GPSM2

Chr 1AR

G protein signaling modulator 2

Also known as: CMCS, DFNB82, LGN, PINS

NCBI Gene: 29899ENSG00000121957UniProt: P81274

The protein encoded by this gene belongs to a family of proteins that modulate activation of G proteins, which transduce extracellular signals received by cell surface receptors into integrated cellular responses. The N-terminal half of this protein contains 10 copies of leu-gly-asn (LGN) repeat, and the C-terminal half contains 4 GoLoco motifs, which are involved in guanine nucleotide exchange. This protein may play a role in neuroblast division and in the development of normal hearing. Mutations in this gene are associated with autosomal recessive nonsyndromic deafness (DFNB82). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

Primary Disease Associations & Inheritance

Chudley-McCullough syndromeMIM #604213
AR
364
ClinVar variants
51
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GPSM2
🧬
Gene-Disease Validity (ClinGen)
Chudley-McCullough syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
51 Pathogenic / Likely Pathogenic· 182 VUS of 364 total submissions

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.
0.86LOEUF
pLI 0.000
Z-score 2.21
OE 0.60 (0.43–0.86)
Tolerant

Typical tolerance to LoF variation

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.
1.26Z-score
OE missense 0.81 (0.74–0.90)
297 obs / 364.4 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.0.60 (0.43–0.86)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.74–0.90)
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.0.79
0≤1.21.6
LoF obs/exp: 22 / 36.4Missense obs/exp: 297 / 364.4Syn Z: 1.85

ClinVar Variant Classifications

364 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic27
VUS182
Likely Benign84
Benign28
Conflicting19
24
Pathogenic
27
Likely Pathogenic
182
VUS
84
Likely Benign
28
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
18
0
24
Likely Pathogenic
17
1
9
0
27
VUS
2
132
44
4
182
Likely Benign
0
7
46
31
84
Benign
0
0
28
0
28
Conflicting
—19
Total2514014535364

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

View in ClinVar →

Protein Context — Lollipop Plot

GPSM2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GPSM2-related sensorineural hearing loss with corpus callosum hypoplasia, gray matter heterotopia and arachnoid cysts

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEar
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Chudley-McCullough syndrome

MIM #604213

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — GPSM2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
GPSM2 Serves as an Independent Prognostic Biomarker for Liver Cancer Survival.
Yang D et al.·Technol Cancer Res Treat
2020
A novel nonsense GPSM2 mutation in a Yemeni family underlying Chudley-McCullough syndrome.
Hamzeh AR et al.·Eur J Med Genet
2016Case report
GPSM2 and Chudley-McCullough syndrome: a Dutch founder variant brought to North America.
Almomani R et al.·Am J Med Genet A
2013
Critical roles of LGN/GPSM2 phosphorylation by PBK/TOPK in cell division of breast cancer cells.
Fukukawa C et al.·Genes Chromosomes Cancer
2010
[GPSM2 is highly expressed in gastric cancer to affect patient prognosis by promoting tumor cell proliferation].
Song X et al.·Nan Fang Yi Ke Da Xue Xue Bao
2025
The GPSM2/LGN GoLoco motifs are essential for hearing.
Bhonker Y et al.·Mamm Genome
2016
G-Protein Signaling Modulator 2 as a Potential Biomarker in Colorectal Cancer: Integrative Analysis Using Genetic Profiling and Pan-Cancer Studies.
Kadhim DJ et al.·Genes (Basel)
2024
CCNB1 and AURKA are critical genes for prostate cancer progression and castration-resistant prostate cancer resistant to vinblastine.
Chen X et al.·Front Endocrinol (Lausanne)
2022
Subcortical heterotopic gray matter brain malformations: Classification study of 107 individuals.
Oegema R et al.·Neurology
2019
Identification of key genes and pathways in renal cell carcinoma through expression profiling data.
Liu X et al.·Kidney Blood Press Res
2015
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools