Is USP28 p.Ser856Phe (c.2567C>T) pathogenic?

USP28 p.Ser856Phe (c.2567C>T) is classified Uncertain significance in USP28 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: likely pathogenic (0.6678); Ultra-rare (popmax 0.0214%, afr).

How common is USP28 p.Ser856Phe (c.2567C>T) in the general population?

USP28 p.Ser856Phe (c.2567C>T) is ultra-rare (popmax 0.0214%, afr) (gnomAD).

What do computational predictors say about USP28 p.Ser856Phe (c.2567C>T)?

AlphaMissense predicts likely pathogenic (score 0.6678) — an in-silico prediction, not a clinical call.

USP28 p.Ser856Phe

c.2567C>T · rs139463252 · VCV2369305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6678 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6678	likely pathogenic
REVEL	0.359	indeterminate
SaProt	LLR -9.28	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S794F vs ClinVar S856F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0214% African / African-American · 16/74,714 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00341% 55/1,612,064 alleles · ultra-rare exomes 46/1,459,898 · genomes 9/152,166 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0214%	4,670
Middle Eastern	0.0166%	6,038
Remaining individualsnot grpmax-eligible	0.0112%	8,915
European (non-Finnish)	0.00254%	39,304
South Asian	0.0011%	90,942

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.Ser856Phe
Coding: c.2567C>T
MANE Select: NM_001346252
dbSNP: rs139463252
Type: single nucleotide variant
Location: chr11:113806508 (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-ser856phe (accessed [today's date]).

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