Is MEN1 p.Arg516Gln (c.1547G>A) pathogenic?

MEN1 p.Arg516Gln (c.1547G>A) is classified Uncertain significance in MEN1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.076); Very rare (popmax 0.00223%, eas); Associated with multiple endocrine neoplasia type 1.

What condition is associated with MEN1 p.Arg516Gln (c.1547G>A)?

MEN1 p.Arg516Gln (c.1547G>A) is associated with multiple endocrine neoplasia type 1, hereditary neoplastic syndrome (ClinVar).

How common is MEN1 p.Arg516Gln (c.1547G>A) in the general population?

MEN1 p.Arg516Gln (c.1547G>A) is very rare (popmax 0.00223%, eas) (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.Arg516Gln (c.1547G>A)?

AlphaMissense predicts likely benign (score 0.076) — an in-silico prediction, not a clinical call.

MEN1 p.Arg516Gln

c.1547G>A · rs1565637104 · VCV651907

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

multiple endocrine neoplasia type 1

Computational evidence

Protein change
AlphaMissense	0.076	likely benign
REVEL	0.384	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 180 bp · p 0.7 · regional, not allelic
Overall
CADD	17.34	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 R521Q vs ClinVar R516Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,792 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000275% 4/1,455,560 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,792
Remaining individualsnot grpmax-eligible	0.0016%	62,326
European (non-Finnish)	0.00017%	589,272

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.Arg516Gln
Coding: c.1547G>A
MANE Select: NM_001370259
dbSNP: rs1565637104
Type: single nucleotide variant
Location: chr11:64804620 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 516: the 'disordered' 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.Arg516Trp Uncertain significance ★★ ⚠ same residue
MEN1 p.Arg516Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
MEN1 p.Arg516Pro Uncertain significance ★ same residue
MEN1 p.Arg516fs Pathogenic ★★ same residue
MEN1 p.Arg516= Likely benign ★ 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-arg516gln (accessed [today's date]).

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