Is USP5 p.Pro520Ser (c.1558C>T) pathogenic?

USP5 p.Pro520Ser (c.1558C>T) is classified Uncertain significance in USP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-20). AlphaMissense: ambiguous (0.4171); Ultra-rare (popmax 0.0147%, afr).

How common is USP5 p.Pro520Ser (c.1558C>T) in the general population?

USP5 p.Pro520Ser (c.1558C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about USP5 p.Pro520Ser (c.1558C>T)?

AlphaMissense predicts ambiguous (score 0.4171) — an in-silico prediction, not a clinical call.

USP5 p.Pro520Ser

c.1558C>T · VCV3467218

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4171 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4171	ambiguous
REVEL	0.086	moderately benign-leaning
SaProt	LLR -14.73	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 11 kb · p 4e-24 · regional, not allelic
Overall
CADD	25.3	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 0.0147% African / African-American · 11/74,706 alleles

Filtering AF 0.00818% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00635%

Overall 0.000687% 11/1,600,436 alleles · ultra-rare

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: USP5
Protein: p.Pro520Ser
Coding: c.1558C>T
MANE Select: NM_001098536
Type: single nucleotide variant
Location: chr12:6861502 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 12 PDB
Residue 520: the usp domain; an α-helix

Full USP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP5 p.Leu380= Benign ★★ same type
USP5 p.Leu489= Benign ★★ same type
USP5 p.Pro609= Benign ★★ same type
USP5 p.Val18= Benign ★★ same type
USP5 p.Ala495Thr Uncertain significance ★ ⚠ same type
USP5 p.Ala549Val Uncertain significance ★ ⚠ same type
USP5 p.Ala718Thr Uncertain significance ★ ⚠ same type
USP5 p.Ala780Ser 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/usp5-p-pro520ser (accessed [today's date]).

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