SMIM22

Chr 16

small integral membrane protein 22

Also known as: CASIMO1

NCBI Gene: 440335 ENSG00000267795 UniProt: K7EJ46

SMIM22 encodes a protein that modulates lipid droplet formation through interaction with squalene epoxidase (SQLE) and regulates actin cytoskeleton organization. The gene is highly constrained against loss-of-function variants (pLI ~1.0), suggesting that mutations would likely cause severe developmental disorders, though specific disease associations have not yet been established. Based on the constraint metrics, pathogenic variants would most likely follow an autosomal dominant inheritance pattern.

ResearchSummary from RefSeq, UniProt

Involved in several processes, including lipid droplet formation; positive regulation of cell migration; and regulation of actin cytoskeleton organization. Predicted to be located in late endosome and membrane. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.95

Clinical Summary— SMIM22

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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

1 total variants — no pathogenic classifications of 1 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.95LOEUF

pLI 0.000

Z-score -1.36

OE 1.90 (0.81–1.95)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.96Z-score

OE missense 1.42 (1.15–1.75)

60 obs / 42.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.90 (0.81–1.95)

0≤0.351.4

Missense OE?1.42 (1.15–1.75)

0≤0.61.4

Synonymous OE?1.39

0≤1.21.6

LoF obs/exp: 5 / 2.6Missense obs/exp: 60 / 42.4Syn Z: -1.33

This gene — mechanism propensity

0.76top 25%

GOF

0.80top 10%

LOF

0.2091th %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

1 submitted variants in ClinVar

ClinVar

Classification Summary

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories· variant type breakdown unavailable

Classification	LoF	Missense + Inframe	Non-coding	Synonymous
Pathogenic	—	—	—	—
Likely Pathogenic	—	—	—	—
VUS	—	—	—	—
Likely Benign	—	—	—	—
Benign	—	—	—	—
Total	—

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

27 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap SMIM22 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →