Is MDM2 p.Pro228Leu (c.683C>T) pathogenic?

MDM2 p.Pro228Leu (c.683C>T) is classified Uncertain significance in MDM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-09). AlphaMissense: likely benign (0.07); Very rare (popmax 0.00401%, afr); Associated with Accelerated tumor formation, susceptibility to.

What condition is associated with MDM2 p.Pro228Leu (c.683C>T)?

MDM2 p.Pro228Leu (c.683C>T) is associated with Accelerated tumor formation, susceptibility to (ClinVar).

How common is MDM2 p.Pro228Leu (c.683C>T) in the general population?

MDM2 p.Pro228Leu (c.683C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about MDM2 p.Pro228Leu (c.683C>T)?

AlphaMissense predicts likely benign (score 0.07) — an in-silico prediction, not a clinical call.

MDM2 p.Pro228Leu

c.683C>T · rs1387843274 · VCV851326

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.07 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Accelerated tumor formation, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.07	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -5.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -3.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 19 kb · p 8.3e-06 · regional, not allelic
Overall
CADD	20.2	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 P222L vs ClinVar P228L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,864 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000496% 8/1,613,312 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,955
European (non-Finnish)	0.000424%	235,936

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.Pro228Leu
Coding: c.683C>T
MANE Select: NM_002392
dbSNP: rs1387843274
Type: single nucleotide variant
Location: chr12:68828930 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.24 · 148 PDB
Residue 228: the 'arf-binding' region; the 'disordered' region; the 'interaction with usp7' region; the 'interaction with pyhin1 and necessary for interaction with rffl and rnf34' region; the 'interaction with mtbp' region; the 'mediates interaction with rad54b' 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-pro228leu (accessed [today's date]).

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