# NM_000546.6(TP53):c.215C>G (p.Pro72Arg)

https://sugi.bio/variant/tp53-p-pro72arg

## Summary

**TP53 p.Pro72Arg (c.215C>G)** is classified **Benign** in TP53 (ClinVar, Expert panel, 34 submitters; last evaluated 2025-12-05). AlphaMissense: likely benign (0.0724); Common (popmax 74.8%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Li-Fraumeni syndrome.

**At a glance:** Benign · review: Expert panel · rsID rs1042522 · 34 submitters · 15 linked conditions · AlphaMissense likely benign · common (popmax 74.8%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the TP53 gene that is classified as benign — not considered disease-causing, submitted by 34 submitters, and is linked to Li-Fraumeni 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (United Kingdom) |
| Clinical trials | 21 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TP53 is a diagnostic-grade gene on 19 Genomics England panels |

**Commonly reported features of Li-Fraumeni syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Neoplasm — Very frequent (99-80%)
- Breast carcinoma — Frequent (79-30%)
- Leukemia — Occasional (29-5%)
- Lymphoma — Occasional (29-5%)
- Osteosarcoma — Occasional (29-5%)
- Rhabdomyosarcoma — Occasional (29-5%)
- Ependymoma — Occasional (29-5%)
- Adrenocortical carcinoma — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006902/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TP53](https://sugi.bio/atlas/gene/TP53/) |
| Protein change (HGVS p.) | p.Pro72Arg |
| Coding change (HGVS c.) | c.215C>G |
| MANE Select transcript | [NM_000546](https://www.ncbi.nlm.nih.gov/nuccore/NM_000546) |
| dbSNP | [rs1042522](https://www.ncbi.nlm.nih.gov/snp/rs1042522/) |
| Variant type | single nucleotide variant |
| Location | chr17:7676154-7676154 (GRCh38) |
| ClinVar | [VCV12351](https://www.ncbi.nlm.nih.gov/clinvar/variation/12351/) |

**All HGVS expressions:** `LRG_321:g.16397C>G`, `LRG_321t1:c.215C>G`, `LRG_321t3:c.215C>G`, `NC_000017.10:g.7579472G>C`, `NC_000017.11:g.7676154G>C`, `NG_017013.2:g.16397C>G`, `NM_000546.6:c.215C>G`, `NM_001126112.3:c.215C>G`, `NM_001126113.3:c.215C>G`, `NM_001126114.3:c.215C>G`, `NM_001126118.2:c.98C>G`, `NM_001276695.3:c.98C>G`, `NM_001276696.3:c.98C>G`, `NM_001276760.3:c.98C>G`, `NM_001276761.3:c.98C>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 74.8%, nfe) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0724)
- REVEL 0.368 (indeterminate)
- SaProt LLR -9.106 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 1.509, GERP 1.09, phastCons 0.015 — weakly conserved position
- CADD: **PHRED 12.91**. 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.*
- Regional missense constraint: **o/e 0.89** across the covering region of the MANE Select transcript (7,669,612–7,676,594), spanning 6,982 bp. Chi-square p 0.0085. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **74.8%** (nfe) · FAF95 74.6% · FAF99 74.6% · 882,123/1,179,968 in the highest group · 1,142,226/1,613,582 alleles overall — common (popmax 74.8%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 74.8% | 1 |
| Finnish (not grpmax-eligible) | 73.3% | 1 |
| Ashkenazi Jewish (not grpmax-eligible) | 71.9% | 1 |
| Admixed American | 71.1% | 1 |
| Remaining individuals (not grpmax-eligible) | 69.4% | 1 |
| Amish (not grpmax-eligible) | 67% | 1 |
| Middle Eastern | 60.6% | 2 |
| East Asian | 60.1% | 2 |
| South Asian | 50.7% | 2 |
| African / African-American | 38.2% | 3 |

*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}

**TP53** population constraint: LOEUF 0.449, pLI 0.99798, missense-Z 1.1539; 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):

- **Li-Fraumeni syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **72** lies in a UniProt-annotated variant site (in sporadic cancers; somatic mutation; requires 2 nucleotide substitutions); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in); the 'interaction with ccar2' region; the 'interaction with hrmt1l2' region; the 'disordered' region; the 'interaction with wwox' region.

AlphaFold model confidence (whole protein): pLDDT 75.83, 54% of residues very-high.

**321 experimental structure(s)** (PDB): [1A1U](https://www.rcsb.org/structure/1A1U), [1AIE](https://www.rcsb.org/structure/1AIE), [1C26](https://www.rcsb.org/structure/1C26), [1DT7](https://www.rcsb.org/structure/1DT7), [1GZH](https://www.rcsb.org/structure/1GZH), [1H26](https://www.rcsb.org/structure/1H26) — incl. mutant structure 1A1U.

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

*Describes the biological roles of TP53 (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:** TP53's established molecular role includes transcription cis-regulatory region binding. p.Pro72Arg falls in the interaction with ccar2 region. In Reactome, TP53 is annotated in disease pathway(s) including **Loss of function of TP53 in cancer due to loss of tetramerization ability**, **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** TP53 loss or alteration is curated in [Loss of function of TP53 in cancer due to loss of tetramerization ability](https://reactome.org/content/detail/R-HSA-9723905), [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370).

### Pathways affected {#pathways}

TP53 participates in **47 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Loss of function of TP53 in cancer due to loss of tetramerization ability](https://reactome.org/content/detail/R-HSA-9723905) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| [Activation of NOXA and translocation to mitochondria](https://reactome.org/content/detail/R-HSA-111448) | curated |
| [Activation of PUMA and translocation to mitochondria](https://reactome.org/content/detail/R-HSA-139915) | curated |
| [Autodegradation of the E3 ubiquitin ligase COP1](https://reactome.org/content/detail/R-HSA-349425) | curated |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [Formation of Senescence-Associated Heterochromatin Foci (SAHF)](https://reactome.org/content/detail/R-HSA-2559584) | curated |
| [G2/M Checkpoints](https://reactome.org/content/detail/R-HSA-69481) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [Negative transcriptional regulation of urea cycle enzymes](https://reactome.org/content/detail/R-HSA-9988426) | curated |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | curated |
| [Ovarian tumor domain proteases](https://reactome.org/content/detail/R-HSA-5689896) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [PI5P Regulates TP53 Acetylation](https://reactome.org/content/detail/R-HSA-6811555) | curated |
| [PKR-mediated signaling](https://reactome.org/content/detail/R-HSA-9833482) | curated |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | curated |
| [Pyroptosis](https://reactome.org/content/detail/R-HSA-5620971) | curated |
| [RUNX3 regulates CDKN1A transcription](https://reactome.org/content/detail/R-HSA-8941855) | curated |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |
| [Regulation of NF-kappa B signaling](https://reactome.org/content/detail/R-HSA-9758274) | curated |
| [Regulation of TP53 Activity through Acetylation](https://reactome.org/content/detail/R-HSA-6804758) | curated |
| [Regulation of TP53 Activity through Association with Co-factors](https://reactome.org/content/detail/R-HSA-6804759) | curated |
| [Regulation of TP53 Activity through Methylation](https://reactome.org/content/detail/R-HSA-6804760) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [Regulation of TP53 Expression](https://reactome.org/content/detail/R-HSA-6804754) | curated |
| [SUMOylation of transcription factors](https://reactome.org/content/detail/R-HSA-3232118) | curated |
| [Stabilization of p53](https://reactome.org/content/detail/R-HSA-69541) | curated |
| [TP53 Regulates Metabolic Genes](https://reactome.org/content/detail/R-HSA-5628897) | curated |
| [TP53 Regulates Transcription of Caspase Activators and Caspases](https://reactome.org/content/detail/R-HSA-6803207) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [TP53 Regulates Transcription of Death Receptors and Ligands](https://reactome.org/content/detail/R-HSA-6803211) | curated |
| [TP53 Regulates Transcription of Genes Involved in Cytochrome C Release](https://reactome.org/content/detail/R-HSA-6803204) | curated |
| [TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest](https://reactome.org/content/detail/R-HSA-6804116) | curated |
| [TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest](https://reactome.org/content/detail/R-HSA-6804114) | curated |
| [TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain](https://reactome.org/content/detail/R-HSA-6804115) | curated |
| [TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain](https://reactome.org/content/detail/R-HSA-6803205) | curated |
| [The role of GTSE1 in G2/M progression after G2 checkpoint](https://reactome.org/content/detail/R-HSA-8852276) | curated |
| [Transcriptional  activation of  cell cycle inhibitor p21 ](https://reactome.org/content/detail/R-HSA-69895) | curated |
| [Transcriptional Regulation by VENTX](https://reactome.org/content/detail/R-HSA-8853884) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [Association of TriC/CCT with target proteins during biosynthesis](https://reactome.org/content/detail/R-HSA-390471) | electronic |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | electronic |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | electronic |
| [Urea cycle](https://reactome.org/content/detail/R-HSA-70635) | other |
| [Zygotic genome activation (ZGA)](https://reactome.org/content/detail/R-HSA-9819196) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, cis-regulatory region sequence-specific DNA binding, core promoter sequence-specific DNA binding, TFIID-class transcription factor complex binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, hematopoietic progenitor cell differentiation, nucleotide-excision repair, regulation of DNA-templated transcription, regulation of transcription by RNA polymerase II, autophagy.

## Clinical significance {#significance}

**Benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-12-05.

**Submitter consensus:** conflicting (31 Benign, 1 not provided, 1 Uncertain significance).

**Submission history:** 35 submissions (2009–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| GeneKor MSA | Benign | criteria provided, single submitter | clinical testing | 2025-07-10 |
| IntelligeneCG | Benign | criteria provided, single submitter | clinical testing | 2017-08-18 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2022-06-18 |
| Dr. Afia Zoology Lab, University of Education | Benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| OMIM | Benign | no assertion criteria provided | literature only | 2009-10-01 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital |  | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2016-04-05 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-04-01 |
| ClinGen TP53 Variant Curation Expert Panel, ClinGen | Benign | reviewed by expert panel | curation | 2025-12-05 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-07-30 |
| ITMI | not provided | no classification provided | reference population | 2013-09-19 |
| Pathway Genomics | Uncertain significance | no assertion criteria provided | clinical testing | 2014-07-24 |
| Color Diagnostics, LLC DBA Color Health | Benign | criteria provided, single submitter | clinical testing | 2014-11-05 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | no assertion criteria provided | clinical testing |  |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-03-06 |
| Institute of Human Genetics, University of Leipzig Medical Center | Benign | criteria provided, single submitter | clinical testing | 2019-01-01 |
| Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | Benign | no assertion criteria provided | clinical testing |  |
| National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Benign | criteria provided, single submitter | clinical testing | 2022-04-19 |
| Genetics Program, Instituto Nacional de Cancer | Benign | criteria provided, single submitter | research | 2021-11-01 |
| Fulgent Genetics, Fulgent Genetics | Benign | criteria provided, single submitter | clinical testing | 2021-12-20 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2014-11-18 |
| All of Us Research Program, National Institutes of Health | Benign | criteria provided, single submitter | clinical testing | 2024-10-03 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Benign | criteria provided, single submitter | clinical testing | 2020-03-02 |
| Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Benign | no assertion criteria provided | research | 2012-07-13 |
| Biochemistry Department, University of Zimbabwe |  | no assertion criteria provided | reference population | 2020-06-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |

## Associated conditions {#conditions}

[Li-Fraumeni syndrome](https://sugi.bio/atlas/disease/li-fraumeni-syndrome/), [bone osteosarcoma](https://sugi.bio/atlas/disease/bone-osteosarcoma/), [hereditary breast ovarian cancer syndrome](https://sugi.bio/atlas/disease/hereditary-breast-ovarian-cancer-syndrome/), [exocrine pancreatic carcinoma](https://sugi.bio/atlas/disease/exocrine-pancreatic-carcinoma/), [colorectal cancer](https://sugi.bio/atlas/disease/colorectal-cancer/), [hepatocellular carcinoma](https://sugi.bio/atlas/disease/hepatocellular-carcinoma/), [adrenocortical carcinoma, hereditary](https://sugi.bio/atlas/disease/adrenocortical-carcinoma-hereditary/), [choroid plexus papilloma](https://sugi.bio/atlas/disease/choroid-plexus-papilloma/), [basal cell carcinoma, susceptibility to, 7](https://sugi.bio/atlas/disease/basal-cell-carcinoma-susceptibility-to-7/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [nasopharyngeal carcinoma](https://sugi.bio/atlas/disease/nasopharyngeal-carcinoma/), [hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/), [acute myeloid leukemia](https://sugi.bio/atlas/disease/acute-myeloid-leukemia/), [glioma susceptibility 1](https://sugi.bio/atlas/disease/glioma-susceptibility-1/), [bone marrow failure syndrome 5](https://sugi.bio/atlas/disease/bone-marrow-failure-syndrome-5/).

**Reported phenotype names (ClinVar):** Li-Fraumeni syndrome, TP53 POLYMORPHISM, not provided, not specified, Hereditary cancer-predisposing syndrome, Li-Fraumeni syndrome 1, Hereditary breast ovarian cancer syndrome, Adrenocortical carcinoma, hereditary, Basal cell carcinoma, susceptibility to, 7, Bone marrow failure syndrome 5.

## Same-residue context {#hotspot}

Residue **72** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TP53 p.Pro72fs](/variant/tp53-p-pro72fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Cancer therapy associations (CIViC) {#civic}

Curated clinical evidence for this variant from CIViC (profile *P72R*):

| Disease | Therapies | Type | Level | Significance |
| --- | --- | --- | --- | --- |
| Lung Carcinoma |  | Prognostic | B | Poor Outcome |
| Cervical Cancer |  | Prognostic | B | Poor Outcome |
| Oligodendroglioma |  | Prognostic | B | Poor Outcome |
*CIViC evidence levels A–E (A strongest). Therapy associations are context-specific — not a treatment recommendation.*

## Pharmacogenomics (PharmGKB) {#pgx}

Clinical drug-response annotations:

| Drug(s) | Evidence level | Category | Phenotype |
| --- | --- | --- | --- |
| antineoplastic agents | 3 | Toxicity | Drug Toxicity |
| Platinum compounds | 3 | Efficacy | Overall survival |
*PharmGKB levels 1A/1B (highest) → 4. Discuss any medication decision with your prescriber — reference information, not advice.*

## Similar variants {#similar}

Related TP53 variant pages (same residue, condition, or type): [TP53 p.Pro72Ala](/variant/tp53-p-pro72ala), [TP53 p.Pro72His](/variant/tp53-p-pro72his), [TP53 p.Pro72Leu](/variant/tp53-p-pro72leu), [TP53 p.Pro72Thr](/variant/tp53-p-pro72thr), [TP53 p.Pro72Cys](/variant/tp53-p-pro72cys), [TP53 p.Pro72Ser](/variant/tp53-p-pro72ser), [TP53 p.Pro72fs](/variant/tp53-p-pro72fs), [TP53 p.Pro72_Val73delinsArgMet](/variant/tp53-p-pro72-val73delinsargmet).

### 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 2026-10-14); 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 12351). 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.*