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SMIM2

Chr 13

small integral membrane protein 2

Also known as: C13orf44

NCBI Gene: 79024 UniProt: Q9BVW6

SMIM2 encodes a protein predicted to be located in cellular membranes, though its specific function remains unclear. Currently, no established Mendelian diseases have been definitively linked to mutations in this gene. The gene shows tolerance to loss-of-function variants with low constraint metrics, suggesting it may not be essential for normal development.

ResearchSummary from RefSeq

MultiplemechanismLOEUF 1.74

Clinical Summary— SMIM2

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

50 unique Pathogenic / Likely Pathogenic· 1 VUS of 52 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.74LOEUF

pLI 0.042

Z-score 0.51

OE 0.68 (0.27–1.74)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

0.91Z-score

OE missense 0.64 (0.48–0.86)

32 obs / 50.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.68 (0.27–1.74)

0≤0.351.4

Missense OE0.64 (0.48–0.86)

0≤0.61.4

Synonymous OE0.62

0≤1.21.6

LoF obs/exp: 2 / 2.9Missense obs/exp: 32 / 50.2Syn Z: 1.30

0.79top 25%

GOF

0.88top 5%

LOF

0.1598th %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.