TMEM245

Chr 9

transmembrane protein 245

Also known as: C9orf5, CG-2, CG2

NCBI Gene: 23731 ENSG00000106771 UniProt: Q9H330 OMIM: 620252

The protein is predicted to be located in membrane structures, but its specific cellular function remains unknown. Mutations in TMEM245 cause neurodevelopmental disorders through a predicted dominant-negative mechanism. The inheritance pattern and specific clinical phenotypes associated with TMEM245 mutations are not established based on the available data.

OMIM ResearchSummary from RefSeq, Mechanism

MultiplemechanismLOEUF 0.59

Clinical Summary— TMEM245

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.59LOEUF

pLI 0.000

Z-score 3.68

OE 0.40 (0.27–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

1.24Z-score

OE missense 0.83 (0.76–0.91)

354 obs / 426.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.40 (0.27–0.59)

0≤0.351.4

Missense OE0.83 (0.76–0.91)

0≤0.61.4

Synonymous OE1.17

0≤1.21.6

LoF obs/exp: 17 / 43.0Missense obs/exp: 354 / 426.2Syn Z: -1.71

0.78top 25%

GOF

0.73top 25%

LOF

0.2873th %ile

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

DNprediction above median

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.