Is USP28 p.Phe232Ser (c.695T>C) pathogenic?

USP28 p.Phe232Ser (c.695T>C) is classified Uncertain significance in USP28 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-18). AlphaMissense: likely pathogenic (0.9556); Ultra-rare (popmax 0.0266%, nfe).

How common is USP28 p.Phe232Ser (c.695T>C) in the general population?

USP28 p.Phe232Ser (c.695T>C) is ultra-rare (popmax 0.0266%, nfe) (gnomAD).

What do computational predictors say about USP28 p.Phe232Ser (c.695T>C)?

AlphaMissense predicts likely pathogenic (score 0.9556) — an in-silico prediction, not a clinical call.

USP28 p.Phe232Ser

c.695T>C · rs147814422 · VCV3187346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9556 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0266%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9556	likely pathogenic
REVEL	0.311	indeterminate
SaProt	LLR -8.92	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP -3.1, phastCons 1
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0266% European (non-Finnish) · 314/1,180,034 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0232%

Overall 0.0202% 326/1,614,070 alleles · ultra-rare exomes 305/1,461,878 · genomes 21/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0266%	3,758
Remaining individualsnot grpmax-eligible	0.008%	12,498
Admixed American	0.005%	19,999
African / African-American	0.00267%	37,462
South Asian	0.0022%	45,539

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.Phe232Ser
Coding: c.695T>C
MANE Select: NM_001346252
dbSNP: rs147814422
Type: single nucleotide variant
Location: chr11:113833484 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.20 · 15 PDB
Residue 232: the usp domain; a β-strand

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

Similar variants

USP28 p.Phe232Leu Uncertain significance ★ ⚠ same residue
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

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-phe232ser (accessed [today's date]).

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