Is MEN1 p.Leu338Val (c.1012C>G) pathogenic?

MEN1 p.Leu338Val (c.1012C>G) is classified Conflicting classifications of pathogenicity in MEN1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.6621); Very rare (popmax 0.01%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with MEN1 p.Leu338Val (c.1012C>G)?

MEN1 p.Leu338Val (c.1012C>G) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Leu338Val (c.1012C>G) in the general population?

MEN1 p.Leu338Val (c.1012C>G) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about MEN1 p.Leu338Val (c.1012C>G)?

AlphaMissense predicts likely pathogenic (score 0.6621) — an in-silico prediction, not a clinical call.

MEN1 p.Leu338Val

c.1012C>G · rs759337318 · VCV403808

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.6621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6621	likely pathogenic
REVEL	0.795	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.052, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 4,962 bp · p 4.4e-20 · regional, not allelic
Overall
CADD	22.5	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 L343V vs ClinVar L338V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,028 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00041% 6/1,461,868 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.Leu338Val
Coding: c.1012C>G
MANE Select: NM_001370259
dbSNP: rs759337318
Type: single nucleotide variant
Location: chr11:64806269 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 338: the 'interaction with fancd2' region; an α-helix

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.Leu338Pro Likely pathogenic ★★ same residue
MEN1 p.Leu338Arg Pathogenic ★ same residue
MEN1 p.Leu338= Likely benign ★ same residue
MEN1 p.Leu338fs 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
MEN1 c.1350+1G>A 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-leu338val (accessed [today's date]).

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