Is USP19 p.Arg548Pro (c.1643G>C) pathogenic?

USP19 p.Arg548Pro (c.1643G>C) is classified Uncertain significance in USP19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). AlphaMissense: ambiguous (0.4057); Ultra-rare (popmax 0.0395%, sas).

How common is USP19 p.Arg548Pro (c.1643G>C) in the general population?

USP19 p.Arg548Pro (c.1643G>C) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

What do computational predictors say about USP19 p.Arg548Pro (c.1643G>C)?

AlphaMissense predicts ambiguous (score 0.4057) — an in-silico prediction, not a clinical call.

USP19 p.Arg548Pro

c.1643G>C · VCV4602620

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4057 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4057	ambiguous
REVEL	0.213	benign-leaning
SaProt	LLR -4.89	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,407 bp · p 0.42 · regional, not allelic
Overall
CADD	23.5	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 R445P vs ClinVar R548P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0395% South Asian · 36/91,046 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00223% 36/1,613,732 alleles · ultra-rare exomes 36/1,461,418 · genomes 0/152,314 · 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.Arg548Pro
Coding: c.1643G>C
MANE Select: NM_001199161
Type: single nucleotide variant
Location: chr3:49115773 (GRCh38)
Gene constraint: LOEUF 0.297 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.32 · 5 PDB
Residue 445 UniProt numbering: the 'disordered' region

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-arg548pro (accessed [today's date]).

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