Is MEN1 p.Arg335Trp (c.1003C>T) pathogenic?

MEN1 p.Arg335Trp (c.1003C>T) is classified Uncertain significance in MEN1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-11). AlphaMissense: ambiguous (0.384); Very rare (popmax 0.000169%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MEN1 p.Arg335Trp (c.1003C>T)?

MEN1 p.Arg335Trp (c.1003C>T) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Arg335Trp (c.1003C>T) in the general population?

MEN1 p.Arg335Trp (c.1003C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about MEN1 p.Arg335Trp (c.1003C>T)?

AlphaMissense predicts ambiguous (score 0.384) — an in-silico prediction, not a clinical call.

MEN1 p.Arg335Trp

c.1003C>T · rs371364206 · VCV457274

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.384 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.384	ambiguous
REVEL	0.868	moderately pathogenic-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.53 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 4,962 bp · p 4.4e-20 · regional, not allelic
Overall
CADD	33.0	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 R340W vs ClinVar R335W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,008 alleles

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

Overall 0.000137% 2/1,461,854 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.Arg335Trp
Coding: c.1003C>T
MANE Select: NM_001370259
dbSNP: rs371364206
Type: single nucleotide variant
Location: chr11:64806278 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 335: 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.Arg335Gln Uncertain significance ★★ same residue
MEN1 p.Arg335Gly Uncertain significance ★★ ⚠ same residue
MEN1 p.Arg335= Conflicting classifications of pathogenicity ★ same residue
MEN1 p.Arg335fs 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-arg335trp (accessed [today's date]).

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