Is MMP9 p.Lys115Arg (c.344A>G) pathogenic?

MMP9 p.Lys115Arg (c.344A>G) is classified Uncertain significance in MMP9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.0975); Rare (popmax 0.462%, mid); Associated with metaphyseal anadysplasia 2.

What condition is associated with MMP9 p.Lys115Arg (c.344A>G)?

MMP9 p.Lys115Arg (c.344A>G) is associated with metaphyseal anadysplasia 2 (ClinVar).

How common is MMP9 p.Lys115Arg (c.344A>G) in the general population?

MMP9 p.Lys115Arg (c.344A>G) is rare (popmax 0.462%, mid) (gnomAD).

How is Metaphyseal anadysplasia inherited?

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

What do computational predictors say about MMP9 p.Lys115Arg (c.344A>G)?

AlphaMissense predicts likely benign (score 0.0975) — an in-silico prediction, not a clinical call.

MMP9 p.Lys115Arg

c.344A>G · rs202158739 · VCV895811

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0975 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.462%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

metaphyseal anadysplasia 2

Computational evidence

Protein change
AlphaMissense	0.0975	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -5.42	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 4.6	GERP -1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,438 bp · p 0.34 · regional, not allelic
Overall
CADD	22.6	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

Grpmax group 0.462% Middle Eastern · 21/4,546 alleles

Filtering AF 0.309% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.26%

Overall 0.0116% 165/1,424,036 alleles · rare exomes 149/1,275,546 · genomes 16/148,490 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.462%	216
Ashkenazi Jewishnot grpmax-eligible	0.142%	705
Admixed American	0.0447%	2,239
Remaining individualsnot grpmax-eligible	0.0251%	3,981
European (non-Finnish)	0.00637%	15,693
South Asian	0.00607%	16,486
African / African-American	0.00292%	34,268
Finnishnot grpmax-eligible	0.0021%	47,716

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: MMP9
Protein: p.Lys115Arg
Coding: c.344A>G
MANE Select: NM_004994
dbSNP: rs202158739
Type: single nucleotide variant
Location: chr20:46010071 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.96 · 29 PDB
Residue 115: a β-strand

Full MMP9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

metaphyseal anadysplasia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Metaphyseal anadysplasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

MMP9 p.Cys329Ter Pathogenic/Likely pathogenic ★★ same condition
MMP9 p.Arg681His Uncertain significance ★★ ⚠ same condition
MMP9 p.Glu274Lys Uncertain significance ★★ ⚠ same condition
MMP9 p.Gly306Cys Uncertain significance ★★ ⚠ same condition
MMP9 p.Gly327Arg Uncertain significance ★★ ⚠ same condition
MMP9 p.Ile293Asn Uncertain significance ★★ ⚠ same condition
MMP9 p.Met1Lys Uncertain significance ★★ same condition
MMP9 p.Pro153Gln 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/mmp9-p-lys115arg (accessed [today's date]).

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