TMEM108

Chr 3

transmembrane protein 108

Also known as: CT124, RTLN

NCBI Gene: 66000 ENSG00000144868 UniProt: Q6UXF1 OMIM: 617361

Predicted to be involved in several processes, including cellular response to brain-derived neurotrophic factor stimulus; nervous system development; and regulation of signal transduction. Predicted to be located in somatodendritic compartment. Predicted to be active in several cellular components, including endosome; glutamatergic synapse; and postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2025]

OMIM Research

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.19

Clinical Summary— TMEM108

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 94 VUS of 113 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 0.996

Z-score 3.71

OE 0.00 (0.00–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.67Z-score

OE missense 0.90 (0.82–0.99)

313 obs / 348.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.19)

0≤0.351.4

Missense OE?0.90 (0.82–0.99)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 0 / 16.0Missense obs/exp: 313 / 348.0Syn Z: -0.08

This gene — mechanism propensity

0.3296th %ile

GOF

0.5367th %ile

LOF

0.66top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.19

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

113 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS94

Likely Benign9

Benign2

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	0	0	0
VUS	94	0	0	94
Likely Benign	9	0	0	9
Benign	0	0	2	2
Total	103	1	2	106

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

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16 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap TMEM108 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →