MOSMO

Chr 16

modulator of smoothened

Also known as: ATTHOG, BC030336, C16orf52

NCBI Gene: 730094 ENSG00000185716 UniProt: Q8NHV5

The protein acts as a negative regulator of hedgehog signaling by promoting internalization and degradation of smoothened protein in the ciliary membrane, and participates in sonic hedgehog-induced spinal neural progenitor cell differentiation. Mutations cause mosaic variegated aneuploidy syndrome, a rare disorder characterized by growth retardation, intellectual disability, microcephaly, and predisposition to cancer. The condition follows autosomal recessive inheritance.

GeneReviews ResearchSummary from UniProt

Predicted to be involved in negative regulation of smoothened signaling pathway; regulation of neuron differentiation; and regulation of protein stability. Predicted to act upstream of or within several processes, including chordate embryonic development; embryonic limb morphogenesis; and smoothened signaling pathway. Predicted to be located in plasma membrane. Predicted to be active in Golgi apparatus and ciliary membrane. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.82

Clinical Summary— MOSMO

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

3 VUS of 5 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MOSMO

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.259

Z-score 1.89

OE 0.26 (0.11–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.43Z-score

OE missense 0.54 (0.42–0.70)

42 obs / 77.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.11–0.82)

0≤0.351.4

Missense OE?0.54 (0.42–0.70)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 2 / 7.7Missense obs/exp: 42 / 77.3Syn Z: 0.74

This gene — mechanism propensity

0.6550th %ile

GOF

0.75top 25%

LOF

0.3260th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

5 submitted variants in ClinVar

ClinVar

Classification Summary

VUS3

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	3	3
Likely Benign	0	0
Benign	0	0
Total	3	3

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

View in ClinVar →

71 pathogenic / likely-pathogenic (of 130) ClinVar copy-number / structural variants overlap MOSMO — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →