MGP

protein-coding

matrix Gla protein, the group of Gla domain containing

Gene summary

This gene encodes a member of the osteocalcin/matrix Gla family of proteins. The encoded vitamin K-dependent protein is secreted by chondrocytes and vascular smooth muscle cells, and functions as a physiological inhibitor of ectopic tissue calcification. Carboxylation status of the encoded protein is associated with calcification of the vasculature in human patients with cardiovascular disease and calcification of the synovial membranes in osteoarthritis patients. Mutations in this gene cause Keutel syndrome in human patients, which is characterized by abnormal cartilage calcification, peripheral pulmonary stenosis and facial hypoplasia. [provided by RefSeq, Sep 2016]

MANE transcript

NM_000900.5

Inheritance

AD, AR

ClinVar variants

P:7U:40B:18

Top phenotype

Keutel syndrome

gnomAD constraint

pLI —, LoF o/e 0.92

Max pathogenic AF

—

Genomic locus

chr12:14,880,864-14,885,857

External References & Databases

Ensembl (ENSG00000111341)

Transcript & Mutation Effects

hg38 • Region Span ~5.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

skeletal dysplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018230

Submitter: PanelApp Australia

Keutel syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009495

Submitter: ClinGen

The *MGP* gene (OMIM: 154870) is located on chromosome 12 at 12p12.3 and encodes Matrix Gla protein, a vitamin-K dependent protein that is secreted by chondrocytes and cardiovascular cells and inhibits ectopic tissue calcification. Variants in *MGP* were first reported in relation to autosomal recessive Keutel syndrome in 1999 (Munroe et al., PMID: 9916809). Keutel syndrome is a rare disorder characterized by abnormal cartilage calcification, brachytelephalangy, dysmorphic facial features including midface hypoplasia, and peripheral pulmonary artery stenosis. Other reported features include mixed hearing loss, congenital heart defects, pulmonary hypoplasia, respiratory distress, mild short stature, and mild intellectual disability. Evidence supporting this GDR includes case-level data, segregation data and experimental evidence. 8 unique variants including nonsense and splice variants from 7 publications have been included in this curation. All reported variants are homozygous in the affected individuals and all families were consanguineous. Variants in this gene segregate with disease in at least one family. The suggested mechanism of pathogenicity is loss of function. The gene disease relationship is also supported by a knockout mouse model and phenotype rescue (Luo et al., 1997, PMID: 9052783, Marulanda et al., 2017, PMID: 28487368). In summary, there is definitive evidence supporting the relationship between *MGP* and autosomal recessive Keutel syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date May 16th, 2025 (SOP Version 11).

Keutel syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009495

Submitter: G2P

Keutel syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009495

Submitter: PanelApp Australia

Keutel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009495

Submitter: Orphanet

Keutel syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009495

Submitter: Ambry Genetics

Keutel syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009495

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Keutel syndromeAR

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 6468443; 3717211; 2515061; 9674914; 9916809; 15810001

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MGP variants in ClinVar

10 Conditions Cataloged

not providedTotal: 91

Keutel syndromeTotal: 15

MGP-related disorderTotal: 7

not specifiedTotal: 3

Inborn genetic diseasesTotal: 3

Spondyloepiphyseal dysplasiaTotal: 1

Short statureTotal: 1

Short palmTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000900.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	14 clinvar		15
missense		2 clinvar	33 clinvar	3 clinvar	1 clinvar	39
nonsense	1 clinvar		2 clinvar			3
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	3 clinvar			6
Total	3	4	40	17	1	65

Highest pathogenic variant AF is 0.000027304164

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000900.5	RefSeq	NP_000891.2	4	MANE Select
ENST00000539261.6	Ensembl	ENSP00000445907.1	4	MANE Select
NM_001190839.3	RefSeq	NP_001177768.1	5	Standard
ENST00000228938.5	Ensembl	ENSP00000228938.5	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Warfarin Pathway, Pharmacodynamics
NOTCH1 regulation of human endothelial cell calcification
Endochondral Ossification
Validated transcriptional targets of AP1 family members Fra1 and Fra2

Biological Process

cartilage condensation
ossification
cell differentiation
regulation of bone mineralization

Molecular Function

extracellular matrix structural constituent
calcium ion binding
protein binding
structural constituent of bone

Cellular Component

extracellular matrix
collagen-containing extracellular matrix
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000228938
Coding exons: 5
Length: 4746
Individuals with no LoFs: 125705
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125709
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.116	69	71.8	0.962	0.00000442	826
Missense (PolyPhen)		30	28.762	1.043		325
Synonymous	-0.201	27	25.7	1.05	0.00000167	227
Loss of Function	0.209	7	7.62	0.918	4.09e-7	88

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Associates with the organic matrix of bone and cartilage. Thought to act as an inhibitor of bone formation.;
Disease: DISEASE: Keutel syndrome (KTLS) [MIM:245150]: An autosomal recessive disorder characterized by abnormal cartilage calcification, peripheral pulmonary stenosis neural hearing loss and midfacial hypoplasia. {ECO:0000269|PubMed:9916809}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.545
RVIS EVS: 0.77
RVIS percentile EVS: 86.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium