Is MEN1 p.Pro72His (c.215C>A) pathogenic?

MEN1 p.Pro72His (c.215C>A) is classified Uncertain significance in MEN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-16). AlphaMissense: likely benign (0.1075); Very rare (popmax 0.00538%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with MEN1 p.Pro72His (c.215C>A)?

MEN1 p.Pro72His (c.215C>A) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Pro72His (c.215C>A) in the general population?

MEN1 p.Pro72His (c.215C>A) is very rare (popmax 0.00538%, afr) (gnomAD).

What do computational predictors say about MEN1 p.Pro72His (c.215C>A)?

AlphaMissense predicts likely benign (score 0.1075) — an in-silico prediction, not a clinical call.

MEN1 p.Pro72His

c.215C>A · rs878856863 · VCV573444

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00538%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1075	likely benign
REVEL	0.595	indeterminate
SaProt	LLR -9.74	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 12	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	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00538% African / African-American · 4/74,396 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.000376% 6/1,593,644 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00538%	18,599
European (non-Finnish)	0.000171%	584,922

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.Pro72His
Coding: c.215C>A
MANE Select: NM_001370259
dbSNP: rs878856863
Type: single nucleotide variant
Location: chr11:64809895 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 72: a turn

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.Pro72= Likely benign ★★ same residue
MEN1 p.Pro72Leu Uncertain significance ★ ⚠ same residue
MEN1 p.Pro72Ser 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

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-pro72his (accessed [today's date]).

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