# NM_001008895.4(CUL4A):c.1023C>A (p.Ser341Arg)

https://sugi.bio/variant/cul4a-p-ser341arg

## Summary

**CUL4A p.Ser341Arg (c.1023C>A)** is classified **Uncertain significance** in CUL4A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-26). AlphaMissense: likely pathogenic (0.601); Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the CUL4A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CUL4A](https://sugi.bio/atlas/gene/CUL4A/) |
| Protein change (HGVS p.) | p.Ser341Arg |
| Coding change (HGVS c.) | c.1023C>A |
| MANE Select transcript | [NM_001008895](https://www.ncbi.nlm.nih.gov/nuccore/NM_001008895) |
| Variant type | single nucleotide variant |
| Location | chr13:113239539-113239539 (GRCh38) |
| ClinVar | [VCV3498631](https://www.ncbi.nlm.nih.gov/clinvar/variation/3498631/) |

**All HGVS expressions:** `NC_000013.10:g.113893853C>A`, `NC_000013.11:g.113239539C>A`, `NM_001008895.4:c.1023C>A`, `NM_001278513.3:c.723C>A`, `NM_001278514.3:c.747C>A`, `NM_001354938.2:c.723C>A`, `NM_001354939.2:c.723C>A`, `NM_001354940.2:c.723C>A`, `NM_001354941.2:c.588C>A`, `NM_001354942.2:c.588C>A`, `NM_003589.4:c.723C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.601)
- REVEL 0.178 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -10.032 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP -1.098, GERP -1.37, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 15.91**. 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.*
- Regional missense constraint: **o/e 0.63** across the covering region of the MANE Select transcript (113,233,947–113,244,496), spanning 10,549 bp. Chi-square p 4.9e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.94 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,174 in the highest group · 1/1,459,878 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**CUL4A** population constraint: LOEUF 0.324, pLI 1, missense-Z 2.9265. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **341** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 89.26, 74% of residues very-high.

**20 experimental structure(s)** (PDB): [2HYE](https://www.rcsb.org/structure/2HYE), [4A0K](https://www.rcsb.org/structure/4A0K), [7OKQ](https://www.rcsb.org/structure/7OKQ), [7OPC](https://www.rcsb.org/structure/7OPC), [7OPD](https://www.rcsb.org/structure/7OPD), [8B3G](https://www.rcsb.org/structure/8B3G).

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

*Describes the biological roles of CUL4A (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.*

**How this variant is thought to act:** CUL4A's established molecular role includes ubiquitin protein ligase binding.


### Pathways affected {#pathways}

CUL4A 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}

**Molecular function:** ubiquitin protein ligase binding, ubiquitin protein ligase activity, ubiquitin ligase complex scaffold activity.

**Biological process:** DNA damage response, spermatogenesis, protein ubiquitination, cellular response to UV, T cell activation, ribosome biogenesis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-26.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-26 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CUL4A variant pages (same residue, condition, or type): [CUL4A p.Ala13Pro](/variant/cul4a-p-ala13pro), [CUL4A p.Ala208Val](/variant/cul4a-p-ala208val), [CUL4A p.Ala486Thr](/variant/cul4a-p-ala486thr), [CUL4A p.Arg144Gly](/variant/cul4a-p-arg144gly), [CUL4A p.Arg385Gln](/variant/cul4a-p-arg385gln), [CUL4A p.Arg49Gln](/variant/cul4a-p-arg49gln), [CUL4A p.Arg80Lys](/variant/cul4a-p-arg80lys), [CUL4A p.Asn603Ser](/variant/cul4a-p-asn603ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3498631). 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.*