Is MEN1 p.Ser593Pro (c.1777T>C) pathogenic?

MEN1 p.Ser593Pro (c.1777T>C) is classified Conflicting classifications of pathogenicity in MEN1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-26). AlphaMissense: likely benign (0.1059); Very rare (popmax 0.00667%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with MEN1 p.Ser593Pro (c.1777T>C)?

MEN1 p.Ser593Pro (c.1777T>C) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Ser593Pro (c.1777T>C) in the general population?

MEN1 p.Ser593Pro (c.1777T>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about MEN1 p.Ser593Pro (c.1777T>C)?

AlphaMissense predicts likely benign (score 0.1059) — an in-silico prediction, not a clinical call.

MEN1 p.Ser593Pro

c.1777T>C · rs1411766225 · VCV575287

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1059 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1059	likely benign
REVEL	0.543	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP -0.7, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 178 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	23.9	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 S598P vs ClinVar S593P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,990 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,613,990 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.Ser593Pro
Coding: c.1777T>C
MANE Select: NM_001370259
dbSNP: rs1411766225
Type: single nucleotide variant
Location: chr11:64804390 (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.Ser593= Conflicting classifications of pathogenicity ★ same residue
MEN1 p.Ser593Phe 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
MEN1 c.1350+1G>A Pathogenic ★★ same condition
MEN1 c.1351-2A>C Pathogenic/Likely pathogenic ★★ same condition
MEN1 c.1351-2A>G 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-ser593pro (accessed [today's date]).

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