Is CUL4B p.Ser166Pro (c.496T>C) pathogenic?

CUL4B p.Ser166Pro (c.496T>C) is classified Uncertain significance in CUL4B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-23). AlphaMissense: likely benign (0.1544); Very rare (popmax 0.00112%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CUL4B p.Ser166Pro (c.496T>C)?

CUL4B p.Ser166Pro (c.496T>C) is associated with Inborn genetic diseases, X-linked intellectual disability, Cabezas type (ClinVar).

How common is CUL4B p.Ser166Pro (c.496T>C) in the general population?

CUL4B p.Ser166Pro (c.496T>C) is very rare (popmax 0.00112%, nfe) (gnomAD).

What do computational predictors say about CUL4B p.Ser166Pro (c.496T>C)?

AlphaMissense predicts likely benign (score 0.1544) — an in-silico prediction, not a clinical call.

CUL4B p.Ser166Pro

c.496T>C · rs748328122 · VCV2712473

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1544 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1544	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -7.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 495 bp · p 0.069 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S184P vs ClinVar S166P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00112% European (non-Finnish) · 10/895,523 alleles

Filtering AF 0.000565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000412%

Overall 0.000825% 10/1,211,947 alleles · very rare exomes 10/1,098,154 · genomes 0/113,793 · joint denominator

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.Ser166Pro
Coding: c.496T>C
MANE Select: NM_001079872
dbSNP: rs748328122
Type: single nucleotide variant
Location: chrX:120560143 (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

Also linked: X-linked intellectual disability, Cabezas type

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-ser166pro (accessed [today's date]).

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