Is MEN1 p.Leu254= (c.762G>A) pathogenic?

MEN1 p.Leu254= (c.762G>A) is classified Conflicting classifications of pathogenicity in MEN1 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.099%, mid); Associated with hyperparathyroidism.

What condition is associated with MEN1 p.Leu254= (c.762G>A)?

MEN1 p.Leu254= (c.762G>A) is associated with hyperparathyroidism, multiple endocrine neoplasia type 1, hereditary neoplastic syndrome (ClinVar).

How common is MEN1 p.Leu254= (c.762G>A) in the general population?

MEN1 p.Leu254= (c.762G>A) is ultra-rare (popmax 0.099%, mid) (gnomAD).

MEN1 p.Leu254=

c.762G>A · rs199909967 · VCV215966

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

Conditions

hyperparathyroidism

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.32, phastCons 1
Overall
CADD	12.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.099% Middle Eastern · 6/6,062 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0294%

Overall 0.0212% 342/1,614,198 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
Finnishnot grpmax-eligible	0.0266%	3,765
South Asian	0.0253%	3,960
European (non-Finnish)	0.0242%	4,126
Remaining individualsnot grpmax-eligible	0.0144%	6,945
African / African-American	0.00133%	75,054

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.Leu254=
Coding: c.762G>A
MANE Select: NM_001370259
dbSNP: rs199909967
Type: single nucleotide variant
Location: chr11:64807573 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 254: the 'interaction with fancd2' region; an α-helix

Full MEN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperparathyroidism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple endocrine neoplasia type 1 hereditary neoplastic syndrome

Similar variants

MEN1 p.Leu254Arg Uncertain significance ★ ⚠ same residue
MEN1 p.Leu254Met Uncertain significance ★ ⚠ same residue
MEN1 p.Leu254Pro 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-leu254 (accessed [today's date]).

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