Is CUL4B p.Pro654= (c.1962G>A) pathogenic?

CUL4B p.Pro654= (c.1962G>A) is classified Benign/Likely benign in CUL4B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-01). Ultra-rare (popmax 0.0464%, mid); Associated with X-linked intellectual disability, Cabezas type.

What condition is associated with CUL4B p.Pro654= (c.1962G>A)?

CUL4B p.Pro654= (c.1962G>A) is associated with X-linked intellectual disability, Cabezas type (ClinVar).

How common is CUL4B p.Pro654= (c.1962G>A) in the general population?

CUL4B p.Pro654= (c.1962G>A) is ultra-rare (popmax 0.0464%, mid) (gnomAD).

CUL4B p.Pro654=

c.1962G>A · rs185389157 · VCV719923

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0464%, mid)

Conditions

X-linked intellectual disability, Cabezas type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -5.4, phastCons 1
Overall
CADD	1.518	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0464% Middle Eastern · 2/4,308 alleles

Filtering AF 0.0082% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00343%

Overall 0.00895% 107/1,195,779 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.319%	314
Middle Easterngrpmax	0.0464%	2,154
Remaining individualsnot grpmax-eligible	0.0276%	3,627
East Asian	0.0119%	8,428
African / African-American	0.0088%	11,368
South Asian	0.00354%	28,250
Admixed American	0.00219%	45,711
European (non-Finnish)	0.00113%	88,268

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CUL4B
Protein: p.Pro654=
Coding: c.1962G>A
MANE Select: NM_001079872
dbSNP: rs185389157
Type: single nucleotide variant
Location: chrX:120537011 (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.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
CUL4B p.Cys712Arg 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-pro654 (accessed [today's date]).

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