Is USP19 p.Pro289Ser (c.865C>T) pathogenic?

USP19 p.Pro289Ser (c.865C>T) is classified Uncertain significance in USP19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). Very rare (popmax 0.00167%, nfe).

How common is USP19 p.Pro289Ser (c.865C>T) in the general population?

USP19 p.Pro289Ser (c.865C>T) is very rare (popmax 0.00167%, nfe) (gnomAD).

USP19 p.Pro289Ser

c.865C>T · VCV3978423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.057	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,407 bp · p 0.42 · regional, not allelic
Overall
CADD	18.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% European (non-Finnish) · 19/1,136,484 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000862%

Overall 0.00124% 19/1,531,650 alleles · very rare exomes 16/1,379,550 · genomes 3/152,100 · joint denominator

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: USP19
Protein: p.Pro289Ser
Coding: c.865C>T
MANE Select: NM_001199161
Type: single nucleotide variant
Location: chr3:49117103 (GRCh38)
Gene constraint: LOEUF 0.297 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.32 · 5 PDB
Residue 289: the cs 2 domain; a β-strand

Full USP19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP19 c.2292+7T>C Benign ★★ same type
USP19 p.Pro487= Benign ★★ same type
USP19 c.4039-440G>A Uncertain significance ★ ⚠ same type
USP19 c.4039-477G>A Uncertain significance ★ ⚠ same type
USP19 c.4039-482C>G Uncertain significance ★ ⚠ same type
USP19 c.4039-518G>A Uncertain significance ★ ⚠ same type
USP19 c.4039-519C>T Uncertain significance ★ ⚠ same type
USP19 c.4039-543A>T 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/usp19-p-pro289ser (accessed [today's date]).

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