Is MMP2 p.Pro449Ser (c.1345C>T) pathogenic?

MMP2 p.Pro449Ser (c.1345C>T) is classified Uncertain significance in MMP2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0605); Absent from gnomAD v4.1; Associated with multicentric osteolysis, nodulosis, and arthropathy.

What condition is associated with MMP2 p.Pro449Ser (c.1345C>T)?

MMP2 p.Pro449Ser (c.1345C>T) is associated with multicentric osteolysis, nodulosis, and arthropathy (ClinVar).

How common is MMP2 p.Pro449Ser (c.1345C>T) in the general population?

MMP2 p.Pro449Ser (c.1345C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MMP2 p.Pro449Ser (c.1345C>T)?

AlphaMissense predicts likely benign (score 0.0605) — an in-silico prediction, not a clinical call.

MMP2 p.Pro449Ser

Q: How is Multicentric osteolysis-nodulosis-arthropathy spectrum inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1345C>T · rs1596819943 · VCV3234888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0605 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multicentric osteolysis, nodulosis, and arthropathy

Computational evidence

Protein change
AlphaMissense	0.0605	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -6.90	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 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	21.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MMP2
Protein: p.Pro449Ser
Coding: c.1345C>T
MANE Select: NM_004530
dbSNP: rs1596819943
Type: single nucleotide variant
Location: chr16:55493166 (GRCh38)
Gene constraint: LOEUF 0.654 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.31 · 14 PDB
Residue 449: an α-helix; the 'collagenase-like 2' region; the 'required for inhibitor timp2 binding' region

Full MMP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multicentric osteolysis, nodulosis, and arthropathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multicentric osteolysis-nodulosis-arthropathy spectrum (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

MMP2 p.Tyr244Ter Pathogenic ★★ same condition
MMP2 p.Arg115Leu Uncertain significance ★★ same condition
MMP2 p.Asp382Asn Uncertain significance ★★ ⚠ same condition
MMP2 p.Val621Met Uncertain significance ★★ ⚠ same condition
MMP2 c.1610-1G>C Likely pathogenic ★ same condition
MMP2 p.Arg101Cys Pathogenic ★ same condition
MMP2 p.Glu404Lys Likely pathogenic ★ same condition
MMP2 p.Glu529Ter 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/mmp2-p-pro449ser (accessed [today's date]).

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