# NM_001370259.2(MEN1):c.653G>C (p.Arg218Pro)

https://sugi.bio/variant/men1-p-arg218pro

## Summary

**MEN1 p.Arg218Pro (c.653G>C)** is classified **Uncertain significance** in MEN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.9867); Absent from gnomAD v4.1; Associated with multiple endocrine neoplasia type 1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1423517569 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MEN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to multiple endocrine neoplasia type 1.

*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) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 17 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MEN1 is a diagnostic-grade gene on 16 Genomics England panels |

**Commonly reported features of Multiple endocrine neoplasia type 1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypercalcemia — Very frequent (99-80%)
- Primary hyperparathyroidism — Very frequent (99-80%)
- Parathyroid hyperplasia — Very frequent (99-80%)
- Angiofibromas — Very frequent (99-80%)
- Impairment of activities of daily living — Very frequent (99-80%)
- Impotence — Frequent (79-30%)
- Adrenocortical abnormality — Frequent (79-30%)
- Multiple lipomas — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003829/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MEN1](https://sugi.bio/atlas/gene/MEN1/) |
| Protein change (HGVS p.) | p.Arg218Pro |
| Coding change (HGVS c.) | c.653G>C |
| MANE Select transcript | [NM_001370259](https://www.ncbi.nlm.nih.gov/nuccore/NM_001370259) |
| dbSNP | [rs1423517569](https://www.ncbi.nlm.nih.gov/snp/rs1423517569/) |
| Variant type | single nucleotide variant |
| Location | chr11:64807892-64807892 (GRCh38) |
| ClinVar | [VCV942756](https://www.ncbi.nlm.nih.gov/clinvar/variation/942756/) |

**All HGVS expressions:** `LRG_509:g.8403G>C`, `LRG_509t2:c.653G>C`, `NC_000011.10:g.64807892C>G`, `NC_000011.9:g.64575364C>G`, `NG_008929.1:g.8403G>C`, `NG_033040.1:g.350G>C`, `NM_000244.4:c.668G>C`, `NM_001370251.2:c.653G>C`, `NM_001370259.2:c.653G>C`, `NM_001370260.2:c.653G>C`, `NM_001370261.2:c.653G>C`, `NM_001370262.2:c.549+104G>C`, `NM_001370263.2:c.549+104G>C`, `NM_130799.3:c.653G>C`, `NM_130800.3:c.668G>C`, `NM_130801.3:c.668G>C`, `NM_130802.3:c.668G>C`, `NM_130803.3:c.668G>C`, `NM_130804.3:c.668G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9867)
- REVEL 0.808 (moderately pathogenic-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this damaging
- Conservation: phyloP 7.623, GERP 1.45, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R223P** vs ClinVar **R218P**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 26.8**. 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 0.61** across the covering region of the MANE Select transcript (64,805,147–64,810,109), spanning 4,962 bp. Chi-square p 4.4e-20. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.33 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**MEN1** population constraint: LOEUF 0.206, pLI 1, missense-Z 4.2012; 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):

- **multiple endocrine neoplasia type 1** — Definitive (AD)

## Protein context {#protein}

Residue **218** lies in the 'interaction with fancd2' region.

AlphaFold model confidence (whole protein): pLDDT 85.13, 74% of residues very-high.

**69 experimental structure(s)** (PDB): [3U84](https://www.rcsb.org/structure/3U84), [3U85](https://www.rcsb.org/structure/3U85), [3U86](https://www.rcsb.org/structure/3U86), [3U88](https://www.rcsb.org/structure/3U88), [4GPQ](https://www.rcsb.org/structure/4GPQ), [4GQ3](https://www.rcsb.org/structure/4GQ3) — incl. mutant structure 8VA5.

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

*Describes the biological roles of MEN1 (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:** MEN1's established molecular role includes four-way junction DNA binding. p.Arg218Pro falls in the interaction with fancd2 region.


### Pathways affected {#pathways}

MEN1 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Deactivation of the beta-catenin transactivating complex](https://reactome.org/content/detail/R-HSA-3769402) | curated |
| [Formation of WDR5-containing histone-modifying complexes](https://reactome.org/content/detail/R-HSA-9772755) | curated |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [RHO GTPases activate IQGAPs](https://reactome.org/content/detail/R-HSA-5626467) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription](https://reactome.org/content/detail/R-HSA-2173796) | curated |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |

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

**Molecular function:** four-way junction DNA binding, Y-form DNA binding, transcription cis-regulatory region binding, double-stranded DNA binding, protein-macromolecule adaptor activity, phosphoprotein binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, osteoblast development, DNA damage response, response to UV, response to gamma radiation, positive regulation of transforming growth factor beta receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-07.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-08-21 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-07 |

## Associated conditions {#conditions}

[multiple endocrine neoplasia type 1](https://sugi.bio/atlas/disease/multiple-endocrine-neoplasia-type-1/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Multiple endocrine neoplasia, type 1, Hereditary cancer-predisposing syndrome, MEN I, WERMER SYNDROME, Endocrine adenomatosis multiple, MEN 1, MEA I, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome.

## Similar variants {#similar}

Related MEN1 variant pages (same residue, condition, or type): [MEN1 p.Arg218Gln](/variant/men1-p-arg218gln), [MEN1 p.Arg218Trp](/variant/men1-p-arg218trp), [MEN1 p.Arg218=](/variant/men1-p-arg218), [MEN1 c.1049+1G>A](/variant/men1-c-1049-plus-1g-a), [MEN1 c.1049+1G>C](/variant/men1-c-1049-plus-1g-c), [MEN1 c.1049+2T>C](/variant/men1-c-1049-plus-2t-c), [MEN1 c.1350+1G>A](/variant/men1-c-1350-plus-1g-a), [MEN1 c.1351-2A>C](/variant/men1-c-1351-minus-2a-c).

### 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 942756). 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.*