Is MEN1 p.Arg229Cys (c.685C>T) pathogenic?

MEN1 p.Arg229Cys (c.685C>T) is classified Conflicting classifications of pathogenicity in MEN1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.2204); Ultra-rare (popmax 0.0117%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with MEN1 p.Arg229Cys (c.685C>T)?

MEN1 p.Arg229Cys (c.685C>T) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Arg229Cys (c.685C>T) in the general population?

MEN1 p.Arg229Cys (c.685C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about MEN1 p.Arg229Cys (c.685C>T)?

AlphaMissense predicts likely benign (score 0.2204) — an in-silico prediction, not a clinical call.

MEN1 p.Arg229Cys

c.685C>T · rs754378887 · VCV216818

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2204 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2204	likely benign
REVEL	0.624	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 4,962 bp · p 4.4e-20 · regional, not allelic
Overall
CADD	29.6	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 R234C vs ClinVar R229C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,010 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00149% 24/1,614,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,573
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.00102%	98,337

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.Arg229Cys
Coding: c.685C>T
MANE Select: NM_001370259
dbSNP: rs754378887
Type: single nucleotide variant
Location: chr11:64807650 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 229: the 'interaction with fancd2' region; a UniProt-annotated variant site (in men1)

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.Arg229= Benign/Likely benign ★★ same residue
MEN1 p.Arg229Gly Uncertain significance ★ ⚠ same residue
MEN1 p.Arg229His Conflicting classifications of pathogenicity ★ same residue
MEN1 p.Arg229Leu Uncertain significance ★ same residue
MEN1 p.Arg229Ser Uncertain significance ★ ⚠ same residue
MEN1 p.Arg229fs Pathogenic ★ 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-arg229cys (accessed [today's date]).

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