Is USB1 p.Arg252Pro (c.755G>C) pathogenic?

USB1 p.Arg252Pro (c.755G>C) is classified Uncertain significance in USB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-04). AlphaMissense: likely pathogenic (0.9178); Absent from gnomAD v4.1.

How common is USB1 p.Arg252Pro (c.755G>C) in the general population?

USB1 p.Arg252Pro (c.755G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USB1 p.Arg252Pro (c.755G>C)?

AlphaMissense predicts likely pathogenic (score 0.9178) — an in-silico prediction, not a clinical call.

USB1 p.Arg252Pro

c.755G>C · VCV4930312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9178 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9178	likely pathogenic · top 6% in USB1
REVEL	0.401	indeterminate
SaProt	LLR -13.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.79, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 19 kb · p 0.36 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: USB1
Protein: p.Arg252Pro
Coding: c.755G>C
MANE Select: NM_024598
Type: single nucleotide variant
Location: chr16:58020202 (GRCh38)
Gene constraint: LOEUF 1.016 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.91 · 5 PDB
Residue 252: a β-strand

Full USB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USB1 p.Arg252Cys Uncertain significance ★★ ⚠ same residue
USB1 p.Arg252His Uncertain significance ★★ ⚠ same residue
USB1 p.Arg252Ser Uncertain significance ★★ same residue
USB1 p.Arg252Leu Uncertain significance ★ ⚠ same residue
USB1 c.266-1G>A Pathogenic ★★ same type
USB1 p.His208Arg Likely pathogenic ★★ same type
USB1 p.Ala106Ser Uncertain significance ★★ ⚠ same type
USB1 p.Ala218Thr 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/usb1-p-arg252pro (accessed [today's date]).

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