# NM_003591.4(CUL2):c.631T>C (p.Phe211Leu)

https://sugi.bio/variant/cul2-p-phe211leu

## Summary

**CUL2 p.Phe211Leu (c.631T>C)** is classified **Uncertain significance** in CUL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely pathogenic (0.9459); Very rare (popmax 0.00534%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00534%, afr)

## For patients & families {#patients}

This is a change in the CUL2 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 | [CUL2](https://sugi.bio/atlas/gene/CUL2/) |
| Protein change (HGVS p.) | p.Phe211Leu |
| Coding change (HGVS c.) | c.631T>C |
| MANE Select transcript | [NM_003591](https://www.ncbi.nlm.nih.gov/nuccore/NM_003591) |
| Variant type | single nucleotide variant |
| Location | chr10:35044649-35044649 (GRCh38) |
| ClinVar | [VCV3837440](https://www.ncbi.nlm.nih.gov/clinvar/variation/3837440/) |

**All HGVS expressions:** `NC_000010.10:g.35333577A>G`, `NC_000010.11:g.35044649A>G`, `NM_001198777.2:c.631T>C`, `NM_001198778.2:c.688T>C`, `NM_001198779.1:c.670T>C`, `NM_001324375.2:c.442T>C`, `NM_001324376.2:c.238T>C`, `NM_003591.4:c.631T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9459)
- REVEL 0.439 (indeterminate)
- SaProt LLR -9.376 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.116, GERP 2.23, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 23.7**. 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 0.76** across the covering region of the MANE Select transcript (35,033,175–35,071,317), spanning 38,142 bp. Chi-square p 6.8e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.12**, donor gain **0.00**. Largest is acceptor loss, 16 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.12**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00534%** (afr) · FAF95 0.00175% · FAF99 0.00104% · 4/74,902 in the highest group · 12/1,457,358 alleles overall — very rare (popmax 0.00534%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00803% | 12,457 |
| African / African-American (grpmax) | 0.00534% | 18,726 |
| European (non-Finnish) | 0.000254% | 392,986 |

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}

**CUL2** population constraint: LOEUF 0.305, pLI 1, missense-Z 2.5557. *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 **211** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 86.02, 40% of residues very-high.

**42 experimental structure(s)** (PDB): [4WQO](https://www.rcsb.org/structure/4WQO), [5N4W](https://www.rcsb.org/structure/5N4W), [6R6H](https://www.rcsb.org/structure/6R6H), [6R7F](https://www.rcsb.org/structure/6R7F), [6R7H](https://www.rcsb.org/structure/6R7H), [6R7I](https://www.rcsb.org/structure/6R7I).

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

*Describes the biological roles of CUL2 (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:** CUL2's established molecular role includes ubiquitin protein ligase binding.


### Pathways affected {#pathways}

CUL2 participates in **5 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 |
| [Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide](https://reactome.org/content/detail/R-HSA-9954709) | curated |
| [Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha](https://reactome.org/content/detail/R-HSA-1234176) | electronic |
| [Regulation of expression of SLITs and ROBOs](https://reactome.org/content/detail/R-HSA-9010553) | electronic |

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

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

**Biological process:** ubiquitin-dependent protein catabolic process via the C-end degron rule pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-19.

**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 | 2025-02-19 |

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

## Similar variants {#similar}

Related CUL2 variant pages (same residue, condition, or type): [CUL2 p.Arg148=](/variant/cul2-p-arg148), [CUL2 c.1110+1G>A](/variant/cul2-c-1110-plus-1g-a), [CUL2 c.-22-2881A>G](/variant/cul2-c-minus-22-minus-2881a-g), [CUL2 c.-2C>A](/variant/cul2-c-minus-2c-a), [CUL2 p.Ala403Val](/variant/cul2-p-ala403val), [CUL2 p.Ala522Val](/variant/cul2-p-ala522val), [CUL2 p.Ala634Ser](/variant/cul2-p-ala634ser), [CUL2 p.Ala671Ser](/variant/cul2-p-ala671ser).

### 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 3837440). 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.*