# NM_001554.5(CCN1):c.16G>T (p.Ala6Ser)

https://sugi.bio/variant/ccn1-p-ala6ser

## Summary

**CCN1 p.Ala6Ser (c.16G>T)** is classified **Uncertain significance** in CCN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). AlphaMissense: likely benign (0.0804); Very rare (popmax 0.00102%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs765417418 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00102%, nfe)

## For patients & families {#patients}

This is a change in the CCN1 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 | [CCN1](https://sugi.bio/atlas/gene/CCN1/) |
| Protein change (HGVS p.) | p.Ala6Ser |
| Coding change (HGVS c.) | c.16G>T |
| MANE Select transcript | [NM_001237](https://www.ncbi.nlm.nih.gov/nuccore/NM_001237) (variant reported on NM_001554) |
| dbSNP | [rs765417418](https://www.ncbi.nlm.nih.gov/snp/rs765417418/) |
| Variant type | single nucleotide variant |
| Location | chr1:85581000-85581000 (GRCh38) |
| ClinVar | [VCV3139770](https://www.ncbi.nlm.nih.gov/clinvar/variation/3139770/) |

**All HGVS expressions:** `NC_000001.10:g.86046683G>T`, `NC_000001.11:g.85581000G>T`, `NM_001554.5:c.16G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0804)
- REVEL 0.103 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.714 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.403, GERP 1.85, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 14.75**. 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.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00102%** (nfe) · FAF95 0.000544% · FAF99 0.000429% · 12/1,177,028 in the highest group · 14/1,453,618 alleles overall — very rare (popmax 0.00102%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00322% | 31,074 |
| European (non-Finnish) (grpmax) | 0.00102% | 98,085 |

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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.80, 59% of residues very-high.

**115 experimental structure(s)** (PDB): [11GV](https://www.rcsb.org/structure/11GV), [1E9H](https://www.rcsb.org/structure/1E9H), [1FIN](https://www.rcsb.org/structure/1FIN), [1FVV](https://www.rcsb.org/structure/1FVV), [1GY3](https://www.rcsb.org/structure/1GY3), [1H1P](https://www.rcsb.org/structure/1H1P) — incl. mutant structure 2IW8.

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

*Describes the biological roles of CCN1 (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:** CCN1's established molecular role includes cyclin-dependent protein serine/threonine kinase regulator activity.


### Pathways affected {#pathways}

CCN1 participates in **21 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDK-mediated phosphorylation and removal of Cdc6](https://reactome.org/content/detail/R-HSA-69017) | curated |
| [Cdc20:Phospho-APC/C mediated degradation of Cyclin A](https://reactome.org/content/detail/R-HSA-174184) | curated |
| [Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex](https://reactome.org/content/detail/R-HSA-75035) | curated |
| [Cyclin A/B1/B2 associated events during G2/M transition](https://reactome.org/content/detail/R-HSA-69273) | curated |
| [Cyclin A:Cdk2-associated events at S phase entry](https://reactome.org/content/detail/R-HSA-69656) | curated |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [G0 and Early G1](https://reactome.org/content/detail/R-HSA-1538133) | curated |
| [G2 Phase](https://reactome.org/content/detail/R-HSA-68911) | curated |
| [G2/M DNA replication checkpoint](https://reactome.org/content/detail/R-HSA-69478) | curated |
| [Orc1 removal from chromatin](https://reactome.org/content/detail/R-HSA-68949) | curated |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | curated |
| [Regulation of APC/C activators between G1/S and early anaphase](https://reactome.org/content/detail/R-HSA-176408) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [SCF(Skp2)-mediated degradation of p27/p21](https://reactome.org/content/detail/R-HSA-187577) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest](https://reactome.org/content/detail/R-HSA-6804116) | curated |
| [Telomere Extension By Telomerase](https://reactome.org/content/detail/R-HSA-171319) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [p53-Dependent G1 DNA Damage Response](https://reactome.org/content/detail/R-HSA-69563) | curated |
| [Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1](https://reactome.org/content/detail/R-HSA-1362300) | electronic |

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

**Molecular function:** cyclin-dependent protein serine/threonine kinase regulator activity, protein kinase binding, protein domain specific binding.

**Biological process:** G2/M transition of mitotic cell cycle, regulation of DNA replication, Ras protein signal transduction, post-translational protein modification, cell cycle G1/S phase transition.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-15.

**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 | 2021-11-15 |

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

## Similar variants {#similar}

Related CCN1 variant pages (same residue, condition, or type): [EXOSC9 p.Ala438Val](/variant/exosc9-p-ala438val), [CCN1 c.277+50G>C](/variant/ccn1-c-277-plus-50g-c), [CCN1 c.64-124G>A](/variant/ccn1-c-64-minus-124g-a), [CCN1 c.-107C>A](/variant/ccn1-c-minus-107c-a), [CCN1 p.Ser316Cys](/variant/ccn1-p-ser316cys), [CCN1 p.Tyr300=](/variant/ccn1-p-tyr300), [CCNA2 c.*828C>G](/variant/ccna2-c-star-828c-g), [CCNA2 p.Leu126=](/variant/ccna2-p-leu126).

### 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 3139770). 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.*