SMIM12

Chr 1

small integral membrane protein 12

Also known as: C1orf212

NCBI Gene: 113444 ENSG00000163866 UniProt: Q96EX1

SMIM12 encodes a small integral membrane protein located in the mitochondrion, though its specific functional role remains unclear. Mutations in this gene have been associated with neurodevelopmental disorders, but the clinical phenotype and inheritance pattern are not well-established in the current literature. This gene shows moderate constraint against loss-of-function variants.

ResearchSummary from RefSeq

Located in mitochondrion. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.13

Clinical Summary— SMIM12

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.57) — some intolerance to loss-of-function variants.

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ClinVar Variants

11 VUS of 14 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

1.13LOEUF

pLI 0.567

Z-score 1.48

OE 0.00 (0.00–1.13)

Moderately constrained

Highly tolerant — LoF variants common in population

Missense Constraint?

1.20Z-score

OE missense 0.55 (0.42–0.74)

32 obs / 57.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–1.13)

0≤0.351.4

Missense OE?0.55 (0.42–0.74)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 0 / 2.6Missense obs/exp: 32 / 57.7Syn Z: 0.57

This gene — mechanism propensity

0.5673th %ile

GOF

0.6541th %ile

LOF

0.49top 25%

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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

14 submitted variants in ClinVar

ClinVar

Classification Summary

VUS11

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	11	11
Likely Benign	0	0
Benign	0	0
Total	11	11

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap SMIM12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →