Is MEN1 p.Asp418= (c.1254C>T) pathogenic?

MEN1 p.Asp418= (c.1254C>T) is classified Benign in MEN1 (ClinVar, Multiple submitters, 19 submitters; last evaluated 2026-02-04). Common (popmax 48.2%, sas) — too common for a highly-penetrant pathogenic allele; Associated with hyperparathyroidism.

What condition is associated with MEN1 p.Asp418= (c.1254C>T)?

MEN1 p.Asp418= (c.1254C>T) is associated with hyperparathyroidism, multiple endocrine neoplasia type 1, hereditary neoplastic syndrome (ClinVar).

MEN1 p.Asp418=

Q: How common is MEN1 p.Asp418= (c.1254C>T) in the general population?

MEN1 p.Asp418= (c.1254C>T) is common (popmax 48.2%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1254C>T · rs2071313 · VCV96249

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 19 submitters

gnomAD v4.1

Common

common (popmax 48.2%, sas) — too common for a highly-penetrant pathogenic allele

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 -1.6	GERP -2
Overall
CADD	6.084	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 48.2% South Asian · 43,888/91,076 alleles

Filtering AF 47.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 47.7%

Overall 39.7% 640,045/1,613,902 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	48.2%	2
Middle Eastern	43.9%	2
Finnishnot grpmax-eligible	43.9%	2
European (non-Finnish)	41.3%	2
Remaining individualsnot grpmax-eligible	38.8%	3
East Asian	38.1%	3
Ashkenazi Jewishnot grpmax-eligible	34.2%	3
Admixed American	33.2%	3
Amishnot grpmax-eligible	26.9%	4
African / African-American	8.32%	12

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.Asp418=
Coding: c.1254C>T
MANE Select: NM_001370259
dbSNP: rs2071313
Type: single nucleotide variant
Location: chr11:64805130 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 418: a UniProt-annotated variant site (in men1); 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.Asp418Asn Pathogenic ★★ same residue
MEN1 p.Asp418His Pathogenic/Likely pathogenic ★★ same residue
MEN1 p.Asp418Tyr Pathogenic ★★ same residue
MEN1 p.Asp418Glu Uncertain significance ★ ⚠ same residue
MEN1 p.Asp418fs Pathogenic ★★ same residue
MEN1 p.Asp418_Gly419= Benign ★ same residue
MEN1 c.1049+1G>A Pathogenic ★★ same condition
MEN1 c.1049+1G>C 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-asp418 (accessed [today's date]).

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