Is MEN1 p.Arg21Ser (c.61C>A) pathogenic?

MEN1 p.Arg21Ser (c.61C>A) is classified Conflicting classifications of pathogenicity in MEN1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.3173); Rare (popmax 0.137%, sas); Associated with hyperparathyroidism.

What condition is associated with MEN1 p.Arg21Ser (c.61C>A)?

MEN1 p.Arg21Ser (c.61C>A) is associated with hyperparathyroidism, multiple endocrine neoplasia type 1, hereditary neoplastic syndrome (ClinVar).

How common is MEN1 p.Arg21Ser (c.61C>A) in the general population?

MEN1 p.Arg21Ser (c.61C>A) is rare (popmax 0.137%, sas) (gnomAD).

What do computational predictors say about MEN1 p.Arg21Ser (c.61C>A)?

AlphaMissense predicts likely benign (score 0.3173) — an in-silico prediction, not a clinical call.

MEN1 p.Arg21Ser

c.61C>A · rs541476418 · VCV305315

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.3173 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.137%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hyperparathyroidism

Computational evidence

Protein change
AlphaMissense	0.3173	likely benign
REVEL	0.577	indeterminate
SaProt	LLR -8.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 4,962 bp · p 4.4e-20 · regional, not allelic
Overall
CADD	24.7	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 0.137% South Asian · 124/90,218 alleles

Filtering AF 0.118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.11%

Overall 0.00844% 135/1,600,304 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.137%	728
Remaining individualsnot grpmax-eligible	0.0178%	5,609

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.Arg21Ser
Coding: c.61C>A
MANE Select: NM_001370259
dbSNP: rs541476418
Type: single nucleotide variant
Location: chr11:64810049 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 21: 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.Arg21Cys Uncertain significance ★★ ⚠ same residue
MEN1 p.Arg21His Uncertain significance ★★ ⚠ same residue
MEN1 p.Arg21= Conflicting classifications of pathogenicity ★ same residue
MEN1 p.Arg21Gly Uncertain significance ★ ⚠ same residue
MEN1 p.Arg21Leu Uncertain significance ★ ⚠ 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-arg21ser (accessed [today's date]).

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