Is USP8 p.Pro720Arg (c.2159C>G) pathogenic?

USP8 p.Pro720Arg (c.2159C>G) is classified Pathogenic in USP8 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2017-09-26). AlphaMissense: likely pathogenic (0.9526); No allele count reported in gnomAD v4.1 (AN 1,614,136); Associated with Cushing disease due to pituitary adenoma.

What condition is associated with USP8 p.Pro720Arg (c.2159C>G)?

USP8 p.Pro720Arg (c.2159C>G) is associated with Cushing disease due to pituitary adenoma (ClinVar).

How common is USP8 p.Pro720Arg (c.2159C>G) in the general population?

USP8 p.Pro720Arg (c.2159C>G) is no allele count reported in gnomAD v4.1 (AN 1,614,136) (gnomAD).

How is Cushing disease inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about USP8 p.Pro720Arg (c.2159C>G)?

AlphaMissense predicts likely pathogenic (score 0.9526) — an in-silico prediction, not a clinical call.

USP8 p.Pro720Arg

c.2159C>G · rs672601311 · VCV161995

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9526 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,136)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cushing disease due to pituitary adenoma

Computational evidence

Protein change
AlphaMissense	0.9526	likely pathogenic ✓ concordant with ClinVar
REVEL	0.326	indeterminate
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.38	acceptor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 16 kb · p 0.12 · regional, not allelic
Overall
CADD	24.9	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

No allele count reported in gnomAD v4.1 (AN 1,614,136). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: USP8
Protein: p.Pro720Arg
Coding: c.2159C>G
MANE Select: NM_005154
dbSNP: rs672601311
Type: single nucleotide variant
Location: chr15:50490450 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB
Residue 720: a UniProt-annotated variant site (in pita4; uncertain significance; somatic mutation); the 'disordered' region

Full USP8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cushing disease due to pituitary adenoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cushing disease (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

USP8 p.Pro703His Uncertain significance ★★ ⚠ same condition
USP8 p.Ser718Cys Pathogenic ⚠ same condition
USP8 p.Ser718Pro Pathogenic ⚠ same condition
USP8 p.Ser719del Pathogenic same condition
USP8 p.Arg133Trp Uncertain significance ★★ ⚠ same type
USP8 p.Phe875Ser Uncertain significance ★★ ⚠ same type
USP8 c.104+16C>T Benign ★★ same type
USP8 c.250-8A>C Benign ★★ same type

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/usp8-p-pro720arg (accessed [today's date]).

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