Is CUL4B p.Arg466Pro (c.1397G>C) pathogenic?

CUL4B p.Arg466Pro (c.1397G>C) is classified Uncertain significance in CUL4B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: likely pathogenic (0.7424); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CUL4B p.Arg466Pro (c.1397G>C)?

CUL4B p.Arg466Pro (c.1397G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CUL4B p.Arg466Pro (c.1397G>C) in the general population?

CUL4B p.Arg466Pro (c.1397G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CUL4B p.Arg466Pro (c.1397G>C)?

AlphaMissense predicts likely pathogenic (score 0.7424) — an in-silico prediction, not a clinical call.

CUL4B p.Arg466Pro

c.1397G>C · rs1172227126 · VCV3078959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7424 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7424	likely pathogenic
REVEL	0.334	indeterminate
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 17 kb · p 7.5e-08 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R484P vs ClinVar R466P) — verify the residue.

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: CUL4B
Protein: p.Arg466Pro
Coding: c.1397G>C
MANE Select: NM_001079872
dbSNP: rs1172227126
Type: single nucleotide variant
Location: chrX:120541648 (GRCh38)
Structure: AlphaFold pLDDT 80.02 · 5 PDB

Full CUL4B 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

CUL4B p.Arg466Ter Likely pathogenic ★ same residue
CUL4B p.Arg466Gln Uncertain significance ★ ⚠ same residue
CUL4B p.Arg466= Likely benign ★ same residue
CUL4B p.His397Tyr Uncertain significance ★★ ⚠ same condition
CUL4B p.Ser166Pro Uncertain significance ★★ ⚠ same condition
CUL4B c.1324+15G>A Benign ★★ same condition
CUL4B p.Arg878= Benign/Likely benign ★★ same condition
CUL4B p.Asp884= 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/cul4b-p-arg466pro (accessed [today's date]).

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