# NM_001370259.2(MEN1):c.1003C>A (p.Arg335=)

https://sugi.bio/variant/men1-p-arg335

## Summary

**MEN1 p.Arg335= (c.1003C>A)** is classified **Conflicting classifications of pathogenicity** in MEN1 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-27). Rare (popmax 0.111%, eas); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs371364206 · 11 submitters · 3 linked conditions · rare (popmax 0.111%, eas)

## For patients & families {#patients}

This is a change in the MEN1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 11 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.Arg335= |
| Coding change (HGVS c.) | c.1003C>A |
| MANE Select transcript | [NM_001370259](https://www.ncbi.nlm.nih.gov/nuccore/NM_001370259) |
| dbSNP | [rs371364206](https://www.ncbi.nlm.nih.gov/snp/rs371364206/) |
| Variant type | single nucleotide variant |
| Location | chr11:64806278-64806278 (GRCh38) |
| ClinVar | [VCV255616](https://www.ncbi.nlm.nih.gov/clinvar/variation/255616/) |

**All HGVS expressions:** `LRG_509:g.10017C>A`, `LRG_509t1:c.1018C>A`, `LRG_509t2:c.1003C>A`, `NC_000011.10:g.64806278G>T`, `NC_000011.9:g.64573750G>T`, `NG_008929.1:g.10017C>A`, `NG_033040.1:g.1964C>A`, `NM_000244.4:c.1018C>A`, `NM_001370251.2:c.1003C>A`, `NM_001370259.2:c.1003C>A`, `NM_001370260.2:c.1003C>A`, `NM_001370261.2:c.1003C>A`, `NM_001370262.2:c.898C>A`, `NM_001370263.2:c.898C>A`, `NM_130799.3:c.1003C>A`, `NM_130800.3:c.1018C>A`, `NM_130801.3:c.1018C>A`, `NM_130802.3:c.1018C>A`, `NM_130803.3:c.1018C>A`, `NM_130804.3:c.1018C>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.53) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 11.611, GERP 1.11, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 19.57**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.03**, acceptor gain **0.00**, donor gain **0.53**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.53**.
- Population frequency (gnomAD v4.1): grpmax **0.111%** (eas) · FAF95 0.0867% · FAF99 0.078% · 50/44,892 in the highest group · 67/1,614,204 alleles overall — rare (popmax 0.111%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.111% | 898 |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,251 |
| South Asian | 0.00549% | 18,217 |
| Admixed American | 0.00333% | 30,014 |

*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 **335** lies in the 'interaction with fancd2' region; 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. p.Arg335= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-27.

**Submitter consensus:** conflicting (4 Likely benign, 3 Benign, 2 Uncertain significance, 1 Likely Benign, 1 benign).

**Submission history:** 14 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2018-02-14 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-18 |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing |  |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2016-08-03 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-28 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2017-04-28 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-12-07 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-11-04 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | benign | criteria provided, single submitter | clinical testing | 2025-07-24 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, not specified, Multiple endocrine neoplasia, type 1, Hyperparathyroidism, Malignant tumor of esophagus, Malignant tumor of urinary bladder, not provided, Hereditary Cancer Syndrome, Tumor predisposition, Hereditary neoplastic syndrome.

## Same-residue context {#hotspot}

Residue **335** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MEN1 p.Arg335fs](/variant/men1-p-arg335fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MEN1 variant pages (same residue, condition, or type): [MEN1 p.Arg335Gln](/variant/men1-p-arg335gln), [MEN1 p.Arg335Gly](/variant/men1-p-arg335gly), [MEN1 p.Arg335Trp](/variant/men1-p-arg335trp), [MEN1 p.Arg335fs](/variant/men1-p-arg335fs), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 255616). 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.*