Is MEN1 p.Pro540Ile (c.1618_1619delinsAT) pathogenic?

MEN1 p.Pro540Ile (c.16181619delinsAT) is classified Uncertain significance in MEN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-04). Associated with multiple endocrine neoplasia type 1.

What condition is associated with MEN1 p.Pro540Ile (c.1618_1619delinsAT)?

MEN1 p.Pro540Ile (c.1618_1619delinsAT) is associated with multiple endocrine neoplasia type 1 (ClinVar).

How is Multiple endocrine neoplasia type 1 inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

MEN1 p.Pro540Ile

c.1618_1619delinsAT · VCV3600092

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

Conditions

multiple endocrine neoplasia type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.4	GERP 0.27, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 180 bp · p 0.7 · regional, not allelic

Variant & gene context

Gene: MEN1
Protein: p.Pro540Ile
Coding: c.1618_1619delinsAT
MANE Select: NM_001370259
Type: Indel
Location: chr11:64804548 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 540: a UniProt-annotated variant site (in men1); the 'disordered' region

Full MEN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multiple endocrine neoplasia type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple endocrine neoplasia type 1 (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MEN1 p.Pro540Arg Uncertain significance ★ ⚠ same residue
MEN1 p.Pro540Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MEN1 p.Pro540Thr Likely benign ★ same residue
MEN1 p.Arg14fs Pathogenic ★★ same condition
MEN1 p.Val215_Arg218delinsGlyProTrp Uncertain significance ★★ same condition
MEN1 p.Glu179_Asp180delinsAspTyr Pathogenic ★ same condition
MEN1 p.Gly548_Met558delinsPro Pathogenic ★ same condition
MEN1 p.Pro540fs Pathogenic ★ same residue

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/men1-p-pro540ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown