# NM_004064.5(CDKN1B):c.269dup (p.Pro91fs)

https://sugi.bio/variant/cdkn1b-p-pro91fs

## Summary

**CDKN1B p.Pro91fs (c.269dup)** is classified **Pathogenic** in CDKN1B (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-26). No gnomAD frequency available for this variant; Associated with multiple endocrine neoplasia type 4.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1946492962 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CDKN1B gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to multiple endocrine neoplasia type 4.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Not applicable |
| Age of onset (of this condition) | Adult |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CDKN1B is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Multiple endocrine neoplasia type 4** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the endocrine system — Very frequent (99-80%)
- Hyperparathyroidism — Very frequent (99-80%)
- Parathyroid adenoma — Very frequent (99-80%)
- Hypercalcemia — Very frequent (99-80%)
- Elevated circulating parathyroid hormone level — Very frequent (99-80%)
- Parathyroid hyperplasia — Very frequent (99-80%)
- Hyperinsulinemic hypoglycemia — Frequent (79-30%)
- Elevated circulating growth hormone concentration — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017275/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDKN1B](https://sugi.bio/atlas/gene/CDKN1B/) |
| Protein change (HGVS p.) | p.Pro91fs |
| Coding change (HGVS c.) | c.269dup |
| MANE Select transcript | [NM_004064](https://www.ncbi.nlm.nih.gov/nuccore/NM_004064) |
| dbSNP | [rs1946492962](https://www.ncbi.nlm.nih.gov/snp/rs1946492962/) |
| Variant type | Duplication |
| Location | chr12:12718107-12718108 (GRCh38) |
| ClinVar | [VCV857540](https://www.ncbi.nlm.nih.gov/clinvar/variation/857540/) |

**All HGVS expressions:** `NC_000012.11:g.12871042dup`, `NC_000012.12:g.12718108dup`, `NG_016341.1:g.5741dup`, `NM_004064.5:c.269dup`

## Computational & population evidence {#evidence}

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

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 2.236, GERP -3.11, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — 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.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 3**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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}

**CDKN1B** population constraint: LOEUF 0.804, pLI 0.24233, missense-Z -1.3002; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **multiple endocrine neoplasia type 4** — Definitive (AD)
- **hereditary nonpolyposis colon cancer** — Limited (AR)

## Protein context {#protein}

Residue **91** lies in the 'interaction with cdk2' region; the 'disordered' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 71.08, 36% of residues very-high.

**19 experimental structure(s)** (PDB): [1H27](https://www.rcsb.org/structure/1H27), [1JSU](https://www.rcsb.org/structure/1JSU), [2AST](https://www.rcsb.org/structure/2AST), [5UQ3](https://www.rcsb.org/structure/5UQ3), [6ATH](https://www.rcsb.org/structure/6ATH), [6P8E](https://www.rcsb.org/structure/6P8E).

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

*Describes the biological roles of CDKN1B (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:** CDKN1B's established molecular role includes protein kinase inhibitor activity. p.Pro91fs falls in the interaction with cdk2 region. In Reactome, CDKN1B is annotated in disease pathway(s) including **Constitutive Signaling by AKT1 E17K in Cancer**, **Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)**.

**Disease mechanism (Reactome):** CDKN1B loss or alteration is curated in [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400), [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069).

### Pathways affected {#pathways}

CDKN1B participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400) | curated |
| ⚕ [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069) | curated |
| [AKT phosphorylates targets in the cytosol](https://reactome.org/content/detail/R-HSA-198323) | curated |
| [Cyclin A:Cdk2-associated events at S phase entry](https://reactome.org/content/detail/R-HSA-69656) | curated |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [Cyclin E associated events during G1/S transition ](https://reactome.org/content/detail/R-HSA-69202) | curated |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [Estrogen-dependent nuclear events downstream of ESR-membrane signaling](https://reactome.org/content/detail/R-HSA-9634638) | curated |
| [FLT3 Signaling](https://reactome.org/content/detail/R-HSA-9607240) | curated |
| [PTK6 Regulates Cell Cycle](https://reactome.org/content/detail/R-HSA-8849470) | 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 |
| [p53-Dependent G1 DNA Damage Response](https://reactome.org/content/detail/R-HSA-69563) | curated |
| [FOXO-mediated transcription of cell cycle genes](https://reactome.org/content/detail/R-HSA-9617828) | electronic |
| [RHO GTPases activate CIT](https://reactome.org/content/detail/R-HSA-5625900) | electronic |

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

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

**Biological process:** regulation of cyclin-dependent protein serine/threonine kinase activity, negative regulation of cell population proliferation, negative regulation of cell growth, positive regulation of protein catabolic process, autophagic cell death, nuclear export.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-12-26.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2019-12-26 |

## Associated conditions {#conditions}

[multiple endocrine neoplasia type 4](https://sugi.bio/atlas/disease/multiple-endocrine-neoplasia-type-4/).

**Reported phenotype names (ClinVar):** Multiple endocrine neoplasia type 4, MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV.

## Similar variants {#similar}

Related CDKN1B variant pages (same residue, condition, or type): [CDKN1B p.Pro91Ala](/variant/cdkn1b-p-pro91ala), [CDKN1B p.Pro91His](/variant/cdkn1b-p-pro91his), [CDKN1B p.Pro91Leu](/variant/cdkn1b-p-pro91leu), [CDKN1B p.Pro91=](/variant/cdkn1b-p-pro91), [CDKN1B p.Pro91Arg](/variant/cdkn1b-p-pro91arg), [CDKN1B p.Pro91Ser](/variant/cdkn1b-p-pro91ser), [CDKN1B p.Pro91Thr](/variant/cdkn1b-p-pro91thr), [CDKN1B p.Asn8Ter](/variant/cdkn1b-p-asn8ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 857540). 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.*