) pathogenic?

USP7 p.Arg77Cys (c.229C>T) is classified Uncertain significance in USP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-18). AlphaMissense: likely benign (0.3133); Very rare (popmax 0.000508%, nfe); Associated with Hao-Fountain syndrome due to USP7 mutation.

What condition is associated with USP7 p.Arg77Cys (c.229C>T)?

USP7 p.Arg77Cys (c.229C>T) is associated with Hao-Fountain syndrome due to USP7 mutation (ClinVar).

How common is USP7 p.Arg77Cys (c.229C>T) in the general population?

USP7 p.Arg77Cys (c.229C>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about USP7 p.Arg77Cys (c.229C>T)?

AlphaMissense predicts likely benign (score 0.3133) — an in-silico prediction, not a clinical call.

USP7 p.Arg77Cys

c.229C>T · VCV3381234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Hao-Fountain syndrome due to USP7 mutation

Computational evidence

Protein change
AlphaMissense	0.3133	likely benign
REVEL	0.47	indeterminate
SaProt	LLR -10.56	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 40 kb · p 0.22 · regional, not allelic
Overall
CADD	33.0	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 0.000508% European (non-Finnish) · 6/1,180,054 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,614,056 alleles · very rare exomes 4/1,461,886 · genomes 2/152,170 · 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.Arg77Cys
Coding: c.229C>T
MANE Select: NM_003470
Type: single nucleotide variant
Location: chr16:8923369 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 77: the math domain; the 'interaction with tspyl5' region; a β-strand; the 'interaction with p53/tp53, mdm2 and ebna1' region; the 'necessary for nuclear localization' region

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.Arg77His Uncertain significance ★ ⚠ same residue
USP7 p.Arg77Pro 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

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-arg77cys (accessed [today's date]).

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