# NM_001370259.2(MEN1):c.1555C>T (p.Pro519Ser)

https://sugi.bio/variant/men1-p-pro519ser

## Summary

**MEN1 p.Pro519Ser (c.1555C>T)** is classified **Uncertain significance** in MEN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-29). AlphaMissense: likely benign (0.0573); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1164774071 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · 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 2 submitters, and is linked to hereditary neoplastic 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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/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.Pro519Ser |
| Coding change (HGVS c.) | c.1555C>T |
| MANE Select transcript | [NM_001370259](https://www.ncbi.nlm.nih.gov/nuccore/NM_001370259) |
| dbSNP | [rs1164774071](https://www.ncbi.nlm.nih.gov/snp/rs1164774071/) |
| Variant type | single nucleotide variant |
| Location | chr11:64804612-64804612 (GRCh38) |
| ClinVar | [VCV1775141](https://www.ncbi.nlm.nih.gov/clinvar/variation/1775141/) |

**All HGVS expressions:** `LRG_509:g.11683C>T`, `LRG_509t1:c.1570C>T`, `LRG_509t2:c.1555C>T`, `NC_000011.10:g.64804612G>A`, `NC_000011.9:g.64572084G>A`, `NG_008929.1:g.11683C>T`, `NG_033040.2:g.3602C>T`, `NM_000244.4:c.1570C>T`, `NM_001370251.2:c.1681C>T`, `NM_001370259.2:c.1555C>T`, `NM_001370260.2:c.1555C>T`, `NM_001370261.2:c.1555C>T`, `NM_001370262.2:c.1450C>T`, `NM_001370263.2:c.1450C>T`, `NM_001407142.1:c.1681C>T`, `NM_001407143.1:c.1681C>T`, `NM_001407144.1:c.1681C>T`, `NM_001407145.1:c.1570C>T`, `NM_001407146.1:c.1555C>T`, `NM_001407147.1:c.1555C>T`, `NM_001407148.1:c.1450C>T`, `NM_001407149.1:c.1450C>T`, `NM_001407150.1:c.1696C>T`, `NM_001407151.1:c.1576C>T`, `NM_001407152.1:c.1390C>T`, `NM_130799.3:c.1555C>T`, `NM_130800.3:c.1570C>T`, `NM_130801.3:c.1570C>T`, `NM_130802.3:c.1570C>T`, `NM_130803.3:c.1570C>T`, `NM_130804.3:c.1570C>T`, `NR_176284.1:n.1753C>T`, `NR_176285.1:n.1765C>T`, `NR_176286.1:n.1768C>T`, `NR_176287.1:n.2026C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0573)
- REVEL 0.235 (benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP -0.111, GERP -2.97 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P524S** vs ClinVar **P519S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 1.096**. 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 0.96** across the covering region of the MANE Select transcript (64,804,516–64,804,696), spanning 180 bp. Chi-square p 0.7. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. 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) · 1/1,179,248 in the highest group · 1/1,609,706 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 3/3, 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):

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

## Protein context {#protein}


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.Pro519Ser falls in the disordered 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 2023-08-29.

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

**Submission history:** 2 submissions (2022–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-29 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **519** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MEN1 p.Pro519fs](/variant/men1-p-pro519fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MEN1 variant pages (same residue, condition, or type): [MEN1 p.Pro519Leu](/variant/men1-p-pro519leu), [MEN1 p.Pro519=](/variant/men1-p-pro519), [MEN1 p.Pro519fs](/variant/men1-p-pro519fs), [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 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1775141). 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.*