Is CUL4B p.Arg596Cys (c.1786C>T) pathogenic?

CUL4B p.Arg596Cys (c.1786C>T) is classified Conflicting classifications of pathogenicity in CUL4B (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2015-09-28). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with X-linked intellectual disability, Cabezas type.

What condition is associated with CUL4B p.Arg596Cys (c.1786C>T)?

CUL4B p.Arg596Cys (c.1786C>T) is associated with X-linked intellectual disability, Cabezas type (ClinVar).

How common is CUL4B p.Arg596Cys (c.1786C>T) in the general population?

CUL4B p.Arg596Cys (c.1786C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CUL4B p.Arg596Cys (c.1786C>T)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

CUL4B p.Arg596Cys

c.1786C>T · rs1556200641 · VCV434873

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked intellectual disability, Cabezas type

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 5% in CUL4B
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -13.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 14 kb · p 8.5e-31 · regional, not allelic
Overall
CADD	26.8	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 R614C vs ClinVar R596C) — 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.Arg596Cys
Coding: c.1786C>T
MANE Select: NM_001079872
dbSNP: rs1556200641
Type: single nucleotide variant
Location: chrX:120538726 (GRCh38)
Structure: AlphaFold pLDDT 80.02 · 5 PDB

Full CUL4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked intellectual disability, Cabezas type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CUL4B p.Arg596Leu Likely pathogenic ★ same residue
CUL4B p.Arg351Ter Likely pathogenic ★★ same condition
CUL4B p.Arg370Ter Pathogenic ★★ same condition
CUL4B p.Gln241Ter Pathogenic ★★ same condition
CUL4B p.Thr813= Pathogenic/Likely pathogenic ★★ same condition
CUL4B c.2592+3A>T Uncertain significance ★★ same condition
CUL4B c.777-3C>T Uncertain significance ★★ same condition
CUL4B p.Ala16Pro 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/cul4b-p-arg596cys (accessed [today's date]).

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