# NM_001079872.2(CUL4B):c.9A>G (p.Pro3=)

https://sugi.bio/variant/cul4b-p-pro3

## Summary

**CUL4B p.Pro3= (c.9A>G)** is classified **Likely benign** in CUL4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). Very rare (popmax 0.0044%, amr); Associated with X-linked intellectual disability, Cabezas type.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.0044%, amr)

## For patients & families {#patients}

This is a change in the CUL4B gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to X-linked intellectual disability, Cabezas type.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013244/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CUL4B](https://sugi.bio/atlas/gene/CUL4B/) |
| Protein change (HGVS p.) | p.Pro3= |
| Coding change (HGVS c.) | c.9A>G |
| MANE Select transcript | [NM_001079872](https://www.ncbi.nlm.nih.gov/nuccore/NM_001079872) |
| Variant type | single nucleotide variant |
| Location | chrX:120560630-120560630 (GRCh38) |
| ClinVar | [VCV4744503](https://www.ncbi.nlm.nih.gov/clinvar/variation/4744503/) |

**All HGVS expressions:** `NC_000023.10:g.119694485T>C`, `NC_000023.11:g.120560630T>C`, `NG_009388.1:g.20200A>G`, `NG_063192.2:g.700T>C`, `NM_001079872.2:c.9A>G`, `NM_001330624.2:c.29-5A>G`, `NM_003588.4:c.68-5A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 4.888, GERP 1.74, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.45**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0044%** (amr) · FAF95 0.000729% · FAF99 0.000273% · 2/45,503 in the highest group · 2/1,200,276 alleles overall — very rare (popmax 0.0044%, amr).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CUL4B** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **X-linked intellectual disability, Cabezas type** — Definitive (XL)

## Protein context {#protein}

Residue **3** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 80.02, 61% of residues very-high.

**5 experimental structure(s)** (PDB): [2DO7](https://www.rcsb.org/structure/2DO7), [4A0C](https://www.rcsb.org/structure/4A0C), [4A0L](https://www.rcsb.org/structure/4A0L), [4A64](https://www.rcsb.org/structure/4A64), [8EI1](https://www.rcsb.org/structure/8EI1).

## What this gene does {#gene-function}

*Describes the biological roles of CUL4B (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

CUL4B participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DNA Damage Recognition in GG-NER](https://reactome.org/content/detail/R-HSA-5696394) | curated |
| [Dual Incision in GG-NER](https://reactome.org/content/detail/R-HSA-5696400) | curated |
| [Dual incision in TC-NER](https://reactome.org/content/detail/R-HSA-6782135) | curated |
| [Formation of Incision Complex in GG-NER](https://reactome.org/content/detail/R-HSA-5696395) | curated |
| [Formation of TC-NER Pre-Incision Complex](https://reactome.org/content/detail/R-HSA-6781823) | curated |
| [Gap-filling DNA repair synthesis and ligation in TC-NER](https://reactome.org/content/detail/R-HSA-6782210) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Negative Regulation of DNA Double Strand Break Response](https://reactome.org/content/detail/R-HSA-9974237) | curated |
| [Recognition of DNA damage by PCNA-containing replication complex](https://reactome.org/content/detail/R-HSA-110314) | curated |
| [Transcription-Coupled Nucleotide Excision Repair (TC-NER)](https://reactome.org/content/detail/R-HSA-6781827) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** proteasomal protein catabolic process, protein ubiquitination, ribosome biogenesis, proteasome-mediated ubiquitin-dependent protein catabolic process, UV-damage excision repair.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-13.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-13 |

## Associated conditions {#conditions}

[X-linked intellectual disability, Cabezas type](https://sugi.bio/atlas/disease/x-linked-intellectual-disability-cabezas-type/).

**Reported phenotype names (ClinVar):** X-linked intellectual disability Cabezas type, Intellectual developmental disorder, X-linked syndromic, Cabezas type, MENTAL RETARDATION, X-LINKED, SYNDROMIC 15, CABEZAS SYNDROME.

## Similar variants {#similar}

Related CUL4B variant pages (same residue, condition, or type): [CUL4B p.Arg351Ter](/variant/cul4b-p-arg351ter), [CUL4B p.Arg370Ter](/variant/cul4b-p-arg370ter), [CUL4B p.Gln241Ter](/variant/cul4b-p-gln241ter), [CUL4B p.Thr813=](/variant/cul4b-p-thr813), [CUL4B c.2592+3A>T](/variant/cul4b-c-2592-plus-3a-t), [CUL4B c.777-3C>T](/variant/cul4b-c-777-minus-3c-t), [CUL4B p.Ala16Pro](/variant/cul4b-p-ala16pro), [CUL4B p.Cys712Arg](/variant/cul4b-p-cys712arg).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4744503). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*