# NM_000077.5(CDKN2A):c.253_254delinsTT (p.Ala85Phe)

https://sugi.bio/variant/cdkn2a-p-ala85phe

## Summary

**CDKN2A p.Ala85Phe (c.253_254delinsTT)** is classified **Uncertain significance** in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-10). No gnomAD frequency available for this variant; Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1064796336 · 3 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CDKN2A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to hereditary neoplastic 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 | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDKN2A](https://sugi.bio/atlas/gene/CDKN2A/) |
| Protein change (HGVS p.) | p.Ala85Phe |
| Coding change (HGVS c.) | c.253_254delinsTT |
| MANE Select transcript | [NM_000077](https://www.ncbi.nlm.nih.gov/nuccore/NM_000077) |
| dbSNP | [rs1064796336](https://www.ncbi.nlm.nih.gov/snp/rs1064796336/) |
| Variant type | Indel |
| Location | chr9:21971105-21971106 (GRCh38) |
| ClinVar | [VCV423274](https://www.ncbi.nlm.nih.gov/clinvar/variation/423274/) |

**All HGVS expressions:** `LRG_11:g.28386_28387delinsTT`, `LRG_11t1:c.253_254delinsTT`, `LRG_11t2:c.296_297delGCinsTT`, `NC_000009.11:g.21971104_21971105delinsAA`, `NC_000009.12:g.21971105_21971106delinsAA`, `NG_007485.1:g.28386_28387delinsTT`, `NM_000077.4:c.253_254delGCinsTT`, `NM_000077.6:c.253_254delGCinsTT`, `NM_001195132.2:c.253_254delinsTT`, `NM_001363763.2:c.100_101delinsTT`, `NM_058195.4:c.296_297delinsTT`, `NM_058197.5:c.*176_*177delinsTT`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 11.596, GERP 2.05, phastCons 1 — highly conserved position (PP3-type support)
- Regional missense constraint: **o/e 1.13** across the covering region of the MANE Select transcript (21,968,232–21,974,827), spanning 6,595 bp. Chi-square p 0.04. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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}

**CDKN2A** population constraint: LOEUF 0.791, pLI 0.61783, missense-Z -1.3314; 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):

- **melanoma-pancreatic cancer syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **85** lies in an α-helix; a UniProt-annotated variant site (in); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 77.02, 1% of residues very-high.

**5 experimental structure(s)** (PDB): [1A5E](https://www.rcsb.org/structure/1A5E), [1BI7](https://www.rcsb.org/structure/1BI7), [1DC2](https://www.rcsb.org/structure/1DC2), [2A5E](https://www.rcsb.org/structure/2A5E), [7OZT](https://www.rcsb.org/structure/7OZT) — incl. mutant structure 7OZT.

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

*Describes the biological roles of CDKN2A (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:** CDKN2A's established molecular role includes RNA binding. p.Ala85Phe falls in the disordered region. In Reactome, CDKN2A is annotated in disease pathway(s) including **Defective Intrinsic Pathway for Apoptosis Due to p14ARF Loss of Function**, **Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4**.

**Disease mechanism (Reactome):** CDKN2A loss or alteration is curated in [Defective Intrinsic Pathway for Apoptosis Due to p14ARF Loss of Function](https://reactome.org/content/detail/R-HSA-9645722), [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4](https://reactome.org/content/detail/R-HSA-9630791), [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6](https://reactome.org/content/detail/R-HSA-9630794).

### Pathways affected {#pathways}

CDKN2A participates in **20 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective Intrinsic Pathway for Apoptosis Due to p14ARF Loss of Function](https://reactome.org/content/detail/R-HSA-9645722) | curated |
| ⚕ [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4](https://reactome.org/content/detail/R-HSA-9630791) | curated |
| ⚕ [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6](https://reactome.org/content/detail/R-HSA-9630794) | curated |
| ⚕ [Evasion of Oncogene Induced Senescence Due to p14ARF Defects](https://reactome.org/content/detail/R-HSA-9646303) | curated |
| ⚕ [Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4](https://reactome.org/content/detail/R-HSA-9632697) | curated |
| ⚕ [Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6](https://reactome.org/content/detail/R-HSA-9632700) | curated |
| ⚕ [Evasion of Oxidative Stress Induced Senescence Due to p14ARF Defects](https://reactome.org/content/detail/R-HSA-9646304) | curated |
| [Apoptotic factor-mediated response](https://reactome.org/content/detail/R-HSA-111471) | curated |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [Nuclear events mediated by NFE2L2](https://reactome.org/content/detail/R-HSA-9759194) | curated |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [Regulation of MITF-M-dependent genes involved in cell cycle and proliferation](https://reactome.org/content/detail/R-HSA-9825892) | curated |
| [Regulation of RUNX3 expression and activity](https://reactome.org/content/detail/R-HSA-8941858) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |
| [SUMOylation of transcription factors](https://reactome.org/content/detail/R-HSA-3232118) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [Stabilization of p53](https://reactome.org/content/detail/R-HSA-69541) | curated |
| [Transcriptional Regulation by VENTX](https://reactome.org/content/detail/R-HSA-8853884) | curated |

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

**Molecular function:** RNA binding, cyclin-dependent protein serine/threonine kinase inhibitor activity, protein kinase binding, NF-kappaB binding, p53 binding, SUMO transferase activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, negative regulation of cell-matrix adhesion, Ras protein signal transduction, negative regulation of cell population proliferation, negative regulation of cell growth, negative regulation of cyclin-dependent protein serine/threonine kinase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-10.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2017–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-01-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-06-22 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-10 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [familial melanoma](https://sugi.bio/atlas/disease/familial-melanoma/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, not specified, Familial melanoma, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Hereditary melanoma, Hereditary cutaneous melanoma, AllHighlyPenetrant.

## Similar variants {#similar}

Related CDKN2A variant pages (same residue, condition, or type): [CDKN2A p.Ala85Pro](/variant/cdkn2a-p-ala85pro), [CDKN2A p.Ala85Ser](/variant/cdkn2a-p-ala85ser), [CDKN2A p.Ala85Thr](/variant/cdkn2a-p-ala85thr), [CDKN2A p.Ala85Val](/variant/cdkn2a-p-ala85val), [CDKN2A p.Ala85=](/variant/cdkn2a-p-ala85), [CDKN2A p.Ala68Leu](/variant/cdkn2a-p-ala68leu), [CDKN2A p.Arg128fs](/variant/cdkn2a-p-arg128fs), [CDKN2A p.Asp14fs](/variant/cdkn2a-p-asp14fs).

### 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 423274). 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.*