Is USP7 p.Ala756Val (c.2267C>T) pathogenic?

USP7 p.Ala756Val (c.2267C>T) is classified Uncertain significance in USP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.8916); Absent from gnomAD v4.1; Associated with Hao-Fountain syndrome.

What condition is associated with USP7 p.Ala756Val (c.2267C>T)?

USP7 p.Ala756Val (c.2267C>T) is associated with Hao-Fountain syndrome (ClinVar).

How common is USP7 p.Ala756Val (c.2267C>T) in the general population?

USP7 p.Ala756Val (c.2267C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USP7 p.Ala756Val (c.2267C>T)?

AlphaMissense predicts likely pathogenic (score 0.8916) — an in-silico prediction, not a clinical call.

USP7 p.Ala756Val

c.2267C>T · VCV4883280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8916 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Hao-Fountain syndrome

Computational evidence

Protein change
AlphaMissense	0.8916	likely pathogenic
REVEL	0.294	indeterminate
SaProt	LLR -10.68	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 6,603 bp · p 1.4e-25 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Ala756Val
Coding: c.2267C>T
MANE Select: NM_003470
Type: single nucleotide variant
Location: chr16:8900572 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 756: 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); the 'interaction with icp0/vmw110' region

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

Disease context

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

For Hao-Fountain syndrome (Orphanet):

Onset: Infancy, Neonatal

Similar variants

USP7 p.Gln866Ter Pathogenic/Likely pathogenic ★★ same condition
USP7 c.3039+3A>G Uncertain significance ★★ same condition
USP7 c.852-4A>G Uncertain significance ★★ same condition
USP7 p.Thr177Asn Uncertain significance ★★ ⚠ same condition
USP7 p.Val929Met Uncertain significance ★★ ⚠ same condition
USP7 p.Glu345Lys Likely pathogenic ★ same condition
USP7 p.Leu386Ter Likely pathogenic ★ same condition
USP7 p.Phe118Leu 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-ala756val (accessed [today's date]).

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