GPSM2

Chr 1

G protein signaling modulator 2

Also known as: CMCS, DFNB82, LGN, PINS

NCBI Gene: 29899 ENSG00000121957 UniProt: P81274

The encoded protein regulates G protein signaling and organizes mitotic spindle poles, playing essential roles in cell division and asymmetric neuroblast divisions. Mutations cause Chudley-McCullough syndrome, an autosomal recessive disorder characterized by sensorineural hearing loss and brain malformations. This gene shows very low constraint against loss-of-function variants (pLI near zero), consistent with its recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.86

Clinical Summary— GPSM2

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Gene-Disease Validity (ClinGen)

Chudley-McCullough syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

37 unique Pathogenic / Likely Pathogenic· 164 VUS of 353 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GPSM2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.000

Z-score 2.21

OE 0.60 (0.43–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.26Z-score

OE missense 0.81 (0.74–0.90)

297 obs / 364.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.43–0.86)

0≤0.351.4

Missense OE?0.81 (0.74–0.90)

0≤0.61.4

Synonymous OE?0.79

0≤1.21.6

LoF obs/exp: 22 / 36.4Missense obs/exp: 297 / 364.4Syn Z: 1.85

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGPSM2-related sensorineural hearing loss with corpus callosum hypoplasia, gray matter heterotopia and arachnoid cystsLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.74top 25%

GOF

0.72top 25%

LOF

0.3163th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

353 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic26

VUS164

Likely Benign84

Benign28

Conflicting19

Pathogenic

Likely Pathogenic

164

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	0	0	0	11
Likely Pathogenic	24	1	1	0	26
VUS	2	132	26	4	164
Likely Benign	0	8	45	31	84
Benign	0	1	27	0	28
Conflicting	—				19
Total	37	142	99	35	332

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap GPSM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →