Is USP25 p.Pro220Ser (c.658C>T) pathogenic?

USP25 p.Pro220Ser (c.658C>T) is classified Uncertain significance in USP25 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-06). AlphaMissense: ambiguous (0.4381); Very rare (popmax 0.00369%, amr).

How common is USP25 p.Pro220Ser (c.658C>T) in the general population?

USP25 p.Pro220Ser (c.658C>T) is very rare (popmax 0.00369%, amr) (gnomAD).

What do computational predictors say about USP25 p.Pro220Ser (c.658C>T)?

AlphaMissense predicts ambiguous (score 0.4381) — an in-silico prediction, not a clinical call.

USP25 p.Pro220Ser

c.658C>T · VCV3466799

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4381 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00369%, amr)

Computational evidence

Protein change
AlphaMissense	0.4381	ambiguous
REVEL	0.48	indeterminate
SaProt	LLR -3.03	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 101 kb · p 0.0049 · regional, not allelic
Overall
CADD	24.5	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 0.00369% Admixed American · 2/54,236 alleles

Filtering AF 0.000612% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000229%

Overall 0.000126% 2/1,587,834 alleles · very rare exomes 2/1,435,842 · genomes 0/151,992 · 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: USP25
Protein: p.Pro220Ser
Coding: c.658C>T
MANE Select: NM_001283041
Type: single nucleotide variant
Location: chr21:15805136 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.12 · 7 PDB
Residue 220: the usp domain; an α-helix

Full USP25 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP25 p.Arg217Gln Uncertain significance ★★ ⚠ same type
USP25 p.Val596Ile Uncertain significance ★★ ⚠ same type
USP25 p.Ala474Thr Uncertain significance ★ ⚠ same type
USP25 p.Ala659Ser Uncertain significance ★ ⚠ same type
USP25 p.Ala705Val Uncertain significance ★ ⚠ same type
USP25 p.Ala718Val Uncertain significance ★ ⚠ same type
USP25 p.Ala919Thr Uncertain significance ★ ⚠ same type
USP25 p.Arg1058Gln 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/usp25-p-pro220ser (accessed [today's date]).

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