Is MEN1 p.Val215= (c.645G>A) pathogenic?

MEN1 p.Val215= (c.645G>A) is classified Conflicting classifications of pathogenicity in MEN1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-18). Very rare (popmax 0.000169%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MEN1 p.Val215= (c.645G>A)?

MEN1 p.Val215= (c.645G>A) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Val215= (c.645G>A) in the general population?

MEN1 p.Val215= (c.645G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

MEN1 p.Val215=

c.645G>A · rs1347044526 · VCV1056409

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.32	donor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.059	GERP -2.4, phastCons 0.89
Overall
CADD	8.891	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,012 alleles

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

Overall 0.000205% 3/1,461,830 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)grpmax	0.000169%	590,005

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val215=
Coding: c.645G>A
MANE Select: NM_001370259
dbSNP: rs1347044526
Type: single nucleotide variant
Location: chr11:64807900 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 215: the 'interaction with fancd2' region; an α-helix; a UniProt-annotated variant site (found in a parathyroid carcinoma sample; somatic mutation); a UniProt-annotated variant site (in men1)

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.Val215Met Pathogenic/Likely pathogenic ★★ same residue
MEN1 p.Val215Glu Likely pathogenic ★ same residue
MEN1 p.Val215_Arg218delinsGlyProTrp 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-val215 (accessed [today's date]).

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