Is USP45 p.Arg2Trp (c.4C>T) pathogenic?

USP45 p.Arg2Trp (c.4C>T) is classified Uncertain significance in USP45 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.5731); Very rare (popmax 0.00669%, afr).

How common is USP45 p.Arg2Trp (c.4C>T) in the general population?

USP45 p.Arg2Trp (c.4C>T) is very rare (popmax 0.00669%, afr) (gnomAD).

What do computational predictors say about USP45 p.Arg2Trp (c.4C>T)?

AlphaMissense predicts likely pathogenic (score 0.5731) — an in-silico prediction, not a clinical call.

USP45 p.Arg2Trp

c.4C>T · VCV4603067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5731 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5731	likely pathogenic
REVEL	0.317	indeterminate
SaProt	LLR -8.75	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.2	GERP 0.63, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 75 kb · p 0.15 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% African / African-American · 5/74,770 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00093% 15/1,612,124 alleles · very rare exomes 13/1,460,204 · genomes 2/151,920 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00669%	14,954
Remaining individualsnot grpmax-eligible	0.00321%	31,196
East Asian	0.00223%	44,856
South Asian	0.0022%	45,409
Admixed American	0.00167%	59,926
European (non-Finnish)	0.000339%	294,726

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.Arg2Trp
Coding: c.4C>T
MANE Select: NM_001346022
Type: single nucleotide variant
Location: chr6:99510217 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.28
Residue 2: the 'interaction with ercc1' region; the 'disordered' region

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

Similar variants

USP45 p.Arg2_Val3insTer 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-arg2trp (accessed [today's date]).

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