Is MEN1 p.Pro428Ser (c.1282C>T) pathogenic?

MEN1 p.Pro428Ser (c.1282C>T) is classified Uncertain significance in MEN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-02). AlphaMissense: likely benign (0.3334); Absent from gnomAD v4.1; Associated with multiple endocrine neoplasia type 1.

What condition is associated with MEN1 p.Pro428Ser (c.1282C>T)?

MEN1 p.Pro428Ser (c.1282C>T) is associated with multiple endocrine neoplasia type 1, hereditary neoplastic syndrome (ClinVar).

How common is MEN1 p.Pro428Ser (c.1282C>T) in the general population?

MEN1 p.Pro428Ser (c.1282C>T) is absent from gnomAD v4.1 (gnomAD).

How is Multiple endocrine neoplasia type 1 inherited?

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

What do computational predictors say about MEN1 p.Pro428Ser (c.1282C>T)?

AlphaMissense predicts likely benign (score 0.3334) — an in-silico prediction, not a clinical call.

MEN1 p.Pro428Ser

c.1282C>T · rs2497143442 · VCV2716242

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3334 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

multiple endocrine neoplasia type 1

Computational evidence

Protein change
AlphaMissense	0.3334	likely benign
REVEL	0.633	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.19	constrained · MANE · 104 bp · p 4e-08 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P433S vs ClinVar P428S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MEN1
Protein: p.Pro428Ser
Coding: c.1282C>T
MANE Select: NM_001370259
dbSNP: rs2497143442
Type: single nucleotide variant
Location: chr11:64805102 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB

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

Also linked: hereditary neoplastic syndrome

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.Pro428Ala Uncertain significance ★ ⚠ same residue
MEN1 p.Pro428Leu Uncertain significance ★ same residue
MEN1 p.Pro428= Likely benign ★ same residue
MEN1 p.Pro428fs Pathogenic ★★ 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-pro428ser (accessed [today's date]).

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