Is MDM2 p.Ser182Pro (c.544T>C) pathogenic?

MDM2 p.Ser182Pro (c.544T>C) is classified Conflicting classifications of pathogenicity in MDM2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-30). AlphaMissense: likely benign (0.0494); Very rare (popmax 0.00133%, afr); Associated with Accelerated tumor formation, susceptibility to.

What condition is associated with MDM2 p.Ser182Pro (c.544T>C)?

MDM2 p.Ser182Pro (c.544T>C) is associated with Accelerated tumor formation, susceptibility to, lessel-kubisch syndrome (ClinVar).

How common is MDM2 p.Ser182Pro (c.544T>C) in the general population?

MDM2 p.Ser182Pro (c.544T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MDM2 p.Ser182Pro (c.544T>C)?

AlphaMissense predicts likely benign (score 0.0494) — an in-silico prediction, not a clinical call.

MDM2 p.Ser182Pro

c.544T>C · VCV3575243

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0494 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Accelerated tumor formation, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.0494	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -7.11	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 -0.87	GERP -3.7
Regional constraint	o/e 0.71	unconstrained · MANE · 19 kb · p 8.3e-06 · regional, not allelic
Overall
CADD	5.282	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 S176P vs ClinVar S182P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,916 alleles

Overall 0.000657% 1/152,172 alleles · very rare

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.Ser182Pro
Coding: c.544T>C
MANE Select: NM_002392
Type: single nucleotide variant
Location: chr12:68828791 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.24 · 148 PDB
Residue 182: the 'disordered' region; the 'interaction with pyhin1 and necessary for interaction with rffl and rnf34' region; the 'interaction with mtbp' 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

Also linked: lessel-kubisch syndrome

Similar variants

MDM2 c.523+5A>G Uncertain significance ★★ same condition
MDM2 p.Ala289Thr 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

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-ser182pro (accessed [today's date]).

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