Is MDM2 p.Leu88= (c.264A>G) pathogenic?

MDM2 p.Leu88= (c.264A>G) is classified Likely benign in MDM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-09). Ultra-rare (popmax 0.0178%, eas); Associated with Accelerated tumor formation, susceptibility to.

What condition is associated with MDM2 p.Leu88= (c.264A>G)?

MDM2 p.Leu88= (c.264A>G) is associated with Accelerated tumor formation, susceptibility to (ClinVar).

How common is MDM2 p.Leu88= (c.264A>G) in the general population?

MDM2 p.Leu88= (c.264A>G) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

MDM2 p.Leu88=

c.264A>G · rs760587938 · VCV1086738

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Conditions

Accelerated tumor formation, susceptibility to

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.54	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.43	GERP -3.5, phastCons 0.83
Overall
CADD	7.574	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,846 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000806% 13/1,613,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,606
South Asian	0.00551%	18,146

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: MDM2
Protein: p.Leu88=
Coding: c.264A>G
MANE Select: NM_002392
dbSNP: rs760587938
Type: single nucleotide variant
Location: chr12:68816901 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.24 · 148 PDB
Residue 88: the swib/mdm2 domain; the 'necessary for interaction with usp2' region; the 'sufficient to promote the mitochondrial pathway of apoptosis' region

Full MDM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Accelerated tumor formation, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MDM2 c.523+5A>G Uncertain significance ★★ same condition
MDM2 p.Arg332His Uncertain significance ★★ same condition
MDM2 p.Asn117Ser Uncertain significance ★★ ⚠ same condition
MDM2 p.Asn374Ser Uncertain significance ★★ ⚠ same condition
MDM2 p.Gln414Leu Uncertain significance ★★ ⚠ same condition
MDM2 p.Glu273Ala Uncertain significance ★★ ⚠ same condition
MDM2 p.Gly341Glu Uncertain significance ★★ ⚠ same condition
MDM2 p.Ser122Leu Uncertain significance ★★ ⚠ 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/mdm2-p-leu88 (accessed [today's date]).

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