Is USP20 p.Ser288Leu (c.863C>T) pathogenic?

USP20 p.Ser288Leu (c.863C>T) is classified Uncertain significance in USP20 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely pathogenic (0.8186); Ultra-rare (popmax 0.01%, amr).

How common is USP20 p.Ser288Leu (c.863C>T) in the general population?

USP20 p.Ser288Leu (c.863C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about USP20 p.Ser288Leu (c.863C>T)?

AlphaMissense predicts likely pathogenic (score 0.8186) — an in-silico prediction, not a clinical call.

USP20 p.Ser288Leu

c.863C>T · rs759073791 · VCV2205290

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8186 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8186	likely pathogenic
REVEL	0.371	indeterminate
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 28 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	28.2	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 0.01% Admixed American · 6/59,992 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000682% 11/1,613,916 alleles · ultra-rare exomes 8/1,461,778 · genomes 3/152,138 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,999
African / African-American	0.00401%	24,967
European (non-Finnish)	0.000169%	589,991

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: USP20
Protein: p.Ser288Leu
Coding: c.863C>T
MANE Select: NM_001110303
dbSNP: rs759073791
Type: single nucleotide variant
Location: chr9:129868177 (GRCh38)
Gene constraint: LOEUF 0.784 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.11 · 1 PDB
Residue 288: the usp domain; the 'disordered' region

Full USP20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP20 p.Ser288= Benign ★★ same residue
USP20 p.Arg330Gly Uncertain significance ★★ ⚠ same type
USP20 p.Ile907= Benign ★★ same type
USP20 p.Pro367= Benign ★★ same type
USP20 p.Ser103Tyr Benign ★★ same type
USP20 p.Ala260Ser Uncertain significance ★ ⚠ same type
USP20 p.Ala317Thr Uncertain significance ★ ⚠ same type
USP20 p.Ala355Thr Uncertain significance ★ ⚠ 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/usp20-p-ser288leu (accessed [today's date]).

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