Is USP21 p.Pro347Ser (c.1039C>T) pathogenic?

USP21 p.Pro347Ser (c.1039C>T) is classified Uncertain significance in USP21 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.0875); Very rare (popmax 0.00145%, nfe).

How common is USP21 p.Pro347Ser (c.1039C>T) in the general population?

USP21 p.Pro347Ser (c.1039C>T) is very rare (popmax 0.00145%, nfe) (gnomAD).

What do computational predictors say about USP21 p.Pro347Ser (c.1039C>T)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

USP21 p.Pro347Ser

c.1039C>T · VCV4602670

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00145%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.6	GERP 0.45, phastCons 0.99
Regional constraint	o/e 1.37	unconstrained · MANE · 68 bp · p 0.047 · regional, not allelic
Overall
CADD	19.06	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 0.00145% European (non-Finnish) · 17/1,176,378 alleles

Filtering AF 0.00088% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00072%

Overall 0.00106% 17/1,604,546 alleles · very rare exomes 17/1,452,272 · genomes 0/152,274 · 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: USP21
Protein: p.Pro347Ser
Coding: c.1039C>T
MANE Select: NM_001014443
Type: single nucleotide variant
Location: chr1:161163064 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.70 · 4 PDB
Residue 347: the usp domain

Full USP21 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP21 p.Ala143Val Uncertain significance ★ ⚠ same type
USP21 p.Arg105Trp Uncertain significance ★ ⚠ same type
USP21 p.Arg110His Uncertain significance ★ ⚠ same type
USP21 p.Arg11Cys Uncertain significance ★ ⚠ same type
USP21 p.Arg13Gln Uncertain significance ★ ⚠ same type
USP21 p.Arg145Gln Uncertain significance ★ ⚠ same type
USP21 p.Arg145Trp Uncertain significance ★ ⚠ same type
USP21 p.Arg153His 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/usp21-p-pro347ser (accessed [today's date]).

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