# NM_001122630.2(CDKN1C):c.802C>A (p.Arg268Ser)

https://sugi.bio/variant/cdkn1c-p-arg268ser

## Summary

**CDKN1C p.Arg268Ser (c.802C>A)** is classified **Likely pathogenic** in CDKN1C (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-21). AlphaMissense: likely pathogenic (0.9957); No allele count reported in gnomAD v4.1 (AN 1,499,106); Associated with Monogenic short statue.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs1848883206 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,499,106)

## For patients & families {#patients}

This is a change in the CDKN1C gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to Monogenic short statue.

*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 | [CDKN1C](https://sugi.bio/atlas/gene/CDKN1C/) |
| Protein change (HGVS p.) | p.Arg268Ser |
| Coding change (HGVS c.) | c.802C>A |
| MANE Select transcript | [NM_001122630](https://www.ncbi.nlm.nih.gov/nuccore/NM_001122630) |
| dbSNP | [rs1848883206](https://www.ncbi.nlm.nih.gov/snp/rs1848883206/) |
| Variant type | single nucleotide variant |
| Location | chr11:2884120-2884120 (GRCh38) |
| ClinVar | [VCV986832](https://www.ncbi.nlm.nih.gov/clinvar/variation/986832/) |

**All HGVS expressions:** `LRG_533:g.6646C>A`, `LRG_533t1:c.835C>A`, `NC_000011.10:g.2884120G>T`, `NC_000011.9:g.2905350G>T`, `NG_008022.1:g.6646C>A`, `NM_000076.2:c.835C>A`, `NM_001122630.2:c.802C>A`, `NM_001122631.2:c.802C>A`, `NM_001362474.2:c.835C>A`, `NM_001362475.2:c.270C>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9957) — concordant with the pathogenic call
- REVEL 0.572 (indeterminate)
- SaProt LLR -8.344 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 8.496, GERP -0.393, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R279S** vs ClinVar **R268S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in CDKN1C (of 1,855 modeled).
- CADD: **PHRED 26.7**. 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.*
- 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: **no allele count reported in gnomAD v4.1 (AN 1,499,106)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **268** lies in a modified residue (phosphoserine).

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. 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 pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-21.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 not provided).

**Submission history:** 3 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneReviews | not provided | no classification provided | literature only |  |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-10-23 |
| NHS Central & South Genomic Laboratory Hub | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-10-21 |

## Associated conditions {#conditions}

[Monogenic short statue](https://sugi.bio/atlas/disease/monogenic-short-statue/), [IMAGe syndrome](https://sugi.bio/atlas/disease/image-syndrome/).

**Reported phenotype names (ClinVar):** Monogenic short statue, not provided, IMAGe syndrome, Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies, Intrauterine Growth Restriction, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, and Genital Anomalies, none provided.

## Same-residue context {#hotspot}

Residue **268** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [CDKN1C p.Arg268Leu](/variant/cdkn1c-p-arg268leu), [CDKN1C p.Arg268fs](/variant/cdkn1c-p-arg268fs), [CDKN1C p.Arg268His](/variant/cdkn1c-p-arg268his), [CDKN1C p.Arg268Pro](/variant/cdkn1c-p-arg268pro). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CDKN1C variant pages (same residue, condition, or type): [CDKN1C p.Arg268Cys](/variant/cdkn1c-p-arg268cys), [CDKN1C p.Arg268Leu](/variant/cdkn1c-p-arg268leu), [CDKN1C p.Arg268Pro](/variant/cdkn1c-p-arg268pro), [CDKN1C p.Arg268His](/variant/cdkn1c-p-arg268his), [CDKN1C p.Arg268=](/variant/cdkn1c-p-arg268), [CDKN1C p.Asp263Asn](/variant/cdkn1c-p-asp263asn), [CDKN1C c.788-3C>T](/variant/cdkn1c-c-788-minus-3c-t), [CDKN1C c.-10-13C>T](/variant/cdkn1c-c-minus-10-minus-13c-t).

### 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 986832). 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.*