Is USP45 p.Arg697His (c.2090G>A) pathogenic?

USP45 p.Arg697His (c.2090G>A) is classified Uncertain significance in USP45 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: likely benign (0.1325); Ultra-rare (popmax 0.0161%, afr).

How common is USP45 p.Arg697His (c.2090G>A) in the general population?

USP45 p.Arg697His (c.2090G>A) is ultra-rare (popmax 0.0161%, afr) (gnomAD).

What do computational predictors say about USP45 p.Arg697His (c.2090G>A)?

AlphaMissense predicts likely benign (score 0.1325) — an in-silico prediction, not a clinical call.

USP45 p.Arg697His

c.2090G>A · VCV3467179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1325 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0161%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1325	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -7.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 75 kb · p 0.15 · regional, not allelic
Overall
CADD	29.7	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 0.0161% African / African-American · 12/74,726 alleles

Filtering AF 0.00924% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00723%

Overall 0.00143% 23/1,606,578 alleles · ultra-rare exomes 13/1,454,526 · genomes 10/152,052 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0161%	6,227
Remaining individualsnot grpmax-eligible	0.00483%	20,705
European (non-Finnish)	0.00068%	147,041

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: USP45
Protein: p.Arg697His
Coding: c.2090G>A
MANE Select: NM_001346022
Type: single nucleotide variant
Location: chr6:99439839 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.28
Residue 697: the usp domain; a UniProt-annotated variant site (in lca19; uncertain significance)

Full USP45 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP45 p.Arg697Leu Uncertain significance ★ same residue
USP45 p.Gly570Glu Uncertain significance ★★ ⚠ same type
USP45 c.845+2T>C Benign ★★ same type
USP45 p.Ile418Thr Benign/Likely benign ★★ same type
USP45 p.Arg443Ter Likely pathogenic ★ same type
USP45 p.Ser508Ter Pathogenic ★ same type
USP45 c.2073+1G>T Uncertain significance ★ same type
USP45 c.377+5G>A 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/usp45-p-arg697his (accessed [today's date]).

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