# NM_001370259.2(MEN1):c.139_143dup (p.Ala49fs)

https://sugi.bio/variant/men1-p-ala49fs

## Summary

**MEN1 p.Ala49fs (c.139_143dup)** is classified **Pathogenic** in MEN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-24). No gnomAD frequency available for this variant; Associated with multiple endocrine neoplasia type 1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2497282682 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MEN1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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.Ala49fs |
| Coding change (HGVS c.) | c.139_143dup |
| MANE Select transcript | [NM_001370259](https://www.ncbi.nlm.nih.gov/nuccore/NM_001370259) |
| dbSNP | [rs2497282682](https://www.ncbi.nlm.nih.gov/snp/rs2497282682/) |
| Variant type | Duplication |
| Location | chr11:64809966-64809967 (GRCh38) |
| ClinVar | [VCV2132920](https://www.ncbi.nlm.nih.gov/clinvar/variation/2132920/) |

**All HGVS expressions:** `LRG_509:g.6324_6328dup`, `LRG_509t1:c.138_142dup`, `LRG_509t2:c.138_142dup`, `NC_000011.10:g.64809968_64809972dup`, `NC_000011.9:g.64577440_64577444dup`, `NG_008929.1:g.6324_6328dup`, `NM_000244.4:c.139_143dup`, `NM_001370251.2:c.139_143dup`, `NM_001370259.2:c.139_143dup`, `NM_001370260.2:c.139_143dup`, `NM_001370261.2:c.139_143dup`, `NM_001370262.2:c.139_143dup`, `NM_001370263.2:c.139_143dup`, `NM_001407142.1:c.138_142dup`, `NM_001407143.1:c.138_142dup`, `NM_001407144.1:c.138_142dup`, `NM_001407145.1:c.138_142dup`, `NM_001407146.1:c.138_142dup`, `NM_001407147.1:c.138_142dup`, `NM_001407148.1:c.138_142dup`, `NM_001407149.1:c.138_142dup`, `NM_001407150.1:c.138_142dup`, `NM_001407151.1:c.138_142dup`, `NM_001407152.1:c.138_142dup`, `NM_130799.3:c.139_143dup`, `NM_130800.3:c.139_143dup`, `NM_130801.3:c.139_143dup`, `NM_130802.3:c.139_143dup`, `NM_130803.3:c.139_143dup`, `NM_130804.3:c.139_143dup`, `NR_176284.1:n.187_191dup`, `NR_176285.1:n.199_203dup`, `NR_176286.1:n.187_191dup`, `NR_176287.1:n.445_449dup`

## 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 -0.521, GERP -0.95, phastCons 0.046 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — 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 2 of 10**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**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 **49** lies in 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-24.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-24 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Multiple endocrine neoplasia, type 1, MEN I, WERMER SYNDROME, Endocrine adenomatosis multiple, MEN 1, MEA I.

## Same-residue context {#hotspot}

Residue **49** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MEN1 p.Ala49Pro](/variant/men1-p-ala49pro). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MEN1 variant pages (same residue, condition, or type): [MEN1 p.Ala49Thr](/variant/men1-p-ala49thr), [MEN1 p.Ala49Val](/variant/men1-p-ala49val), [MEN1 p.Ala49Ser](/variant/men1-p-ala49ser), [MEN1 p.Ala380fs](/variant/men1-p-ala380fs), [MEN1 p.Ala467fs](/variant/men1-p-ala467fs), [MEN1 p.Arg108fs](/variant/men1-p-arg108fs), [MEN1 p.Asp123fs](/variant/men1-p-asp123fs), [MEN1 p.Asp136fs](/variant/men1-p-asp136fs).

### 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 2132920). 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.*