GPNMB

Chr 7AR

glycoprotein nmb

Also known as: HGFIN, NMB, PLCA3

NCBI Gene: 10457ENSG00000136235UniProt: Q14956

The protein encoded by this gene is a type I transmembrane glycoprotein which shows homology to the pMEL17 precursor, a melanocyte-specific protein. GPNMB shows expression in the lowly metastatic human melanoma cell lines and xenografts but does not show expression in the highly metastatic cell lines. GPNMB may be involved in growth delay and reduction of metastatic potential. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Amyloidosis, primary localized cutaneous, 3MIM #617920
AR
153
ClinVar variants
46
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— GPNMB
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 76 VUS of 153 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.68LOEUF
pLI 0.000
Z-score -1.35
OE 1.27 (0.98–1.68)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.12Z-score
OE missense 0.98 (0.89–1.08)
318 obs / 324.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.27 (0.98–1.68)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.89–1.08)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 36 / 28.2Missense obs/exp: 318 / 324.3Syn Z: 0.12

ClinVar Variant Classifications

153 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic8
VUS76
Likely Benign21
Benign10
38
Pathogenic
8
Likely Pathogenic
76
VUS
21
Likely Benign
10
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
32
0
38
Likely Pathogenic
4
0
4
0
8
VUS
0
71
5
0
76
Likely Benign
0
11
4
6
21
Benign
0
4
0
6
10
Total10864512153

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GPNMB · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GPNMB-related amyloidosis, primary localised cutaneous

definitive
ARUndeterminedAltered Gene Product Structure
Skin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
GLYCOPROTEIN NMB; GPNMB
MIM #604368 · *

Amyloidosis, primary localized cutaneous, 3

MIM #617920

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Comprehensive proteogenomic characterization of rare kidney tumors.
Li GX et al.·Cell Rep Med
2024
Spatial-reprogramming derived GPNMB(+) macrophages interact with COL6A3(+) fibroblasts to enhance vascular fibrosis in glioblastoma.
Du Y et al.·Genome Med
2025
The soluble glycoprotein NMB (GPNMB) produced by macrophages induces cancer stemness and metastasis via CD44 and IL-33.
Liguori M et al.·Cell Mol Immunol
2021
GPNMB and ATP6V1A interact to mediate microglia phagocytosis of multiple types of pathological particles.
Liu M et al.·Cell Rep
2025
Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage-tumor interaction axes among different lineages of pituitary neuroendocrine tumors.
Lin S et al.·Genome Med
2024
Gpnmb/osteoactivin: an indicator and therapeutic target in tumor and nontumorous lesions.
Zhuo H et al.·Pharmazie
2016Review
CSF GPNMB in Parkinson's disease: A potential association with age and microglial activation.
Zhu XC et al.·J Parkinsons Dis
2024
Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target.
Taya M et al.·Steroids
2018Review
Targeting GPNMB with glembatumumab vedotin: Current developments and future opportunities for the treatment of cancer.
Rose AAN et al.·Pharmacol Ther
2017Review
Proteometabolomics of initial and recurrent glioblastoma highlights an increased immune cell signature with altered lipid metabolism.
Cosenza-Contreras M et al.·Neuro Oncol
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Newly Diagnosed Multiple Myeloma

Expression-linked and R-ISS-adapted Stratification for First Line Therapy in Multiple Myeloma Patients

RECRUITING
NCT05665140Phase PHASE2, PHASE3University Hopsital Schleswig Holstein Campus LübeckStarted 2023-02-03
IsatuximabLenalidomideBortezomib

External Resources

Links to major genomics databases and tools