Is MEN1 p.Pro514Arg (c.1541C>G) pathogenic?

MEN1 p.Pro514Arg (c.1541C>G) is classified Conflicting classifications of pathogenicity in MEN1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.0736); Ultra-rare (popmax 0.0167%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with MEN1 p.Pro514Arg (c.1541C>G)?

MEN1 p.Pro514Arg (c.1541C>G) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Pro514Arg (c.1541C>G) in the general population?

MEN1 p.Pro514Arg (c.1541C>G) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about MEN1 p.Pro514Arg (c.1541C>G)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

MEN1 p.Pro514Arg

c.1541C>G · rs753022747 · VCV241809

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.43, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 180 bp · p 0.7 · regional, not allelic
Overall
CADD	18.85	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 P519R vs ClinVar P514R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/5,980 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000825% 12/1,454,664 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,980
Remaining individualsnot grpmax-eligible	0.00161%	62,298
European (non-Finnish)	0.000849%	117,824

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.Pro514Arg
Coding: c.1541C>G
MANE Select: NM_001370259
dbSNP: rs753022747
Type: single nucleotide variant
Location: chr11:64804626 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 514: the 'disordered' region

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.Pro514His Uncertain significance ★★ ⚠ same residue
MEN1 p.Pro514Leu Uncertain significance ★★ ⚠ same residue
MEN1 p.Pro514= Likely benign ★★ same residue
MEN1 p.Pro514Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MEN1 p.Pro514Thr 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-pro514arg (accessed [today's date]).

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