# NM_014780.5(CUL7):c.1838del (p.Pro613fs)

https://sugi.bio/variant/cul7-p-pro613fs

## Summary

**CUL7 p.Pro613fs (c.1838del)** is classified **Likely pathogenic** in CUL7 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 8.48e-05%, nfe); Associated with 3M syndrome 1.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2532699127 · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the CUL7 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to 3M syndrome 1.

*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/0015239/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CUL7](https://sugi.bio/atlas/gene/CUL7/) |
| Protein change (HGVS p.) | p.Pro613fs |
| Coding change (HGVS c.) | c.1838del |
| MANE Select transcript | [NM_014780](https://www.ncbi.nlm.nih.gov/nuccore/NM_014780) |
| dbSNP | [rs2532699127](https://www.ncbi.nlm.nih.gov/snp/rs2532699127/) |
| Variant type | Deletion |
| Location | chr6:43048557-43048557 (GRCh38) |
| ClinVar | [VCV2627397](https://www.ncbi.nlm.nih.gov/clinvar/variation/2627397/) |

**All HGVS expressions:** `NC_000006.11:g.43016299del`, `NC_000006.12:g.43048561del`, `NG_016205.1:g.10389del`, `NM_001168370.2:c.1934del`, `NM_001374872.1:c.1934del`, `NM_001374873.1:c.1838del`, `NM_001374874.1:c.1838del`, `NM_014780.5:c.1838del`

## 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 -8.274, GERP -2.94 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.62, pLI 1.197e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 26**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,746 in the highest group · 2/1,613,740 alleles overall — very rare (popmax 8.48e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |
| European (non-Finnish) (grpmax) | 8.48e-05% | 1,179,746 |

Remaining individuals shows a higher raw frequency than the grpmax group. 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.

*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}

**CUL7** population constraint: LOEUF 0.62, pLI 1.197e-11, missense-Z 2.9059. *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 **613** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 70.11, 4% of residues very-high.

**2 experimental structure(s)** (PDB): [2JNG](https://www.rcsb.org/structure/2JNG), [7Z8B](https://www.rcsb.org/structure/7Z8B).

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

*Describes the biological roles of CUL7 (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:** CUL7's established molecular role includes ubiquitin ligase complex scaffold activity. p.Pro613fs falls in the disordered region.


### Pathways affected {#pathways}

CUL7 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [XBP1(S) activates chaperone genes](https://reactome.org/content/detail/R-HSA-381038) | curated |

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

**Molecular function:** ubiquitin ligase complex scaffold activity.

**Biological process:** microtubule cytoskeleton organization, mitotic cytokinesis, epithelial to mesenchymal transition, placenta development, ubiquitin-dependent protein catabolic process, regulation of mitotic nuclear division.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[3M syndrome 1](https://sugi.bio/atlas/disease/3m-syndrome-1/).

**Reported phenotype names (ClinVar):** 3M syndrome 1, 3-M Syndrome, CUL7-Related.

## Similar variants {#similar}

Related CUL7 variant pages (same residue, condition, or type): [CUL7 p.Leu1046fs](/variant/cul7-p-leu1046fs), [CUL7 p.Leu1308_Ser1309insTer](/variant/cul7-p-leu1308-ser1309inster), [CUL7 p.Trp1127fs](/variant/cul7-p-trp1127fs), [CUL7 p.Val738fs](/variant/cul7-p-val738fs), [CUL7 p.Val88fs](/variant/cul7-p-val88fs), [CUL7 c.1563_1569+5del](/variant/cul7-c-1563-1569-plus-5del), [CUL7 c.4295-6_4313del](/variant/cul7-c-4295-minus-6-4313del), [CUL7 c.727_732+18del](/variant/cul7-c-727-732-plus-18del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2627397). 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.*