Is CUL4B p.Ser66Phe (c.197C>T) pathogenic?

CUL4B p.Ser66Phe (c.197C>T) is classified Uncertain significance in CUL4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: likely benign (0.1058); Very rare (popmax 0.00174%, afr); Associated with X-linked intellectual disability, Cabezas type.

What condition is associated with CUL4B p.Ser66Phe (c.197C>T)?

CUL4B p.Ser66Phe (c.197C>T) is associated with X-linked intellectual disability, Cabezas type (ClinVar).

How common is CUL4B p.Ser66Phe (c.197C>T) in the general population?

CUL4B p.Ser66Phe (c.197C>T) is very rare (popmax 0.00174%, afr) (gnomAD).

What do computational predictors say about CUL4B p.Ser66Phe (c.197C>T)?

AlphaMissense predicts likely benign (score 0.1058) — an in-silico prediction, not a clinical call.

CUL4B p.Ser66Phe

c.197C>T · VCV4781705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1058 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00174%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked intellectual disability, Cabezas type

Computational evidence

Protein change
AlphaMissense	0.1058	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -10.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 495 bp · p 0.069 · regional, not allelic
Overall
CADD	24.8	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 S84F vs ClinVar S66F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00174% African / African-American · 1/57,597 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000274% 3/1,095,910 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00174%	57,597
European (non-Finnish)	0.000224%	446,722

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.Ser66Phe
Coding: c.197C>T
MANE Select: NM_001079872
Type: single nucleotide variant
Location: chrX:120560442 (GRCh38)
Structure: AlphaFold pLDDT 80.02 · 5 PDB
Residue 66: the 'disordered' region

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.Ser66Tyr Uncertain significance ★ ⚠ 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-ser66phe (accessed [today's date]).

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