Is USP7 p.Asp366Ala (c.1097A>C) pathogenic?

USP7 p.Asp366Ala (c.1097A>C) is classified Uncertain significance in USP7 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-06-16). AlphaMissense: likely pathogenic (0.9216); Absent from gnomAD v4.1; Associated with Hao-Fountain syndrome.

What condition is associated with USP7 p.Asp366Ala (c.1097A>C)?

USP7 p.Asp366Ala (c.1097A>C) is associated with Hao-Fountain syndrome (ClinVar).

How common is USP7 p.Asp366Ala (c.1097A>C) in the general population?

USP7 p.Asp366Ala (c.1097A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USP7 p.Asp366Ala (c.1097A>C)?

AlphaMissense predicts likely pathogenic (score 0.9216) — an in-silico prediction, not a clinical call.

USP7 p.Asp366Ala

c.1097A>C · rs2549235509 · VCV988717

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9216 · 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	0.9216	likely pathogenic
REVEL	0.544	indeterminate
SaProt	LLR -12.04	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 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 4,485 bp · p 0.56 · regional, not allelic
Overall
CADD	27.4	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.Asp366Ala
Coding: c.1097A>C
MANE Select: NM_003470
dbSNP: rs2549235509
Type: single nucleotide variant
Location: chr16:8910809 (GRCh38)
Gene constraint: LOEUF 0.085 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 86 PDB
Residue 366: 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 — 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-asp366ala (accessed [today's date]).

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