Is USP5 p.Pro609= (c.1827C>T) pathogenic?

USP5 p.Pro609= (c.1827C>T) is classified Benign in USP5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-04-04). Common (popmax 7.96%, afr) — too common for a highly-penetrant pathogenic allele.

USP5 p.Pro609=

Q: How common is USP5 p.Pro609= (c.1827C>T) in the general population?

USP5 p.Pro609= (c.1827C>T) is common (popmax 7.96%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1827C>T · rs35165406 · VCV781062

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 7.96%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.9	GERP -5.1
Overall
CADD	0.289	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.96% African / African-American · 5,972/75,000 alleles

Filtering AF 7.79% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.72%

Overall 0.443% 7,146/1,614,114 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.96%	13
Remaining individualsnot grpmax-eligible	0.565%	177
Middle Eastern	0.561%	178
Admixed American	0.477%	210
Ashkenazi Jewishnot grpmax-eligible	0.162%	617
South Asian	0.0516%	1,938
European (non-Finnish)	0.0332%	3,010
East Asian	0.0312%	3,206

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: USP5
Protein: p.Pro609=
Coding: c.1827C>T
MANE Select: NM_001098536
dbSNP: rs35165406
Type: single nucleotide variant
Location: chr12:6863250 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 12 PDB
Residue 609: the usp domain; a disulfide bond

Full USP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP5 p.Pro609Ser Uncertain significance ★ ⚠ same residue
USP5 p.Leu380= Benign ★★ same type
USP5 p.Leu489= Benign ★★ same type
USP5 p.Val18= Benign ★★ same type
USP5 p.Ala495Thr Uncertain significance ★ ⚠ same type
USP5 p.Ala549Val Uncertain significance ★ ⚠ same type
USP5 p.Ala718Thr Uncertain significance ★ ⚠ same type
USP5 p.Ala780Ser 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/usp5-p-pro609 (accessed [today's date]).

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