# NM_030937.6(CCNL2):c.1391G>A (p.Arg464Gln)

https://sugi.bio/variant/ccnl2-p-arg464gln

## Summary

**CCNL2 p.Arg464Gln (c.1391G>A)** is classified **Uncertain significance** in CCNL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). AlphaMissense: likely benign (0.114); Very rare (popmax 0.00314%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00314%, nfe)

## For patients & families {#patients}

This is a change in the CCNL2 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 | [CCNL2](https://sugi.bio/atlas/gene/CCNL2/) |
| Protein change (HGVS p.) | p.Arg464Gln |
| Coding change (HGVS c.) | c.1391G>A |
| MANE Select transcript | [NM_030937](https://www.ncbi.nlm.nih.gov/nuccore/NM_030937) |
| Variant type | single nucleotide variant |
| Location | chr1:1387403-1387403 (GRCh38) |
| ClinVar | [VCV4650117](https://www.ncbi.nlm.nih.gov/clinvar/variation/4650117/) |

**All HGVS expressions:** `NC_000001.10:g.1322783C>T`, `NC_000001.11:g.1387403C>T`, `NG_029782.1:g.16936G>A`, `NM_001320153.3:c.725G>A`, `NM_001320155.3:c.725G>A`, `NM_001350497.2:c.725G>A`, `NM_001350498.2:c.725G>A`, `NM_001350499.2:c.998G>A`, `NM_001350500.2:c.998G>A`, `NM_030937.6:c.1391G>A`, `NR_135154.2:n.3574G>A`, `NR_146722.2:n.1942G>A`, `NR_146723.2:n.2392G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.114)
- REVEL 0.103 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.5 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.296, GERP 1.85, phastCons 0.998 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.9**. 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 1.07** across the covering region of the MANE Select transcript (1,387,234–1,390,788), spanning 3,554 bp. Chi-square p 0.19. 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>A, Δ0.26 acceptor 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 **0.00314%** (nfe) · FAF95 0.00231% · FAF99 0.00202% · 37/1,180,056 in the highest group · 39/1,614,020 alleles overall — very rare (popmax 0.00314%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00314% | 31,893 |
| Admixed American | 0.00167% | 60,004 |
| African / African-American | 0.00133% | 74,926 |

*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}

**CCNL2** population constraint: LOEUF 0.665, pLI 0.0019761, missense-Z 0.20509. *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 **464** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 70.06, 46% of residues very-high.

**4 experimental structure(s)** (PDB): [31ZN](https://www.rcsb.org/structure/31ZN), [9QKT](https://www.rcsb.org/structure/9QKT), [9QKZ](https://www.rcsb.org/structure/9QKZ), [9QL1](https://www.rcsb.org/structure/9QL1).

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

*Describes the biological roles of CCNL2 (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:** CCNL2's established molecular role includes cyclin-dependent protein serine/threonine kinase regulator activity. p.Arg464Gln falls in the disordered region.


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

**Molecular function:** cyclin-dependent protein serine/threonine kinase regulator activity.

**Biological process:** regulation of RNA splicing, regulation of mRNA splicing, via spliceosome.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-12.

**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 | 2025-11-12 |

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

## Similar variants {#similar}

Related CCNL2 variant pages (same residue, condition, or type): [CCNL2 p.Arg476Trp](/variant/ccnl2-p-arg476trp), [CCNL2 p.Ala10Thr](/variant/ccnl2-p-ala10thr), [CCNL2 p.Ala18Thr](/variant/ccnl2-p-ala18thr), [CCNL2 p.Ala19Ser](/variant/ccnl2-p-ala19ser), [CCNL2 p.Ala22Ser](/variant/ccnl2-p-ala22ser), [CCNL2 p.Ala310Val](/variant/ccnl2-p-ala310val), [CCNL2 p.Ala332Val](/variant/ccnl2-p-ala332val), [CCNL2 p.Ala362Gly](/variant/ccnl2-p-ala362gly).

### 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 4650117). 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.*