# NM_001761.3(CCNF):c.734G>A (p.Arg245Gln)

https://sugi.bio/variant/ccnf-p-arg245gln

## Summary

**CCNF p.Arg245Gln (c.734G>A)** is classified **Uncertain significance** in CCNF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: ambiguous (0.5589); Very rare (popmax 0.000339%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the CCNF 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 | [CCNF](https://sugi.bio/atlas/gene/CCNF/) |
| Protein change (HGVS p.) | p.Arg245Gln |
| Coding change (HGVS c.) | c.734G>A |
| MANE Select transcript | [NM_001761](https://www.ncbi.nlm.nih.gov/nuccore/NM_001761) |
| Variant type | single nucleotide variant |
| Location | chr16:2439783-2439783 (GRCh38) |
| ClinVar | [VCV4222092](https://www.ncbi.nlm.nih.gov/clinvar/variation/4222092/) |

**All HGVS expressions:** `NC_000016.10:g.2439783G>A`, `NC_000016.9:g.2489784G>A`, `NM_001323538.2:c.-191G>A`, `NM_001761.3:c.734G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5589) — no call either way
- REVEL 0.473 (indeterminate)
- SaProt LLR -5.322 (tolerated)
- Conservation: phyloP 11.77, GERP 1.78, phastCons 1 — highly conserved
- CADD: **PHRED 32.0**. 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 0.86** across the covering region of the MANE Select transcript (2,429,482–2,448,892), spanning 19,410 bp. Chi-square p 0.0017. 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 (G>T, Δ0.23 donor loss), 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 **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,180,022 in the highest group · 5/1,614,054 alleles overall — very rare (popmax 0.000339%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |
| European (non-Finnish) (grpmax) | 0.000339% | 295,005 |

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}

**CCNF** population constraint: LOEUF 0.531, pLI 0.70443, missense-Z 1.3035. *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):

- **frontotemporal dementia and/or amyotrophic lateral sclerosis 5** — Limited (AD)

## Protein context {#protein}

Residue **245** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 72.34, 51% of residues very-high.

**1 experimental structure(s)** (PDB): [9CB3](https://www.rcsb.org/structure/9CB3).

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

*Describes the biological roles of CCNF (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:** CCNF's established molecular role includes anaphase-promoting complex binding.


### Pathways affected {#pathways}

CCNF participates in **2 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 |

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

**Molecular function:** anaphase-promoting complex binding, ubiquitin-like ligase-substrate adaptor activity.

**Biological process:** negative regulation of centrosome duplication, protein ubiquitination, SCF-dependent proteasomal ubiquitin-dependent protein catabolic process, regulation of cell cycle.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-19.

**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 | 2025-08-19 |

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

## Similar variants {#similar}

Related CCNF variant pages (same residue, condition, or type): [CCNF p.Arg245Gly](/variant/ccnf-p-arg245gly), [CCNF p.Ser621Gly](/variant/ccnf-p-ser621gly), [CCNF p.Arg140Gln](/variant/ccnf-p-arg140gln), [CCNF p.Arg24Lys](/variant/ccnf-p-arg24lys), [CCNF p.Arg572Gln](/variant/ccnf-p-arg572gln), [CCNF p.Gly254Ala](/variant/ccnf-p-gly254ala), [CCNF p.Gly719Val](/variant/ccnf-p-gly719val), [CCNF c.1095-28A>G](/variant/ccnf-c-1095-minus-28a-g).

### 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 4222092). 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.*