# NM_001122630.2(CDKN1C):c.917G>A (p.Ter306=)

https://sugi.bio/variant/cdkn1c-p-ter306

## Summary

**CDKN1C p.Ter306= (c.917G>A)** is classified **Likely benign** in CDKN1C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). Very rare (popmax 0.00234%, nfe); Associated with Beckwith-Wiedemann syndrome.

**At a glance:** Likely benign · review: Single submitter · rsID rs1363802623 · 1 submitter · 1 linked condition · very rare (popmax 0.00234%, nfe)

## For patients & families {#patients}

This is a change in the CDKN1C gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Beckwith-Wiedemann syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003343/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDKN1C](https://sugi.bio/atlas/gene/CDKN1C/) |
| Protein change (HGVS p.) | p.Ter306= |
| Coding change (HGVS c.) | c.917G>A |
| MANE Select transcript | [NM_001122630](https://www.ncbi.nlm.nih.gov/nuccore/NM_001122630) |
| dbSNP | [rs1363802623](https://www.ncbi.nlm.nih.gov/snp/rs1363802623/) |
| Variant type | single nucleotide variant |
| Location | chr11:2884005-2884005 (GRCh38) |
| ClinVar | [VCV524732](https://www.ncbi.nlm.nih.gov/clinvar/variation/524732/) |

**All HGVS expressions:** `LRG_533:g.6761G>A`, `LRG_533t1:c.950G>A`, `NC_000011.10:g.2884005C>T`, `NC_000011.9:g.2905235C>T`, `NG_008022.1:g.6761G>A`, `NM_000076.2:c.950G>A`, `NM_001122630.2:c.917G>A`, `NM_001122631.2:c.917G>A`, `NM_001362474.2:c.950G>A`, `NM_001362475.2:c.385G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.26) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.381, GERP -0.212, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **stop-loss** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 18.26**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.26**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.26**.
- Pangolin: Δ**0.49** (gain), gain 0.49 / loss 0.02. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00234%** (nfe) · FAF95 0.0016% · FAF99 0.00138% · 27/1,152,412 in the highest group · 27/1,558,690 alleles overall — very rare (popmax 0.00234%, nfe).

*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}

**CDKN1C** population constraint: LOEUF 1.943, pLI 0.00043741, missense-Z -1.85; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **Beckwith-Wiedemann syndrome due to CDKN1C mutation** — Strong (AD)

## Protein context {#protein}

Residue **306** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 63.93, 17% of residues very-high.

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

*Describes the biological roles of CDKN1C (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:** CDKN1C's established molecular role includes cyclin-dependent protein serine/threonine kinase inhibitor activity. p.Ter306= falls in the disordered region. In Reactome, CDKN1C is annotated in disease pathway(s) including **Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)**.

**Disease mechanism (Reactome):** CDKN1C loss or alteration is curated in [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069).

### Pathways affected {#pathways}

CDKN1C participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069) | curated |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |

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

**Molecular function:** cyclin-dependent protein serine/threonine kinase inhibitor activity, protein-containing complex binding, molecular function inhibitor activity.

**Biological process:** positive regulation of transforming growth factor beta receptor signaling pathway, negative regulation of epithelial cell proliferation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-02 |

## Associated conditions {#conditions}

[Beckwith-Wiedemann syndrome](https://sugi.bio/atlas/disease/beckwith-wiedemann-syndrome/).

**Reported phenotype names (ClinVar):** Beckwith-Wiedemann syndrome, EMG SYNDROME, Exomphalos macroglossia gigantism syndrome.

## Similar variants {#similar}

Related CDKN1C variant pages (same residue, condition, or type): [CDKN1C p.Asp263Asn](/variant/cdkn1c-p-asp263asn), [CDKN1C p.Cys19Ter](/variant/cdkn1c-p-cys19ter), [CDKN1C p.Gln219Ter](/variant/cdkn1c-p-gln219ter), [CDKN1C p.Gln221Ter](/variant/cdkn1c-p-gln221ter), [CDKN1C p.Gln230Ter](/variant/cdkn1c-p-gln230ter), [CDKN1C p.Glu119Ter](/variant/cdkn1c-p-glu119ter), [CDKN1C p.Glu214Ter](/variant/cdkn1c-p-glu214ter), [CDKN1C p.Pro59Leu](/variant/cdkn1c-p-pro59leu).

### 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 524732). 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.*