Is MEN1 p.Arg452Pro (c.1355G>C) pathogenic?

MEN1 p.Arg452Pro (c.1355G>C) is classified Likely pathogenic in MEN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-03). AlphaMissense: likely pathogenic (0.9974); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MEN1 p.Arg452Pro (c.1355G>C)?

MEN1 p.Arg452Pro (c.1355G>C) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Arg452Pro (c.1355G>C) in the general population?

MEN1 p.Arg452Pro (c.1355G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about MEN1 p.Arg452Pro (c.1355G>C)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

MEN1 p.Arg452Pro

c.1355G>C · rs775922507 · VCV485731

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic ✓ concordant with ClinVar
REVEL	0.949	strongly pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 344 bp · p 0.0075 · regional, not allelic
Overall
CADD	28.4	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 R457P vs ClinVar R452P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,080 alleles

Overall 6.92e-05% 1/1,444,662 alleles · very rare

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.Arg452Pro
Coding: c.1355G>C
MANE Select: NM_001370259
dbSNP: rs775922507
Type: single nucleotide variant
Location: chr11:64804812 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 452: an α-helix

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple endocrine neoplasia type 1

Similar variants

MEN1 p.Arg452= Likely benign ★★ same residue
MEN1 p.Arg452Gly Likely pathogenic ★ same residue
MEN1 p.Arg452Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MEN1 p.Arg452Leu Conflicting classifications of pathogenicity ★ same residue
MEN1 p.Arg452Trp Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg452pro (accessed [today's date]).

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