Is USP28 p.Pro879Ser (c.2635C>T) pathogenic?

USP28 p.Pro879Ser (c.2635C>T) is classified Uncertain significance in USP28 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely benign (0.1329); Very rare (popmax 0.00833%, amr).

How common is USP28 p.Pro879Ser (c.2635C>T) in the general population?

USP28 p.Pro879Ser (c.2635C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about USP28 p.Pro879Ser (c.2635C>T)?

AlphaMissense predicts likely benign (score 0.1329) — an in-silico prediction, not a clinical call.

USP28 p.Pro879Ser

c.2635C>T · VCV4197248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1329 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1329	likely benign
REVEL	0.285	benign-leaning
SaProt	LLR -6.86	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 9.9	GERP 2, phastCons 1
Overall
CADD	25.5	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P817S vs ClinVar P879S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,006 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00062% 10/1,613,986 alleles · very rare exomes 9/1,461,852 · genomes 1/152,134 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,001
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.000169%	590,005

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: USP28
Protein: p.Pro879Ser
Coding: c.2635C>T
MANE Select: NM_001346252
Type: single nucleotide variant
Location: chr11:113804998 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.20 · 15 PDB

Full USP28 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP28 p.Asp345Asn Uncertain significance ★★ ⚠ same type
USP28 p.Ala104Thr Uncertain significance ★ ⚠ same type
USP28 p.Ala132Val Uncertain significance ★ ⚠ same type
USP28 p.Ala270Ser Uncertain significance ★ ⚠ same type
USP28 p.Ala739Val Uncertain significance ★ ⚠ same type
USP28 p.Ala83Ser Uncertain significance ★ ⚠ same type
USP28 p.Ala89Thr Uncertain significance ★ ⚠ same type
USP28 p.Ala932Val 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/usp28-p-pro879ser (accessed [today's date]).

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