Is USP53 p.Ser690fs (c.2068dup) pathogenic?

USP53 p.Ser690fs (c.2068dup) is classified Pathogenic in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-05). Very rare (popmax 0.0078%, nfe).

How common is USP53 p.Ser690fs (c.2068dup) in the general population?

USP53 p.Ser690fs (c.2068dup) is very rare (popmax 0.0078%, nfe) (gnomAD).

USP53 p.Ser690fs

c.2068dup · rs769939924 · VCV2075241

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0078%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Overall
CADD	34.0	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 0.0078% European (non-Finnish) · 92/1,180,022 alleles

Filtering AF 0.00648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.006%

Overall 0.00582% 94/1,614,060 alleles · very rare exomes 93/1,461,838 · genomes 1/152,222 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0078%	12,826
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: USP53
Protein: p.Ser690fs
Coding: c.2068dup
MANE Select: NM_001371395
dbSNP: rs769939924
Type: Duplication
Location: chr4:119271925 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 690: a UniProt-annotated variant site (in pfic7)

Full USP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP53 p.Ala27fs Likely pathogenic ★ same type
USP53 p.Arg8fs Pathogenic ★ same type
USP53 p.Ile546fs Likely pathogenic ★ same type
USP53 p.Ile650fs Pathogenic ★ same type
USP53 p.Ser357fs Pathogenic ★ same type
USP53 c.372+14_372+16dup Likely benign ★ 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/usp53-p-ser690fs (accessed [today's date]).

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