Is USP28 p.Pro37Ser (c.109C>T) pathogenic?

USP28 p.Pro37Ser (c.109C>T) is classified Uncertain significance in USP28 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.0918); Ultra-rare (popmax 0.0176%, sas).

How common is USP28 p.Pro37Ser (c.109C>T) in the general population?

USP28 p.Pro37Ser (c.109C>T) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

What do computational predictors say about USP28 p.Pro37Ser (c.109C>T)?

AlphaMissense predicts likely benign (score 0.0918) — an in-silico prediction, not a clinical call.

USP28 p.Pro37Ser

c.109C>T · rs764785803 · VCV3187330

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0918 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0918	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -5.49	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 7.6	GERP 1.8, phastCons 1
Overall
CADD	19.82	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 0.0176% South Asian · 16/91,064 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00105% 17/1,613,842 alleles · ultra-rare exomes 16/1,461,686 · genomes 1/152,156 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,691
Remaining individualsnot grpmax-eligible	0.0016%	62,474

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.Pro37Ser
Coding: c.109C>T
MANE Select: NM_001346252
dbSNP: rs764785803
Type: single nucleotide variant
Location: chr11:113854284 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.20 · 15 PDB
Residue 37: an α-helix

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-pro37ser (accessed [today's date]).

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