# NM_001370259.2(MEN1):c.1243C>T (p.Arg415Ter)

https://sugi.bio/variant/men1-p-arg415ter

## Summary

**MEN1 p.Arg415Ter (c.1243C>T)** is classified **Pathogenic** in MEN1 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-01-02). Very rare (popmax 8.47e-05%, nfe); Associated with MEN1-related disorder.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1060499974 · 14 submitters · 3 linked conditions · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the MEN1 gene that is considered disease-causing, submitted by 14 submitters, and is linked to MEN1-related disorder.

*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 | [MEN1](https://sugi.bio/atlas/gene/MEN1/) |
| Protein change (HGVS p.) | p.Arg415Ter |
| Coding change (HGVS c.) | c.1243C>T |
| MANE Select transcript | [NM_001370259](https://www.ncbi.nlm.nih.gov/nuccore/NM_001370259) |
| dbSNP | [rs1060499974](https://www.ncbi.nlm.nih.gov/snp/rs1060499974/) |
| Variant type | single nucleotide variant |
| Location | chr11:64805141-64805141 (GRCh38) |
| ClinVar | [VCV403802](https://www.ncbi.nlm.nih.gov/clinvar/variation/403802/) |

**All HGVS expressions:** `LRG_509:g.11154C>T`, `LRG_509t2:c.1243C>T`, `NC_000011.10:g.64805141G>A`, `NC_000011.9:g.64572613G>A`, `NG_008929.1:g.11154C>T`, `NG_033040.1:g.3101C>T`, `NM_000244.4:c.1258C>T`, `NM_001370251.2:c.1369C>T`, `NM_001370259.2:c.1243C>T`, `NM_001370260.2:c.1243C>T`, `NM_001370261.2:c.1243C>T`, `NM_001370262.2:c.1138C>T`, `NM_001370263.2:c.1138C>T`, `NM_130799.3:c.1243C>T`, `NM_130800.3:c.1258C>T`, `NM_130801.3:c.1258C>T`, `NM_130802.3:c.1258C>T`, `NM_130803.3:c.1258C>T`, `NM_130804.3:c.1258C>T`

## 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 6.482, GERP 1.35, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.206, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 10**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 52.0**. 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 **8.47e-05%** (nfe) · 1/1,180,024 in the highest group · 1/152,198 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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 **415** lies in a UniProt-annotated variant site (in men1); an α-helix.

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.


### 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-02.

**Submitter consensus:** unanimous (14/14 Pathogenic).

**Submission history:** 14 submissions (2014–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Pathogenic | criteria provided, single submitter | clinical testing | 2014-12-19 |
| Molecular Diagnostics Laboratory, Catalan Institute of Oncology | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-13 |
| Centre of Medical Genetics, University Hospital Muenster | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-15 |
| MGZ Medical Genetics Center | Pathogenic | criteria provided, single submitter | clinical testing | 2022-07-22 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-08 |
| All of Us Research Program, National Institutes of Health | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-23 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-23 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-12 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-06 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-12 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-02 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-21 |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-01 |

## Associated conditions {#conditions}

[MEN1-related disorder](https://sugi.bio/atlas/disease/men1-related-disorder/), [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):** MEN1-related disorder, Multiple endocrine neoplasia, type 1, not provided, Hereditary cancer-predisposing syndrome, MEN1-related condition, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, none provided.

## Similar variants {#similar}

Related MEN1 variant pages (same residue, condition, or type): [MEN1 p.Arg415Gln](/variant/men1-p-arg415gln), [MEN1 p.Arg415Pro](/variant/men1-p-arg415pro), [MEN1 p.Arg415=](/variant/men1-p-arg415), [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 403802). 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.*