Is USP53 p.Pro94Ser (c.280C>T) pathogenic?

USP53 p.Pro94Ser (c.280C>T) is classified Uncertain significance in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely pathogenic (0.6797); Very rare (popmax 0.00667%, afr); Associated with Inborn genetic diseases.

What condition is associated with USP53 p.Pro94Ser (c.280C>T)?

USP53 p.Pro94Ser (c.280C>T) is associated with Inborn genetic diseases (ClinVar).

How common is USP53 p.Pro94Ser (c.280C>T) in the general population?

USP53 p.Pro94Ser (c.280C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about USP53 p.Pro94Ser (c.280C>T)?

AlphaMissense predicts likely pathogenic (score 0.6797) — an in-silico prediction, not a clinical call.

USP53 p.Pro94Ser

c.280C>T · rs772606705 · VCV2484861

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6797	likely pathogenic
REVEL	0.268	benign-leaning
SaProt	LLR -9.52	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.0026 · regional, not allelic
Overall
CADD	26.1	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 0.00667% African / African-American · 5/74,918 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000434% 7/1,613,916 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,984
Admixed American	0.00333%	30,000

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.Pro94Ser
Coding: c.280C>T
MANE Select: NM_001371395
dbSNP: rs772606705
Type: single nucleotide variant
Location: chr4:119248790 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 94: the usp domain; a UniProt-annotated variant site (in pfic7); a UniProt-annotated variant site (in pfic7; uncertain significance)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USP53 p.Asn97Asp Uncertain significance ★★ ⚠ same condition
USP53 p.Asn97Ser Uncertain significance ★★ ⚠ same condition
USP53 p.Asp482His Uncertain significance ★★ ⚠ same condition
USP53 p.Ile613Thr Uncertain significance ★★ ⚠ same condition
USP53 p.Ser185Phe Uncertain significance ★★ ⚠ same condition
USP53 p.Ser334Phe Uncertain significance ★★ ⚠ same condition
USP53 p.Thr1046Met Uncertain significance ★★ ⚠ same condition
USP53 p.Val845Ile Uncertain significance ★★ ⚠ 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/usp53-p-pro94ser (accessed [today's date]).

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