# NM_000389.5(CDKN1A):c.12G>A (p.Pro4=)

https://sugi.bio/variant/cdkn1a-p-pro4

## Summary

**CDKN1A p.Pro4= (c.12G>A)** is classified **Benign/Likely benign** in CDKN1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-01). Rare (popmax 0.578%, afr).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs4986868 · 2 submitters · rare (popmax 0.578%, afr)

## For patients & families {#patients}

This is a change in the CDKN1A gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters.

*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 | [CDKN1A](https://sugi.bio/atlas/gene/CDKN1A/) |
| Protein change (HGVS p.) | p.Pro4= |
| Coding change (HGVS c.) | c.12G>A |
| MANE Select transcript | [NM_000389](https://www.ncbi.nlm.nih.gov/nuccore/NM_000389) |
| dbSNP | [rs4986868](https://www.ncbi.nlm.nih.gov/snp/rs4986868/) |
| Variant type | single nucleotide variant |
| Location | chr6:36684113-36684113 (GRCh38) |
| ClinVar | [VCV736380](https://www.ncbi.nlm.nih.gov/clinvar/variation/736380/) |

**All HGVS expressions:** `NC_000006.11:g.36651890G>A`, `NC_000006.12:g.36684113G>A`, `NG_009364.1:g.10432G>A`, `NM_000389.5:c.12G>A`, `NM_001220777.2:c.12G>A`, `NM_001220778.2:c.12G>A`, `NM_001291549.3:c.114G>A`, `NM_001374509.1:c.114G>A`, `NM_001374510.1:c.51G>A`, `NM_001374511.1:c.12G>A`, `NM_001374512.1:c.12G>A`, `NM_001374513.1:c.12G>A`, `NM_078467.3:c.12G>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 (below), not from a missing predictor score.
- Conservation: phyloP -9.697, GERP -2.77 — fast-evolving / accelerated position
- CADD: **PHRED 0.255**. 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 **0.578%** (afr) · FAF95 0.533% · FAF99 0.516% · 434/75,048 in the highest group · 563/1,613,368 alleles overall — rare (popmax 0.578%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.578% | 173 |
| Remaining individuals (not grpmax-eligible) | 0.0752% | 1,329 |
| Admixed American | 0.0416% | 2,401 |
| South Asian | 0.0231% | 4,336 |
| European (non-Finnish) | 0.00297% | 33,714 |
| East Asian | 0.00223% | 44,874 |

*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}

**CDKN1A** population constraint: LOEUF 1.492, pLI 1.7576e-05, missense-Z 0.82899. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **4** lies in a UniProt-annotated variant site (in).

AlphaFold model confidence (whole protein): pLDDT 70.16, 29% of residues very-high.

**13 experimental structure(s)** (PDB): [1AXC](https://www.rcsb.org/structure/1AXC), [2ZVV](https://www.rcsb.org/structure/2ZVV), [2ZVW](https://www.rcsb.org/structure/2ZVW), [4RJF](https://www.rcsb.org/structure/4RJF), [5E0U](https://www.rcsb.org/structure/5E0U), [6CBI](https://www.rcsb.org/structure/6CBI) — incl. mutant structure 5E0U.

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

*Describes the biological roles of CDKN1A (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:** CDKN1A's established molecular role includes cyclin-dependent protein serine/threonine kinase inhibitor activity. In Reactome, CDKN1A 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):** CDKN1A 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), [STAT5 activation downstream of FLT3 ITD mutants](https://reactome.org/content/detail/R-HSA-9702518).

### Pathways affected {#pathways}

CDKN1A participates in **25 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400) | other |
| ⚕ [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069) | other |
| ⚕ [STAT5 activation downstream of FLT3 ITD mutants](https://reactome.org/content/detail/R-HSA-9702518) | other |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | other |
| ⚕ [Signaling by FLT3 fusion proteins](https://reactome.org/content/detail/R-HSA-9703465) | other |
| [AKT phosphorylates targets in the cytosol](https://reactome.org/content/detail/R-HSA-198323) | other |
| [Cyclin A:Cdk2-associated events at S phase entry](https://reactome.org/content/detail/R-HSA-69656) | other |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | other |
| [Cyclin E associated events during G1/S transition ](https://reactome.org/content/detail/R-HSA-69202) | other |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | other |
| [FOXO-mediated transcription of cell cycle genes](https://reactome.org/content/detail/R-HSA-9617828) | other |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | other |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | other |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | other |
| [RUNX3 regulates CDKN1A transcription](https://reactome.org/content/detail/R-HSA-8941855) | other |
| [Regulation of MITF-M-dependent genes involved in cell cycle and proliferation](https://reactome.org/content/detail/R-HSA-9825892) | other |
| [SCF(Skp2)-mediated degradation of p27/p21](https://reactome.org/content/detail/R-HSA-187577) | other |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | other |
| [TFAP2 (AP-2) family regulates transcription of cell cycle factors](https://reactome.org/content/detail/R-HSA-8866911) | other |
| [TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest](https://reactome.org/content/detail/R-HSA-6804116) | other |
| [The role of GTSE1 in G2/M progression after G2 checkpoint](https://reactome.org/content/detail/R-HSA-8852276) | other |
| [Transcriptional  activation of  cell cycle inhibitor p21 ](https://reactome.org/content/detail/R-HSA-69895) | other |
| [Transcriptional regulation by RUNX2](https://reactome.org/content/detail/R-HSA-8878166) | other |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | other |
| [p53-Dependent G1 DNA Damage Response](https://reactome.org/content/detail/R-HSA-69563) | other |

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

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

**Biological process:** negative regulation of protein phosphorylation, positive regulation of protein phosphorylation, DNA damage response, mitotic G2 DNA damage checkpoint signaling, Ras protein signal transduction, negative regulation of cell population proliferation.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-01.

**Submitter consensus:** conflicting (1 Benign, 1 Likely benign).

**Submission history:** 2 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-04-24 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CDKN1A variant pages (same residue, condition, or type): [CDKN1A p.Pro4Leu](/variant/cdkn1a-p-pro4leu), [CDKN1A p.Arg84Gln](/variant/cdkn1a-p-arg84gln), [CDKN1A p.Ser31=](/variant/cdkn1a-p-ser31), [CDKN1A p.Thr80=](/variant/cdkn1a-p-thr80), [CDKN1A p.Ala106Val](/variant/cdkn1a-p-ala106val), [CDKN1A p.Arg20His](/variant/cdkn1a-p-arg20his), [CDKN1A p.Arg32His](/variant/cdkn1a-p-arg32his), [CDKN1A p.Arg46His](/variant/cdkn1a-p-arg46his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 736380). 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.*