Is MEN1 p.Pro540Ser (c.1618C>T) pathogenic?

MEN1 p.Pro540Ser (c.1618C>T) is classified Conflicting classifications of pathogenicity in MEN1 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0644); Ultra-rare (popmax 0.0683%, amr); Associated with Hereditary cancer.

What condition is associated with MEN1 p.Pro540Ser (c.1618C>T)?

MEN1 p.Pro540Ser (c.1618C>T) is associated with Hereditary cancer, hyperparathyroidism, multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Pro540Ser (c.1618C>T) in the general population?

MEN1 p.Pro540Ser (c.1618C>T) is ultra-rare (popmax 0.0683%, amr) (gnomAD).

What do computational predictors say about MEN1 p.Pro540Ser (c.1618C>T)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

MEN1 p.Pro540Ser

c.1618C>T · rs745404679 · VCV200987

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0683%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary cancer

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.69	pathogenic-leaning
SaProt	LLR -6.40	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 0.26, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 180 bp · p 0.7 · regional, not allelic
Overall
CADD	18.58	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P545S vs ClinVar P540S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0683% Admixed American · 41/60,028 alleles

Filtering AF 0.0517% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0459%

Overall 0.00713% 115/1,613,574 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0683%	1,464
Remaining individualsnot grpmax-eligible	0.0208%	4,807
European (non-Finnish)	0.00517%	19,344

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MEN1
Protein: p.Pro540Ser
Coding: c.1618C>T
MANE Select: NM_001370259
dbSNP: rs745404679
Type: single nucleotide variant
Location: chr11:64804549 (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

Hereditary cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperparathyroidism multiple endocrine neoplasia type 1 hereditary neoplastic syndrome

Similar variants

MEN1 p.Pro540Arg Uncertain significance ★ ⚠ same residue
MEN1 p.Pro540= Likely benign ★ same residue
MEN1 p.Pro540Thr Likely benign ★ same residue
MEN1 p.Pro540Ile Uncertain significance ★★ same residue
MEN1 c.1049+1G>A Pathogenic ★★ same condition
MEN1 c.1049+1G>C Pathogenic ★★ same condition
MEN1 c.1049+2T>C Pathogenic/Likely pathogenic ★★ same condition
MEN1 c.1350+1G>A Pathogenic ★★ same condition

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-pro540ser (accessed [today's date]).

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