Is USP53 p.Pro770Thr (c.2308C>A) pathogenic?

USP53 p.Pro770Thr (c.2308C>A) is classified Uncertain significance in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-08). AlphaMissense: likely benign (0.0693); Very rare (popmax 0.00196%, nfe); Associated with Inborn genetic diseases.

What condition is associated with USP53 p.Pro770Thr (c.2308C>A)?

USP53 p.Pro770Thr (c.2308C>A) is associated with Inborn genetic diseases (ClinVar).

How common is USP53 p.Pro770Thr (c.2308C>A) in the general population?

USP53 p.Pro770Thr (c.2308C>A) is very rare (popmax 0.00196%, nfe) (gnomAD).

What do computational predictors say about USP53 p.Pro770Thr (c.2308C>A)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

USP53 p.Pro770Thr

c.2308C>A · VCV3467248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00196%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -6.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.043	GERP -1.5
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.0026 · regional, not allelic
Overall
CADD	10.05	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 0.00196% European (non-Finnish) · 23/1,171,886 alleles

Filtering AF 0.00131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00144% 23/1,597,002 alleles · very rare exomes 22/1,445,742 · genomes 1/151,260 · joint denominator

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.Pro770Thr
Coding: c.2308C>A
MANE Select: NM_001371395
Type: single nucleotide variant
Location: chr4:119291221 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 770: a UniProt-annotated variant site (in pfic7)

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-pro770thr (accessed [today's date]).

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