Is MEN1 p.Ser253Trp (c.758C>G) pathogenic?

MEN1 p.Ser253Trp (c.758C>G) is classified Pathogenic in MEN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-29). AlphaMissense: likely pathogenic (0.9979); Absent from gnomAD v4.1; Associated with multiple endocrine neoplasia type 1.

What condition is associated with MEN1 p.Ser253Trp (c.758C>G)?

MEN1 p.Ser253Trp (c.758C>G) is associated with multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Ser253Trp (c.758C>G) in the general population?

MEN1 p.Ser253Trp (c.758C>G) is absent from gnomAD v4.1 (gnomAD).

How is Multiple endocrine neoplasia type 1 inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MEN1 p.Ser253Trp (c.758C>G)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

MEN1 p.Ser253Trp

c.758C>G · rs386134259 · VCV403831

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

multiple endocrine neoplasia type 1

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic ✓ concordant with ClinVar
REVEL	0.951	strongly 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 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	29.0	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 S258W vs ClinVar S253W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MEN1
Protein: p.Ser253Trp
Coding: c.758C>G
MANE Select: NM_001370259
dbSNP: rs386134259
Type: single nucleotide variant
Location: chr11:64807577 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 253: the 'interaction with fancd2' region; a UniProt-annotated variant site (in men1); a UniProt-annotated variant site (in parathyroid tumor)

Full MEN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multiple endocrine neoplasia type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple endocrine neoplasia type 1 (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MEN1 p.Ser253Ter Likely pathogenic ★★ same residue
MEN1 p.Ser253= Likely benign ★★ same residue
MEN1 p.Ser253Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MEN1 p.Ser253fs 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-ser253trp (accessed [today's date]).

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