Is MEN1 p.Glu486Lys (c.1456G>A) pathogenic?

MEN1 p.Glu486Lys (c.1456G>A) is classified Uncertain significance in MEN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-08). AlphaMissense: likely pathogenic (0.977); Absent from gnomAD v4.1; Associated with multiple endocrine neoplasia type 1.

What condition is associated with MEN1 p.Glu486Lys (c.1456G>A)?

MEN1 p.Glu486Lys (c.1456G>A) is associated with multiple endocrine neoplasia type 1, hereditary neoplastic syndrome (ClinVar).

How common is MEN1 p.Glu486Lys (c.1456G>A) in the general population?

MEN1 p.Glu486Lys (c.1456G>A) 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.Glu486Lys (c.1456G>A)?

AlphaMissense predicts likely pathogenic (score 0.977) — an in-silico prediction, not a clinical call.

MEN1 p.Glu486Lys

c.1456G>A · rs2136089217 · VCV2450239

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.977 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,596,316)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple endocrine neoplasia type 1

Computational evidence

Protein change
AlphaMissense	0.977	likely pathogenic
REVEL	0.726	pathogenic-leaning
SaProt	LLR -8.13	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 344 bp · p 0.0075 · regional, not allelic
Overall
CADD	24.3	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 E491K vs ClinVar E486K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,596,316). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MEN1
Protein: p.Glu486Lys
Coding: c.1456G>A
MANE Select: NM_001370259
dbSNP: rs2136089217
Type: single nucleotide variant
Location: chr11:64804711 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 486: 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.Glu486Ter Pathogenic ★★ same residue
MEN1 p.Glu486= Benign/Likely benign ★★ same residue
MEN1 p.Glu486Asp 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
MEN1 c.1351-2A>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-glu486lys (accessed [today's date]).

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