Is USP25 p.Pro478Ser (c.1432C>T) pathogenic?

USP25 p.Pro478Ser (c.1432C>T) is classified Uncertain significance in USP25 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: likely benign (0.0656); Very rare (popmax 0.00267%, afr).

How common is USP25 p.Pro478Ser (c.1432C>T) in the general population?

USP25 p.Pro478Ser (c.1432C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about USP25 p.Pro478Ser (c.1432C>T)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

USP25 p.Pro478Ser

c.1432C>T · VCV3466800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -5.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.68	GERP -4.7, phastCons 0.002
Regional constraint	o/e 0.89	unconstrained · MANE · 101 kb · p 0.0049 · regional, not allelic
Overall
CADD	1.888	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00267% African / African-American · 2/74,932 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000434% 7/1,613,870 alleles · very rare exomes 5/1,461,714 · genomes 2/152,156 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,466
European (non-Finnish)	0.000424%	235,985

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.Pro478Ser
Coding: c.1432C>T
MANE Select: NM_001283041
Type: single nucleotide variant
Location: chr21:15826331 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.12 · 7 PDB
Residue 478: the usp domain; the 'disordered' region

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-pro478ser (accessed [today's date]).

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