# NM_001370259.2(MEN1):c.272C>T (p.Ala91Val)

https://sugi.bio/variant/men1-p-ala91val

## Summary

**MEN1 p.Ala91Val (c.272C>T)** is classified **Uncertain significance** in MEN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). AlphaMissense: ambiguous (0.4305); Very rare (popmax 8.48e-05%, nfe); Associated with multiple endocrine neoplasia type 1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 8.48e-05%, nfe)

## 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 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.Ala91Val |
| Coding change (HGVS c.) | c.272C>T |
| MANE Select transcript | [NM_001370259](https://www.ncbi.nlm.nih.gov/nuccore/NM_001370259) |
| Variant type | single nucleotide variant |
| Location | chr11:64809838-64809838 (GRCh38) |
| ClinVar | [VCV4709862](https://www.ncbi.nlm.nih.gov/clinvar/variation/4709862/) |

**All HGVS expressions:** `LRG_509:g.6457C>T`, `LRG_509t1:c.272C>T`, `LRG_509t2:c.272C>T`, `NC_000011.10:g.64809838G>A`, `NC_000011.9:g.64577310G>A`, `NG_008929.1:g.6457C>T`, `NM_000244.4:c.272C>T`, `NM_001370251.2:c.272C>T`, `NM_001370259.2:c.272C>T`, `NM_001370260.2:c.272C>T`, `NM_001370261.2:c.272C>T`, `NM_001370262.2:c.272C>T`, `NM_001370263.2:c.272C>T`, `NM_001407142.1:c.272C>T`, `NM_001407143.1:c.272C>T`, `NM_001407144.1:c.272C>T`, `NM_001407145.1:c.272C>T`, `NM_001407146.1:c.272C>T`, `NM_001407147.1:c.272C>T`, `NM_001407148.1:c.272C>T`, `NM_001407149.1:c.272C>T`, `NM_001407150.1:c.272C>T`, `NM_001407151.1:c.272C>T`, `NM_001407152.1:c.272C>T`, `NM_130799.3:c.272C>T`, `NM_130800.3:c.272C>T`, `NM_130801.3:c.272C>T`, `NM_130802.3:c.272C>T`, `NM_130803.3:c.272C>T`, `NM_130804.3:c.272C>T`, `NR_176284.1:n.321C>T`, `NR_176285.1:n.333C>T`, `NR_176286.1:n.321C>T`, `NR_176287.1:n.579C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4305) — no call either way
- REVEL 0.667 (pathogenic-leaning)
- SaProt LLR -6.145 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense makes no call
- Conservation: phyloP 11.766, GERP 1.64, phastCons 1 — highly conserved
- CADD: **PHRED 26.1**. 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: **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 **8.48e-05%** (nfe) · 1/1,179,634 in the highest group · 1/1,461,272 alleles overall — very rare (popmax 8.48e-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 **91** lies in an α-helix; a UniProt-annotated variant site (in men1).

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-20.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-20 |

## 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 **91** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MEN1 p.Ala91fs](/variant/men1-p-ala91fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MEN1 variant pages (same residue, condition, or type): [MEN1 p.Ala91Ser](/variant/men1-p-ala91ser), [MEN1 p.Ala91fs](/variant/men1-p-ala91fs), [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), [MEN1 c.1351-2A>G](/variant/men1-c-1351-minus-2a-g).

### 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 4709862). 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.*