Is MEN1 p.Pro291Arg (c.872C>G) pathogenic?

MEN1 p.Pro291Arg (c.872C>G) is classified Uncertain significance in MEN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-14). AlphaMissense: ambiguous (0.4763); Absent from gnomAD v4.1; Associated with multiple endocrine neoplasia type 1.

What condition is associated with MEN1 p.Pro291Arg (c.872C>G)?

MEN1 p.Pro291Arg (c.872C>G) is associated with multiple endocrine neoplasia type 1, hereditary neoplastic syndrome (ClinVar).

How common is MEN1 p.Pro291Arg (c.872C>G) in the general population?

MEN1 p.Pro291Arg (c.872C>G) 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.Pro291Arg (c.872C>G)?

AlphaMissense predicts ambiguous (score 0.4763) — an in-silico prediction, not a clinical call.

MEN1 p.Pro291Arg

c.872C>G · rs745857419 · VCV1376155

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4763 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

multiple endocrine neoplasia type 1

Computational evidence

Protein change
AlphaMissense	0.4763	ambiguous
REVEL	0.612	indeterminate
SaProt	LLR -12.49	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 0.13, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 4,962 bp · p 4.4e-20 · regional, not allelic
Overall
CADD	23.7	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 P296R vs ClinVar P291R) — 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.Pro291Arg
Coding: c.872C>G
MANE Select: NM_001370259
dbSNP: rs745857419
Type: single nucleotide variant
Location: chr11:64807051 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 291: the 'interaction with fancd2' 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

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.Pro291Ala Uncertain significance ★★ ⚠ same residue
MEN1 p.Pro291Ser Uncertain significance ★★ ⚠ same residue
MEN1 p.Pro291= Benign/Likely benign ★★ same residue
MEN1 p.Pro291Thr 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-pro291arg (accessed [today's date]).

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