Is MEN1 p.Phe11Leu (c.33C>G) pathogenic?

MEN1 p.Phe11Leu (c.33C>G) is classified Uncertain significance in MEN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-23). AlphaMissense: likely pathogenic (0.9972); Very rare (popmax 0.00027%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MEN1 p.Phe11Leu (c.33C>G)?

MEN1 p.Phe11Leu (c.33C>G) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Phe11Leu (c.33C>G) in the general population?

MEN1 p.Phe11Leu (c.33C>G) is very rare (popmax 0.00027%, nfe) (gnomAD).

What do computational predictors say about MEN1 p.Phe11Leu (c.33C>G)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

MEN1 p.Phe11Leu

c.33C>G · rs2497290128 · VCV1731011

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00027%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -7.79	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 3.3	GERP 0.54, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 4,962 bp · p 4.4e-20 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00027% European (non-Finnish) · 3/1,110,416 alleles

Filtering AF 7.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000221% 3/1,354,434 alleles · very rare

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.Phe11Leu
Coding: c.33C>G
MANE Select: NM_001370259
dbSNP: rs2497290128
Type: single nucleotide variant
Location: chr11:64810077 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB

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.Phe11= Likely benign ★★ same residue
MEN1 p.Phe11Ser Likely pathogenic ★ ⚠ same residue
MEN1 p.Phe11Tyr Uncertain significance ★ ⚠ same residue
MEN1 p.Phe11Val Uncertain significance ★ ⚠ same residue
MEN1 p.Phe11fs Pathogenic ★ 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-phe11leu (accessed [today's date]).

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