Is USP21 p.Pro103Ala (c.307C>G) pathogenic?

USP21 p.Pro103Ala (c.307C>G) is classified Uncertain significance in USP21 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-25). AlphaMissense: likely benign (0.0702); Absent from gnomAD v4.1.

How common is USP21 p.Pro103Ala (c.307C>G) in the general population?

USP21 p.Pro103Ala (c.307C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USP21 p.Pro103Ala (c.307C>G)?

AlphaMissense predicts likely benign (score 0.0702) — an in-silico prediction, not a clinical call.

USP21 p.Pro103Ala

c.307C>G · rs2525071761 · VCV2540497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0702 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0702	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -7.26	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 2.8	GERP 1.9, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 1,398 bp · p 0.86 · regional, not allelic
Overall
CADD	21.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: USP21
Protein: p.Pro103Ala
Coding: c.307C>G
MANE Select: NM_001014443
dbSNP: rs2525071761
Type: single nucleotide variant
Location: chr1:161160947 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.70 · 4 PDB
Residue 103: the 'disordered' region

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-pro103ala (accessed [today's date]).

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