Is USP21 p.Pro31Ser (c.91C>T) pathogenic?

USP21 p.Pro31Ser (c.91C>T) is classified Uncertain significance in USP21 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: likely benign (0.0771); Very rare (popmax 0.00167%, amr).

How common is USP21 p.Pro31Ser (c.91C>T) in the general population?

USP21 p.Pro31Ser (c.91C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about USP21 p.Pro31Ser (c.91C>T)?

AlphaMissense predicts likely benign (score 0.0771) — an in-silico prediction, not a clinical call.

USP21 p.Pro31Ser

c.91C>T · VCV3814106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0771	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.49	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 0.42	GERP 1.7, phastCons 0.048
Regional constraint	o/e 1.01	unconstrained · MANE · 1,398 bp · p 0.86 · regional, not allelic
Overall
CADD	15.31	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 0.00167% Admixed American · 1/60,008 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,084 alleles · very rare exomes 1/1,461,872 · genomes 2/152,212 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,008
European (non-Finnish)	0.000169%	590,030

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.Pro31Ser
Coding: c.91C>T
MANE Select: NM_001014443
Type: single nucleotide variant
Location: chr1:161160731 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.70 · 4 PDB
Residue 31: 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-pro31ser (accessed [today's date]).

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