Is MDM2 p.Leu331Arg (c.992T>G) pathogenic?

MDM2 p.Leu331Arg (c.992T>G) is classified Uncertain significance in MDM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-06). AlphaMissense: likely benign (0.1542); Very rare (popmax 0.00446%, eas); Associated with Accelerated tumor formation, susceptibility to.

What condition is associated with MDM2 p.Leu331Arg (c.992T>G)?

MDM2 p.Leu331Arg (c.992T>G) is associated with Accelerated tumor formation, susceptibility to (ClinVar).

How common is MDM2 p.Leu331Arg (c.992T>G) in the general population?

MDM2 p.Leu331Arg (c.992T>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about MDM2 p.Leu331Arg (c.992T>G)?

AlphaMissense predicts likely benign (score 0.1542) — an in-silico prediction, not a clinical call.

MDM2 p.Leu331Arg

c.992T>G · rs1451286579 · VCV2733344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1542 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Accelerated tumor formation, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.1542	likely benign
REVEL	0.503	indeterminate
SaProt	LLR -6.87	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 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 378 bp · p 0.63 · regional, not allelic
Overall
CADD	25.3	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L325R vs ClinVar L331R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,856 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000186% 3/1,613,814 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,428
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Leu331Arg
Coding: c.992T>G
MANE Select: NM_002392
dbSNP: rs1451286579
Type: single nucleotide variant
Location: chr12:68839347 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.24 · 148 PDB
Residue 331: the 'region ii' region; the 'necessary for interaction with usp2' region; an α-helix

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-leu331arg (accessed [today's date]).

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