Is USP45 p.Lys774Ter (c.2320A>T) pathogenic?

USP45 p.Lys774Ter (c.2320A>T) is classified Uncertain significance in USP45 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-01-01). Very rare (popmax 0.000849%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with USP45 p.Lys774Ter (c.2320A>T)?

USP45 p.Lys774Ter (c.2320A>T) is associated with inherited retinal dystrophy (ClinVar).

How common is USP45 p.Lys774Ter (c.2320A>T) in the general population?

USP45 p.Lys774Ter (c.2320A>T) is very rare (popmax 0.000849%, nfe) (gnomAD).

USP45 p.Lys774Ter

c.2320A>T · VCV3249277

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000849%, nfe)

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (18 of 18) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.26	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 2	GERP -0.059, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000849% European (non-Finnish) · 10/1,178,214 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000684% 11/1,607,850 alleles · very rare exomes 10/1,455,656 · genomes 1/152,194 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,270
European (non-Finnish)grpmax	0.000849%	117,821

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys774Ter
Coding: c.2320A>T
MANE Select: NM_001346022
Type: single nucleotide variant
Location: chr6:99435841 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.28
Residue 774: 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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USP45 c.2073+1G>T Uncertain significance ★ same condition
USP45 p.Ala680Val Uncertain significance ★ ⚠ same condition
USP45 p.Glu220Ter Conflicting classifications of pathogenicity ★ same condition
USP45 p.Tyr598Ter Uncertain significance ★ same condition
USP45 p.Tyr730Ter Conflicting classifications of pathogenicity ★ same condition
USP45 p.Cys199Trp Uncertain significance ⚠ same condition
USP45 p.His114Arg Uncertain significance ⚠ same condition
USP45 p.Val337fs Benign/Likely benign ★★ same condition

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-lys774ter (accessed [today's date]).

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