Is USP8 p.Ser718Pro (c.2152T>C) pathogenic?

USP8 p.Ser718Pro (c.2152T>C) is classified Pathogenic in USP8 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2017-09-26). AlphaMissense: likely pathogenic (0.994); Very rare (popmax 8.47e-05%, nfe); Associated with Cushing disease due to pituitary adenoma.

What condition is associated with USP8 p.Ser718Pro (c.2152T>C)?

USP8 p.Ser718Pro (c.2152T>C) is associated with Cushing disease due to pituitary adenoma (ClinVar).

How common is USP8 p.Ser718Pro (c.2152T>C) in the general population?

USP8 p.Ser718Pro (c.2152T>C) is very rare (popmax 8.47e-05%, nfe) (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.Ser718Pro (c.2152T>C)?

AlphaMissense predicts likely pathogenic (score 0.994) — an in-silico prediction, not a clinical call.

USP8 p.Ser718Pro

c.2152T>C · rs672601307 · VCV161992

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cushing disease due to pituitary adenoma

Computational evidence

Protein change
AlphaMissense	0.994	likely pathogenic ✓ concordant with ClinVar · top 6% in USP8
REVEL	0.247	benign-leaning
SaProt	LLR -10.71	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 16 kb · p 0.12 · regional, not allelic
Overall
CADD	25.5	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 8.47e-05% European (non-Finnish) · 1/1,180,014 alleles

Overall 6.2e-05% 1/1,614,074 alleles · very rare exomes 1/1,461,890 · genomes 0/152,184 · 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: USP8
Protein: p.Ser718Pro
Coding: c.2152T>C
MANE Select: NM_005154
dbSNP: rs672601307
Type: single nucleotide variant
Location: chr15:50490443 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB
Residue 718: a modified residue (phosphoserine); a UniProt-annotated variant site (in pita4; uncertain significance; somatic mutation); a UniProt-annotated variant site (in pita4; uncertain significance; somatic mutation; localizes to nucleus instead of cytoplasm); 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.Ser718Cys Pathogenic ⚠ same residue
USP8 p.Pro703His Uncertain significance ★★ ⚠ same condition
USP8 p.Pro720Arg 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-ser718pro (accessed [today's date]).

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